Abstract “Objective To investigate whether psilocybin therapy could improve symptoms of depression, burnout, and PTSD in US clinicians who developed these symptoms from frontline clinical work during the pandemic. Design, Setting, and Participants This double-blind randomized clinical trial enrolled participants from February to December 2022. Participants included physicians, APPs, and nurses who provided frontline care for more than 1 month during the pandemic and had no pre-pandemic mental health diagnoses but had moderate to severe symptoms of depression at enrollment. Participants were randomly assigned to either the psilocybin or niacin arm. Data analysis was conducted between December 2023 and May 2024 and was based on the intention-to-treat principle. Intervention One intervention episode consisted of 2 preparation visits, 1 medication session, and 2 integration visits. At the medication session, participants received psilocybin, 25 mg, or niacin, 100 mg, orally. Main Outcome and Measures The primary outcome was a change from baseline (preparation session 1) to day 28 (after medication administration) in symptoms of depression as measured by the clinician-administered Montgomery-Asberg Depression Rating Scale (MADRS) used by blinded raters. Secondary outcomes were changes in symptoms of burnout (measured with the Stanford Professional Fulfillment Index [SPFI]) and symptoms of PTSD (measured with the Posttraumatic Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [PCL-5]). Results A total of 30 clinicians (15 females [50%]; mean [range] age, 38 [29-60] years) were randomly assigned to receive psilocybin and 15 to receive niacin. The mean decrease in depression (MADRS scores) from preparation 1 session to day 28 was −9.33 (7.32) in the niacin arm, with a mean difference of −12.00 (95% CI, −17.67 to −6.33; P < .001), a decrease in MADRS scores significantly favoring psilocybin. The mean change in SPFI scores from preparation 1 session to day 28 was 1.00 (2.18) in the psilocybin arm vs −0.18 (1.98) in the niacin arm (mean difference, 1.18; P = .05) but was not statistically significant. While SPFI score change did not reach statistical significance, the PCL-5 score change was evaluated descriptively. The mean change in PCL-5 scores showed a numerically larger decrease in symptoms of PTSD from preparation 1 session to day 28 in the psilocybin vs the niacin arm (−16.67 [15.04] vs −6.73 [10.69]), but this difference was not statistically tested.” Authors: Anthony L. Back, Timara K. Freeman-Young, Ladybird Morgan, Tanmeet Sethi, Kelsey K. Baker, Susanna Myers, Bonnie A. McGregor, Kalin Harvey, Marlene Tai, Austin Kollefrath, Brandon J. Thomas, Dennis Sorta, Mendel Kaelen, Benjamin Kelmendi & Ted A. Gooley Read the Full Article

Abstract “Objective To investigate whether psilocybin therapy could improve symptoms of depression, burnout, and PTSD in US clinicians who developed these symptoms from frontline clinical work during the pandemic. Design, Setting, and Participants This double-blind randomized clinical trial enrolled participants from February to December 2022. Participants included physicians, APPs, and nurses who provided frontline care for more than 1 month during the pandemic and had no pre-pandemic mental health diagnoses but had moderate to severe symptoms of depression at enrollment. Participants were randomly assigned to either the psilocybin or niacin arm. Data analysis was conducted between December 2023 and May 2024 and was based on the intention-to-treat principle. Intervention One intervention episode consisted of 2 preparation visits, 1 medication session, and 2 integration visits. At the medication session, participants received psilocybin, 25 mg, or niacin, 100 mg, orally. Main Outcome and Measures The primary outcome was a change from baseline (preparation session 1) to day 28 (after medication administration) in symptoms of depression as measured by the clinician-administered Montgomery-Asberg Depression Rating Scale (MADRS) used by blinded raters. Secondary outcomes were changes in symptoms of burnout (measured with the Stanford Professional Fulfillment Index [SPFI]) and symptoms of PTSD (measured with the Posttraumatic Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [PCL-5]). Results A total of 30 clinicians (15 females [50%]; mean [range] age, 38 [29-60] years) were randomly assigned to receive psilocybin and 15 to receive niacin. The mean decrease in depression (MADRS scores) from preparation 1 session to day 28 was −9.33 (7.32) in the niacin arm, with a mean difference of −12.00 (95% CI, −17.67 to −6.33; P < .001), a decrease in MADRS scores significantly favoring psilocybin. The mean change in SPFI scores from preparation 1 session to day 28 was 1.00 (2.18) in the psilocybin arm vs −0.18 (1.98) in the niacin arm (mean difference, 1.18; P = .05) but was not statistically significant. While SPFI score change did not reach statistical significance, the PCL-5 score change was evaluated descriptively. The mean change in PCL-5 scores showed a numerically larger decrease in symptoms of PTSD from preparation 1 session to day 28 in the psilocybin vs the niacin arm (−16.67 [15.04] vs −6.73 [10.69]), but this difference was not statistically tested.” Authors: Anthony L. Back, Timara K. Freeman-Young, Ladybird Morgan, Tanmeet Sethi, Kelsey K. Baker, Susanna Myers, Bonnie A. McGregor, Kalin Harvey, Marlene Tai, Austin Kollefrath, Brandon J. Thomas, Dennis Sorta, Mendel Kaelen, Benjamin Kelmendi & Ted A. Gooley Read the Full Article

Abstract “A feature in the pathophysiology of major depressive disorder (MDD), a mood disorder, is the impairment of excitatory synapses in the prefrontal cortex. Intriguingly, different types of treatment with fairly rapid antidepressant effects (within days or a few weeks), such as ketamine, electroconvulsive therapy and non-invasive neurostimulation, seem to converge on enhancement of neural plasticity. However, the forms and mechanisms of plasticity that link antidepressant interventions to the restoration of excitatory synaptic function are still unknown. In this Review, we highlight preclinical research from the past 15 years showing that ketamine and psychedelic drugs can trigger the growth of dendritic spines in cortical pyramidal neurons. We compare the longitudinal effects of various psychoactive drugs on neuronal rewiring, and we highlight rapid onset and sustained time course as notable characteristics for putative rapid-acting antidepressant drugs. Furthermore, we consider gaps in the current understanding of drug-evoked in vivo structural plasticity. We also discuss the prospects of using synaptic remodelling to understand other antidepressant interventions, such as repetitive transcranial magnetic stimulation. Finally, we conclude that structural neural plasticity can provide unique insights into the neurobiological actions of psychoactive drugs and antidepressant interventions.” Authors: Clara Liao, Alisha N. Dua, Cassandra Wojtasiewicz, Conor Liston & Alex C. Kwan Read the Full Article

Abstract “Background: Bipolar II disorder (BD-II) is often associated with chronic and treatment resistant major depressive episodes. Psilocybin has shown promise for its rapid-acting antidepressant effects, though its impact on bipolar depression remains unexplored. In the present subgroup analysis of an already published trial on treatment-resistant depression (TRD), we aimed to preliminarily evaluate the safety and efficacy of psilocybin in patients with BD-II. Methods: Adults with TRD associated with BD-II, excluding those with psychosis were included. Participants underwent one or two psilocybin sessions, each with a dose of 25 mg, along with preparatory and integrative psychotherapy sessions. Results: A total of four participants with a mean age of 37.5  ±  4.15 years were included. At baseline, the mean Montgomery–Åsberg Depression Rating Scale (MADRS) score was 32.5 (95% CI: 26.3–38.7, SD = 3.87). By week 2 post-dose, mean MADRS decreased to 20.3, and 2 weeks after dose 2, it further dropped to 19. At the end of the 6-month study, the mean MADRS score was 21.3. Young Mania Rating Scale scores remained stable at a mean of one throughout the study with no evidence of treatment emergent mania, hypomania or psychosis observed in any participants. Conclusions: These findings suggest potential improvement in depressive symptoms with psilocybin administration in BD-II. Future studies with larger sample size are required to replicate our results and further evaluate antidepressant effects of psilocybin in bipolar depression.“ Authors: Shakila Meshka, Erica Kaczmarek, Zoe Doyle, Ryan M. Brudner, Fabiano A. Gomes, Marc G. Blainey, Geneva Weiglein, Roger S. McIntyre, Rodrigo B. Mansur & Joshua D. Rosenblat Read the Full Article

Abstract “Background: Bipolar II disorder (BD-II) is often associated with chronic and treatment resistant major depressive episodes. Psilocybin has shown promise for its rapid-acting antidepressant effects, though its impact on bipolar depression remains unexplored. In the present subgroup analysis of an already published trial on treatment-resistant depression (TRD), we aimed to preliminarily evaluate the safety and efficacy of psilocybin in patients with BD-II. Methods: Adults with TRD associated with BD-II, excluding those with psychosis were included. Participants underwent one or two psilocybin sessions, each with a dose of 25 mg, along with preparatory and integrative psychotherapy sessions. Results: A total of four participants with a mean age of 37.5  ±  4.15 years were included. At baseline, the mean Montgomery–Åsberg Depression Rating Scale (MADRS) score was 32.5 (95% CI: 26.3–38.7, SD = 3.87). By week 2 post-dose, mean MADRS decreased to 20.3, and 2 weeks after dose 2, it further dropped to 19. At the end of the 6-month study, the mean MADRS score was 21.3. Young Mania Rating Scale scores remained stable at a mean of one throughout the study with no evidence of treatment emergent mania, hypomania or psychosis observed in any participants. Conclusions: These findings suggest potential improvement in depressive symptoms with psilocybin administration in BD-II. Future studies with larger sample size are required to replicate our results and further evaluate antidepressant effects of psilocybin in bipolar depression.“ Authors: Shakila Meshka, Erica Kaczmarek, Zoe Doyle, Ryan M. Brudner, Fabiano A. Gomes, Marc G. Blainey, Geneva Weiglein, Roger S. McIntyre, Rodrigo B. Mansur & Joshua D. Rosenblat Read the Full Article

Abstract “Background: Psychedelic drugs show promise in facilitating a variety of long-term psychological changes, but they may also lead to unexpected major life changes that have not been captured by measures typically used in clinical trials. Aim: We aimed to develop a survey instrument that can characterize the quality and self-appraisal of psychedelic-related major life changes. Method: The Psychedelic-related Major Life Changes Questionnaire (P-MLCQ) was created to assess psychedelic-related major life changes across 10 different domains. We evaluated the survey in people reporting naturalistic psychedelic use (N = 581). Results: 482/581 participants (82.96%) reported a major life change in at least one domain influenced by their psychedelic use (M = 3.29, SD = 2.60), including changes in Goals (53.70%), Values (53.53%), Religion/spirituality (49.05%), Social activities (37.01%), Eating habits/diet (34.08%), Occupation/Line of work (32.36%), Hobbies (29.43%), Political views (14.97%), Sexuality (13.08%), and Marital status or a non-marital partner change (12.22%). Major life changes were rated highly positively (M = 4.64, SD = 0.61 on a 5-point scale). There was a positive relationship between frequency of psychedelic use over the last five years and total number of psychedelic-related major life changes (r = 0.34, p < .001). Education level was negatively associated with the total number of psychedelic-related major life changes endorsed (β = -.137, p < .01). Conclusion: Our results support that psychedelic use can be followed by major life changes. Future research is needed to examine the generalizability of these results in representative samples that are less susceptible to positive bias.“ Authors: Jacob S. Aday, Nicolas G. Glynos, Anne Baker, Niloufar Pouyan, Julie Barron, Moss Herberholz, Daniel Kruger, Joshua D. Woolley & Kevin F. Boehnke Read the Full Article

Abstract “Aim: To examine the responsiveness and tolerability of treatment-refractory OCD to intramuscular (IM) ketamine compared to IM fentanyl. Methods: This was a randomised double-blind psychoactive-controlled study with single doses of racemic ketamine 0.5 mg/kg, 1.0 mg/kg or fentanyl 50 µg (psychoactive control). Pre-dosing with 4 mg oral ondansetron provided nausea prophylaxis. Eligible participants were aged between 18 and 50 years with severe treatment-resistant OCD. The primary efficacy measure was the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Tolerability was measured with the Clinician-Administered Dissociative States Scale (CADSS). Repeated measures analysis of variance with orthogonal polynomial trends was used to assess the effect of drug treatment on Y-BOCS and CADSS scores. Results: Twelve participants were randomised and 10 completed the study (7 females, 3 males, mean age 33 years). Two participants dropped out due to not tolerating dissociative effects associated with the study medication. The reductions in Y-BOCS scores were greater and statistically dose-related for both ketamine doses than fentanyl (dose [linear], F(1, 9) = 6.5, p = 0.031). Score changes for all treatments were maximal at 1–2 h with a steady separation of scores out to 168 h. Ketamine was associated with short-term dissociative and cardiovascular effects. Conclusions: We provide further preliminary evidence for the efficacy and tolerability of IM ketamine in an outpatient cohort of OCD. Additional work is required to establish the optimal dosing regimen and longer-term role of ketamine for OCD. These findings are encouraging given the well-known limitations that exist for treatments in this area.” Authors: Ben Beaglehole, Paul Glue, Shona Neehoff, Shabah Shadli, Neil McNaughton, Bridget Kimber, Chrissie Muirhead, Aroha de Bie, Rachel Day-Brown & Natalie J. Hughes-Medlicott Read the Full Article

Abstract “3,4-methylenedioxymethamphetamine (MDMA) assisted therapy has been shown to be a safe and effective treatment for PTSD and emerging research suggests a change in personality traits may be a factor in treatment response. Most prior research on MDMA and personality has focused on cross-sectional comparisons of MDMA users and non-users; as such, well-controlled research assessing personality and affective states change following MDMA vs placebo administration is needed. In the current pre-registered study, we investigated the impact of MDMA administration on five-factor model (FFM) traits and affective states before and 48 h after drug administration in a randomized, placebo-controlled study of healthy adults (N = 34). Statistical significance was not observed for the four a priori hypotheses; however, medium effect sizes were found between MDMA administration and trait Openness and Positive Affect 48 h following drug administration, compared to placebo (d = .79 and .51, respectively). This study provides initial results to help guide future well-powered studies with large samples and longer follow-up timepoints to continue to investigate how MDMA impacts personality and emotional experience, which may inform optimization of MDMA treatment approaches.“ Authors: Jessica L. Maples-Keller, Courtland S. Hyatt, Nathaniel L. Phillips, Brinkley M. Sharpe, Andrew Sherrill, Carly Yasinski, Collin Reiff, Jeffrey Rakofsky, Sheila A. M. Rauch, Boadie W. Dunlop & Barbara O. Rothbaum Read the Full Article

Abstract “Results from multiple recent studies support further evaluation of 3,4-methylenedioxymethamphetamine (MDMA) in conjunction with psychotherapy (i.e., MDMA-Assisted Therapy) in the treatment of post-traumatic stress disorder (PTSD). In two Phase 3 trials, MDMA-Assisted Therapy comprised a short-term, intensive psychotherapy that included three sessions directly facilitated by MDMA (referred to as “experimental sessions”), as well as a number of non-drug psychotherapy sessions. This treatment model aimed to harness the potential of MDMA to facilitate recall and processing of traumatic memories, and to increase learning in a social context, integrating “top-down” and “bottom-up” approaches to trauma-focused care. To date, the conceptual framework for this treatment has not been described in the scientific literature. This omission has contributed to misunderstandings about both the theoretical underpinnings of this modality and the therapeutic approach that emerges from it. This paper delineates the psychotherapeutic concepts, theories, and historical antecedents underlying the inner-directed approach to MDMA-Assisted Therapy for PTSD. Broadly speaking, this therapeutic framework centered the concept of the participant’s inner healing intelligence as the primary agent of change, with the therapeutic relationship being the core facilitative condition fostering the participant’s self-directed movement toward recovery and growth. Corollaries to this holistic, self-directed, relational, and trauma-informed framework include a non-pathologizing approach to the participant’s embodied experience (including the possibility of intense emotional and somatic expression, experiences of multiplicity, suicidal ideation, and multigenerational and transpersonal experiences), as well as the therapists’ own psychodynamic, somatic, and transpersonal awareness, empathic attunement, relational skillfulness, and cultural humility. The use of MDMA in conjunction with this psychotherapy platform outperformed the use of placebo with psychotherapy in Phase 2 and 3 trials, as measured by symptom reduction in participants with PTSD. However, within-group comparisons also identified significant symptom reduction in participants who did not receive MDMA, lending empirical support to the psychotherapy model itself. In addition to comparative efficacy trials, future research should investigate which elements of the conceptual framework and therapeutic approach underlie the clinical benefit in individuals with PTSD.” Authors: Kelley C. O’Donnell, Lauren Okano, Michael Alpert, Christopher R. Nicholas, Chantelle Thomas, Bruce Poulter, Ann T. Mithoefer, Michael C. Mithoefer & Marcela Ot’alora G. Read the Full Article

Abstract “It has been suggested that the recent use and discontinuation of antidepressant drugs compromises the action of psilocybin. As evidence is only available from small or uncontrolled samples, this post hoc analysis investigated this using data from the largest, phase II, randomized controlled trial of psilocybin treatment to date. Data from 233 participants with treatment-resistant depression (TRD) who received 25 mg, 10 mg, or 1 mg of investigational drug COMP360 psilocybin (a proprietary, pharmaceutical-grade synthetic psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.), administered with psychological support, were compared for groups of participants who either discontinued one or more antidepressant drugs during screening or entered the trial antidepressant drug free. Measures of depression symptom severity change during the antidepressant drug discontinuation period, baseline suicidality, acute subjective psychedelic effects, and the study’s primary endpoint (change in depression symptom severity between Baseline and Week 3) are described for both groups. Antidepressant drug discontinuation was not related to worsening of depression severity before Baseline. Suicidality was comparable between groups at Baseline. Psilocybin treatment efficacy and the subjective psychedelic experience did not appear to be compromised by antidepressant drug discontinuation. Thus, it does not limit the feasibility of psilocybin treatment for the future. These findings also support the overall homogeneity of our findings with psilocybin treatment as a monotherapy for TRD. The prior contradictory reports may come to appear misleading.“ Authors: Lindsey Marwood, Megan Croal, Sunil Mistry, Hollie Simmons, Joyce Tsai, Matthew B. Young, & Guy M. Goodwin Read the Full Article

Abstract “It has been suggested that the recent use and discontinuation of antidepressant drugs compromises the action of psilocybin. As evidence is only available from small or uncontrolled samples, this post hoc analysis investigated this using data from the largest, phase II, randomized controlled trial of psilocybin treatment to date. Data from 233 participants with treatment-resistant depression (TRD) who received 25 mg, 10 mg, or 1 mg of investigational drug COMP360 psilocybin (a proprietary, pharmaceutical-grade synthetic psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.), administered with psychological support, were compared for groups of participants who either discontinued one or more antidepressant drugs during screening or entered the trial antidepressant drug free. Measures of depression symptom severity change during the antidepressant drug discontinuation period, baseline suicidality, acute subjective psychedelic effects, and the study’s primary endpoint (change in depression symptom severity between Baseline and Week 3) are described for both groups. Antidepressant drug discontinuation was not related to worsening of depression severity before Baseline. Suicidality was comparable between groups at Baseline. Psilocybin treatment efficacy and the subjective psychedelic experience did not appear to be compromised by antidepressant drug discontinuation. Thus, it does not limit the feasibility of psilocybin treatment for the future. These findings also support the overall homogeneity of our findings with psilocybin treatment as a monotherapy for TRD. The prior contradictory reports may come to appear misleading.“ Authors: Lindsey Marwood, Megan Croal, Sunil Mistry, Hollie Simmons, Joyce Tsai, Matthew B. Young, & Guy M. Goodwin Read the Full Article

Abstract “Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and prefrontal cortex. Functionally, we demonstrated that 5-HT1BR is necessary for the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotor responses to psilocybin. We also measured the persisting antidepressant-like effects of psilocybin using transgenic and pharmacological 5-HT1BR loss-of-function models and found that 5-HT1B was required for the decreased anhedonia and reduced anxiety-like behavior. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Overall, our research implicates the 5-HT1BR, a non-hallucinogenic serotonin receptor, as a critical mediator of the behavioral and neural effects of psilocybin in mice.“ Authors: Sixtine Fleury & Katherine M. Nautiyal Read the Full Article

Abstract “Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and prefrontal cortex. Functionally, we demonstrated that 5-HT1BR is necessary for the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotor responses to psilocybin. We also measured the persisting antidepressant-like effects of psilocybin using transgenic and pharmacological 5-HT1BR loss-of-function models and found that 5-HT1B was required for the decreased anhedonia and reduced anxiety-like behavior. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Overall, our research implicates the 5-HT1BR, a non-hallucinogenic serotonin receptor, as a critical mediator of the behavioral and neural effects of psilocybin in mice.“ Authors: Sixtine Fleury & Katherine M. Nautiyal Read the Full Article

Abstract “Purpose Ketamine has historically been contraindicated in traumatic brain injury (TBI) due to concern for raising intracranial pressure. However, it is increasingly being used in TBI due to the favorable respiratory and hemodynamic properties. To date, no studies have evaluated whether ketamine administered in subjects with TBI is associated with patient survival or disability. Methods We performed a retrospective analysis of data from the multicenter Prehospital Tranexamic Acid Use for Traumatic Brain Injury trial, comparing ketamine-exposed and ketamine-unexposed TBI subjects to determine whether an association exists between ketamine administration and mortality, as well as secondary outcome measures. Results We analyzed 841 eligible subjects from the original study, of which 131 (15.5%) received ketamine. Ketamine-exposed subjects were younger (37.3±16.9 years vs. 42.0±18.6 years, P=0.037), had a worse initial Glasgow Coma Scale score (7±3 vs. 8±4, P=0.003), and were more likely to be intubated than ketamine-unexposed subjects (88.5% vs. 44.2%, P<0.001). Overall, there was no difference in mortality (12.2% vs. 15.5%, P=0.391) or disability measures between groups. Ketamine-exposed subjects had significantly fewer instances of elevated intracranial pressure (ICP) compared to ketamine-unexposed subjects (56.3% vs. 82.3%, P=0.048). In the very rare outcomes of cardiac events and seizure activity, seizure activity was statistically more likely in ketamine-exposed subjects (3.1% vs. 1.0%, P=0.010). In the intracranial hemorrhage subgroup, cardiac events were more likely in ketamine-exposed subjects (2.3% vs. 0.2%, P=0.025). Ketamine exposure was associated with a smaller increase in TBI protein biomarker concentrations. Conclusions Ketamine administration was not associated with worse survival or disability despite being administered to more severely injured subjects. Ketamine exposure was associated with reduced elevations of ICP, more instances of seizure activity, and lower concentrations of TBI protein biomarkers.“ Authors: Austin J. Peters, Saad A. Khan, Seiji Koike, Susan Rowell, & Martin Schreiber Read the Full Article

Abstract There is some evidence that the subjective effects of ketamine and other psychedelics like psilocybin are crucial for their therapeutic outcomes, such as treatment of depression or substance use disorder (SUD). We performed a meta-analysis and systematic review on the correlation of subjective symptoms and dissociation versus ketamine-induced therapeutic outcomes in patients with depression or SUD. A similar analysis was conducted for psilocybin-induced therapeutic improvement. We retrieved 23 papers studying ketamine (21 on depression, 2 on SUD) in 471 patients and 8 papers studying psilocybin (6 on depression, 2 on SUD) in 183 patients. Our study demonstrated a modest role for subjective effects mediating therapeutic outcomes, with R2-values ranging from 5–10% for ketamine and for psilocybin the R2 was 24%. A greater mediating effect for psilocybin compared to ketamine was detected, particularly when restricting the analysis to depression. Additionally there is a greater mediating effect in SUD than depression, irrespective of treatment.“ Authors: Jack D. C. Dahan, David Dadiomov, Tijmen Bostoen & Albert Dahan Read the Full Article

Abstract There is some evidence that the subjective effects of ketamine and other psychedelics like psilocybin are crucial for their therapeutic outcomes, such as treatment of depression or substance use disorder (SUD). We performed a meta-analysis and systematic review on the correlation of subjective symptoms and dissociation versus ketamine-induced therapeutic outcomes in patients with depression or SUD. A similar analysis was conducted for psilocybin-induced therapeutic improvement. We retrieved 23 papers studying ketamine (21 on depression, 2 on SUD) in 471 patients and 8 papers studying psilocybin (6 on depression, 2 on SUD) in 183 patients. Our study demonstrated a modest role for subjective effects mediating therapeutic outcomes, with R2-values ranging from 5–10% for ketamine and for psilocybin the R2 was 24%. A greater mediating effect for psilocybin compared to ketamine was detected, particularly when restricting the analysis to depression. Additionally there is a greater mediating effect in SUD than depression, irrespective of treatment.“ Authors: Jack D. C. Dahan, David Dadiomov, Tijmen Bostoen & Albert Dahan Read the Full Article

Abstract “Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are debilitating psychiatric conditions associated with poor health outcomes similarly observed in non-pathological aging. Ketamine is a dissociative anesthetic and NMDA receptor antagonist with demonstrated rapid reduction in symptoms associated with Treatment Resistant Depression (TRD) and PTSD. Ketamine’s effects on biological aging have not been extensively studied among patients with moderate to severe symptoms of depression and/or trauma. To address this gap, this study looked at the changes in non-epigenetic measures, DNA methylation levels, immune cell composition, and biological age based on various epigenetic biomarkers of aging, of 20 participants at baseline and after completion of a 2-3 week treatment course of 0.5 mg/kg ketamine infusions in individuals with MDD or PTSD. As expected, depression and PTSD scores decreased in participants following ketamine infusion treatments as measured by the PHQ-9 and PCL-5. We observed a reduction in epigenetic age in the OMICmAge, GrimAge V2, and PhenoAge biomarkers. In order to better understand the changes in epigenetic age, we also looked at the underlying levels of various Epigenetic Biomarker Proxies (EBPs) and surrogate protein markers and found significant changes following ketamine treatment. The results are consistent with existing literature on ketamine’s effects on different biomarkers. These results underline the ability of GrimAge V2, PhenoAge, and OMICmAge in particular, to capture signals associated with key clinical biomarkers, and add to the growing body of literature on ketamine’s epigenetic mechanisms and their effect on biological aging.“ Authors: Kristin Dawson, Athena M. J. M. Carangan, Jessica Klunder, Natalia Carreras-Gallo, Raghav Sehgal, Samantha Megilligan, Benjamin C. Askins, Nicole Perkins, Tavis L. Mendez, Ryan Smith, Matthew Dawson, Michael Mallin, Albert T. Higgins-Chen & Varun B. Dwaraka Read the Full Article

Abstract “Psilocin, the active metabolite of psilocybin, is a psychedelic and agonist at the serotonin 2A receptor (5-HT2AR) that has shown positive therapeutic effects for brain disorders such as depression. To elucidate the brain effects of psilocybin, we directly compared the acute effects of 5-HT2AR agonist (psilocybin) and antagonist (ketanserin) on cerebral blood flow (CBF) using pseudo-continuous arterial spin labelling magnetic resonance imaging (MRI) in a single-blind, cross-over study in 28 healthy participants. We evaluated associations between plasma psilocin level (PPL) or subjective drug intensity (SDI) and CBF. We also evaluated drug effects on internal carotid artery (ICA) diameter using time-of-flight MRI angiography. PPL and SDI were significantly negatively associated with regional and global CBF (~11.5% at peak drug effect, p<0.0001). CBF did not significantly change following ketanserin (2.3%, p=0.35). Psilocybin induced a significantly greater decrease in CBF compared to ketanserin in the parietal cortex (pFWER<0.0001). ICA diameter was significantly decreased following psilocybin (10.5%, p<0.0001) but not ketanserin (-0.02%, p=0.99). Our data support an asymmetric 5-HT2AR modulatory effect on CBF and provide the first in vivo human evidence that psilocybin constricts the ICA, which has important implications for understanding the neurophysiological mechanisms underlying its acute effects.“ Authors: Kristian Larsen, Ulrich Lindberg, Brice Ozenne, Drummond E. McCulloch, Sophia Armand, Martin K. Madsen, Annette Johansen, Dea S. Steakbæk, Gitte M. Knudsen & Patrick M. Fisher

Abstract “Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT2A receptors.“ Authors: Aaron Klaiber, Yasmin Schmid, Anna M. Becker, Isabelle Straumann, Livio Erne, Alen Jelusic, Jan Thomann, Dino Luethi & Matthias E. Liechti Read the Full Article

Abstract“Background The enduring and severe depression often suffered by Veterans causes immense suffering and is associated with high rates of suicide and disability. This is the first study to evaluate the efficacy and safety of psilocybin in Veterans with severe treatment-resistant depression (TRD). Methods 15 Veterans with severe TRD (major depressive episode failing to respond to ≥5 treatments, or lasting >2 years) received 25 mg of psilocybin. Primary outcome was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Response was defined s ≥ 50 % reduction in MADRS, and remission as ≤10 MADRS score. Psychedelic experience was assessed using the Five-Dimensional Altered States of Consciousness scale (5D-ASC). Safety measures included assessment of suicidality and adverse events. Participants on antidepressants were tapered to avoid drug interactions. Results Of 15 participants, 60 % met response and 53 % met remission criteria at Week 3. At 12 weeks, 47 % maintained response, and 40 % remission. Co-morbid PTSD did not significantly influence study outcomes. The psychedelic experience reported in 5D-ASC did not correlate with response. Participants judged to need antidepressants were restarted and considered non-responders from that timepoint (n = 4). No unexpected adverse events occurred. Limitations Limitations include the small sample size, and the uncontrolled and unblinded nature of the study. Conclusions In this first study on psilocybin for Veterans with severe TRD, a surprising response and remission was seen. Many Veterans had PTSD though no moderating impact of response was observed. The degree of psychedelic experience did not correlate with depression changes. Further study is warranted.“ Authors: Sara Ellis, Catherine Bostian, Wendy Feng, Eileen Fischer, Garrett Schwartz, Katherine Eisen, Melanie Lean, Elizabeth Conlan, Michael Ostacher, Scott Aaronson & Trisha Suppes

Abstract“Background The enduring and severe depression often suffered by Veterans causes immense suffering and is associated with high rates of suicide and disability. This is the first study to evaluate the efficacy and safety of psilocybin in Veterans with severe treatment-resistant depression (TRD). Methods 15 Veterans with severe TRD (major depressive episode failing to respond to ≥5 treatments, or lasting >2 years) received 25 mg of psilocybin. Primary outcome was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Response was defined s ≥ 50 % reduction in MADRS, and remission as ≤10 MADRS score. Psychedelic experience was assessed using the Five-Dimensional Altered States of Consciousness scale (5D-ASC). Safety measures included assessment of suicidality and adverse events. Participants on antidepressants were tapered to avoid drug interactions. Results Of 15 participants, 60 % met response and 53 % met remission criteria at Week 3. At 12 weeks, 47 % maintained response, and 40 % remission. Co-morbid PTSD did not significantly influence study outcomes. The psychedelic experience reported in 5D-ASC did not correlate with response. Participants judged to need antidepressants were restarted and considered non-responders from that timepoint (n = 4). No unexpected adverse events occurred. Limitations Limitations include the small sample size, and the uncontrolled and unblinded nature of the study. Conclusions In this first study on psilocybin for Veterans with severe TRD, a surprising response and remission was seen. Many Veterans had PTSD though no moderating impact of response was observed. The degree of psychedelic experience did not correlate with depression changes. Further study is warranted.“ Authors: Sara Ellis, Catherine Bostian, Wendy Feng, Eileen Fischer, Garrett Schwartz, Katherine Eisen, Melanie Lean, Elizabeth Conlan, Michael Ostacher, Scott Aaronson & Trisha Suppes

Abstract “Objective The authors sought to assess the prosocial, entactogen effects of ketamine. Methods Pleasure from social situations was assessed in a sample of participants with treatment-resistant depression from randomized, double-blind, placebo-controlled studies, using four items of the Snaith-Hamilton Pleasure Scale (SHAPS) at five time points over 1 week following treatment with ketamine (0.5 mg/kg intravenously) or placebo. The primary endpoint was postinfusion self-reported pleasure on the four SHAPS items pertaining to social situations, including the item on helping others, between the ketamine and placebo groups. In a rodent experiment, the impact of ketamine on helping behaviour in rats was assessed using the harm aversion task. The primary endpoint was a reduction in lever response rate relative to baseline, which indicated the willingness of rats to forgo obtaining sucrose to help protect their cage mate from electric shock. Results Relative to placebo, ketamine increased ratings of feeling pleasure from being with family or close friends, seeing other people’s smiling faces, helping others, and receiving praise, for 1 week following treatment. In the rodent experiment, during the harm aversion task, ketamine-treated rats maintained lower response rates relative to baseline to a greater extent than what was observed in vehicle-treated rats for 6 days posttreatment and delivered fewer shocks overall. Conclusions In patients with treatment-resistant depression, ketamine treatment was associated with increased pleasure from social situations, such as feeling pleasure from helping others. Ketamine-treated rats were more likely to protect their cage mate from harm, at the cost of obtaining sucrose. These findings suggest that ketamine has entactogen effects.” Authors: Evan M. Hess, Dede K. Greenstein, Olivia L. Hutchinson, Carlos A. Zarate & Todd D. Gould Read the Full Article

Abstract “Background: Non-ordinary states of consciousness induced by psychedelics can be accompanied by so-called “peak experiences,” characterized at the emotional level by their intensity and positive valence. These experiences are strong predictors of positive outcomes following psychedelic-assisted therapy, and it is therefore important to better understand their biology. Despite growing evidence that the autonomic nervous system (ANS) plays an important role in mediating emotional experiences, its involvement in the psychedelic experience is poorly understood. The aim of this study was to investigate to what extent changes in the relative influence of the sympathetic (SNS) and parasympathetic nervous systems (PNS) over cardiac activity may reflect the subjective experience induced by the short-acting psychedelic N,N-Dimethyltryptamine (DMT). Methods: We derived measures of SNS and PNS activity from the electrocardiograms of 17 participants (11 males, mean age = 33.8 years, SD = 8.3) while they received either DMT or placebo. Results: Results show that the joint influence of SNS and PNS (“sympathovagal coactivation”) over cardiac activity was positively related to participants’ ratings of “Spiritual Experience” and “Insightfulness” during the DMT experience, while also being related to improved well-being scores 2 weeks after the session. In addition, we found that the state of balance between the two ANS branches (“sympathovagal balance”) before DMT injection predicted scores of “Insightfulness” during the DMT experience, as well as subsequent sympathovagal coactivation. Conclusion: These findings demonstrate the involvement of the ANS in psychedelic-induced peak experiences and may pave the way to the development of biofeedback-based tools to enhance psychedelic therapy.” Authors: Valerie Bonnelle, Amanda Feilding, Fernando E. Rosas, David J. Nutt, Robin L. Carhart-Harris & Christopher Timmermann Read the Full Article

Abstract “Background Psychedelic-assisted therapy (PAT) is permitted in Switzerland under its limited medical use program. Data from patients in this program represent a unique opportunity to analyze the real-world practice of PAT. Aims This study compared the subjective effects of lysergic acid diethylamide (LSD) and psilocybin between patients undergoing PAT and healthy volunteers. For the patients, it also investigated the relationship between antidepressant effects and six measures of acute drug effects. Methods We compared data on acute psychedelic drug effects between 28 PAT patients with data from 28 healthy participants who participated in a randomized, double-blind crossover trial. All participants received varying doses of psilocybin and LSD. Subjective effects were assessed on an hourly basis during the acute drug effects, and the Mystical Experience Questionnaire (MEQ) was completed retrospectively. For patients, depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Results Ratings of overall drug effect and mystical experience were similar across groups. Compared with healthy controls, patients reported lower ratings of ego dissolution. Patients showed a significant decrease in MADRS scores, and the greatest predictor of antidepressant outcome was relaxation during the PAT session. We did not observe a relationship between mystical-type experiences and antidepressant effects. Most patients experienced mild adverse effects which resolved within 48 h. Conclusion PAT reduced depressive symptoms in this heterogeneous patient group. Patients may experience more challenging psychedelic effects and reduced ego dissolution. Hourly assessment of drug effects may predict clinical outcomes better than retrospectively assessed mystical experiences, and the impact of relaxation during PAT should be investigated further.“ Authors: Abigail E. Calder, Benjamin Rausch, Matthias E. Liechti, Friederike Holze & Gregor Hasler

Abstract “Background Psilocybin therapy (PT) produces rapid and persistent antidepressant effects in major depressive disorder (MDD). However, the long-term effects of PT have never been compared with gold-standard treatments for MDD such as pharmacotherapy or psychotherapy alone or in combination. Methods This is a 6-month follow-up study of a phase 2, double-blind, randomised, controlled trial involving patients with moderate-to-severe MDD. Participants were recruited from a hospital in the UK. Male or female patients with major depressive disorder (DSM-IV), moderate to severe depression (HAM-D ≥17), no MRI or SSRI contraindications, confirmed diagnosis by a GP or mental healthcare professional, aged 18–80, and competent in English were eligible. Patients were randomly assigned (1:1) to receive either two 25 mg doses of the psychedelic drug psilocybin administered orally combined with psychological support (‘psilocybin therapy’ or PT) and bookended by further support or a 6-week course of the selective serotonin reuptake inhibitor (SSRI) escitalopram (administered daily at 10 mg for three weeks and 20 mg for the subsequent three weeks) plus matched psychological support (‘escitalopram treatment’ or ET). The primary outcome measure was change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16) at week 6, which has been reported previously. Herein, we present results at the 6-month follow-up time point. Measures of social functioning, connectedness, and meaning in life constituted the study’s secondary outcomes during follow-up. Safety in the follow-up period was not assessed. This trial is registered at ClinicalTrials.gov, NCT03429075. Findings Between January 15th, 2019 and March 20th, 2020, 59 patients were enrolled and 30 (11 females [37%] and 19 males [63%]) were assigned to the psilocybin group and 29 (9 females [31%] and 20 males [69%]) to the escitalopram group. 25 participants in the PT group and 21 in the ET group completed the 6-month follow-up. At the 6-month follow-up, both PT and ET conditions yielded sustained improvements in depressive symptom severity. The mean between-condition difference in QIDS-SR-16 scores at 6-months was 1.51 (95% CI: −1.35, 4.38; p = 0.311). Secondary outcomes demonstrated that PT had greater mean between-condition differences in functioning (WSAS: −7.46; 95% CI: −12.4, −2.47; p < 0.001), psychological connectedness (WCS: 11.02; 95% CI: 1.25, 20.83; p = 0.033), and meaning in life (MLQ: 4.86; 95% CI: 0.67, 9.05; p = 0.021) compared to ET. Interpretation Six-week intensive treatments with either psilocybin or escitalopram (with psychological support) for MDD were associated with long-term improvements in depressive symptom severity. The greater degree of improvement in the PT arm at follow-up on psychosocial functioning, meaning in life, and psychological connectedness suggests warrant future research. However, these results are descriptive and should be interpreted with caution. Key limitations of the study include its suboptimal power to detect small but meaningful differences between treatments, missing data, the potential use of additional interventions during the follow-up period, and reliance on self-reported treatment assessments. These factors may affect the interpretation of the study findings and should be considered when evaluating the results.“ Authors: David Erritzoe, Tommaso Barba, Kyle T. Greenway, Roberta Murphy, Jonny Martell, Bruna Giribaldi, Christopher Timmermann, Ashleigh Murphy-Beiner, Michelle Baker Jones, David J. Nutt, Brandon Weiss & Robin L. Carhart-Harris

Abstract “Background Psilocybin therapy (PT) produces rapid and persistent antidepressant effects in major depressive disorder (MDD). However, the long-term effects of PT have never been compared with gold-standard treatments for MDD such as pharmacotherapy or psychotherapy alone or in combination. Methods This is a 6-month follow-up study of a phase 2, double-blind, randomised, controlled trial involving patients with moderate-to-severe MDD. Participants were recruited from a hospital in the UK. Male or female patients with major depressive disorder (DSM-IV), moderate to severe depression (HAM-D ≥17), no MRI or SSRI contraindications, confirmed diagnosis by a GP or mental healthcare professional, aged 18–80, and competent in English were eligible. Patients were randomly assigned (1:1) to receive either two 25 mg doses of the psychedelic drug psilocybin administered orally combined with psychological support (‘psilocybin therapy’ or PT) and bookended by further support or a 6-week course of the selective serotonin reuptake inhibitor (SSRI) escitalopram (administered daily at 10 mg for three weeks and 20 mg for the subsequent three weeks) plus matched psychological support (‘escitalopram treatment’ or ET). The primary outcome measure was change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16) at week 6, which has been reported previously. Herein, we present results at the 6-month follow-up time point. Measures of social functioning, connectedness, and meaning in life constituted the study’s secondary outcomes during follow-up. Safety in the follow-up period was not assessed. This trial is registered at ClinicalTrials.gov, NCT03429075. Findings Between January 15th, 2019 and March 20th, 2020, 59 patients were enrolled and 30 (11 females [37%] and 19 males [63%]) were assigned to the psilocybin group and 29 (9 females [31%] and 20 males [69%]) to the escitalopram group. 25 participants in the PT group and 21 in the ET group completed the 6-month follow-up. At the 6-month follow-up, both PT and ET conditions yielded sustained improvements in depressive symptom severity. The mean between-condition difference in QIDS-SR-16 scores at 6-months was 1.51 (95% CI: −1.35, 4.38; p = 0.311). Secondary outcomes demonstrated that PT had greater mean between-condition differences in functioning (WSAS: −7.46; 95% CI: −12.4, −2.47; p < 0.001), psychological connectedness (WCS: 11.02; 95% CI: 1.25, 20.83; p = 0.033), and meaning in life (MLQ: 4.86; 95% CI: 0.67, 9.05; p = 0.021) compared to ET. Interpretation Six-week intensive treatments with either psilocybin or escitalopram (with psychological support) for MDD were associated with long-term improvements in depressive symptom severity. The greater degree of improvement in the PT arm at follow-up on psychosocial functioning, meaning in life, and psychological connectedness suggests warrant future research. However, these results are descriptive and should be interpreted with caution. Key limitations of the study include its suboptimal power to detect small but meaningful differences between treatments, missing data, the potential use of additional interventions during the follow-up period, and reliance on self-reported treatment assessments. These factors may affect the interpretation of the study findings and should be considered when evaluating the results.“ Authors: David Erritzoe, Tommaso Barba, Kyle T. Greenway, Roberta Murphy, Jonny Martell, Bruna Giribaldi, Christopher Timmermann, Ashleigh Murphy-Beiner, Michelle Baker Jones, David J. Nutt, Brandon Weiss & Robin L. Carhart-Harris

Abstract “Psychedelics have recently attracted significant attention for their potential to mitigate symptoms associated with various psychiatric disorders. However, the precise neurobiological mechanisms responsible for these effects remain incompletely understood. A valuable approach to gaining insights into the specific mechanisms of action involves comparing psychedelics with substances that have partially overlapping neurophysiological effects, i.e., modulating the same neurotransmitter systems. Imaging data were obtained from the clinical trial NCT03019822, which explored the acute effects of lysergic acid diethylamide (LSD), d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers. The clinical trial employed a double-blind, placebo-controlled, crossover design. Herein, various resting-state connectivity measures were examined, including within-network connectivity (integrity), between-network connectivity (segregation), seed-based connectivity of resting-state networks, and global connectivity. Differences between placebo and the active conditions were assessed using repeated-measures ANOVA, followed by post-hoc pairwise t-tests. Changes in voxel-wise seed-based connectivity were correlated with serotonin 2 A receptor density maps. Compared to placebo, all substances reduced integrity in several networks, indicating both common and unique effects. While LSD uniquely reduced integrity in the default-mode network (DMN), the amphetamines, in contrast to our expectations, reduced integrity in more networks than LSD. However, LSD exhibited more pronounced segregation effects, characterized solely by decreases, in contrast to the amphetamines, which also induced increases. Across all substances, seed-based connectivity mostly increased between networks, with LSD demonstrating more pronounced effects than both amphetamines. Finally, while all substances decreased global connectivity in visual areas, compared to placebo, LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings advance our understanding of the distinctive neurobiological effects of psychedelics, prompting further exploration of their therapeutic potential.” Authors: Mihai Avram, Lydia Fortea, Lea Wollner, Ricarda Coenen, Alexandra Korda, Helena Rogg, Friederike Holze, Patrick Vizeli, Laura Ley, Joaquim Radua, Felix Müller, Matthias E. Liechti & Stefan Bordwardt Read the Full Article

Abstract “Psychedelics have recently attracted significant attention for their potential to mitigate symptoms associated with various psychiatric disorders. However, the precise neurobiological mechanisms responsible for these effects remain incompletely understood. A valuable approach to gaining insights into the specific mechanisms of action involves comparing psychedelics with substances that have partially overlapping neurophysiological effects, i.e., modulating the same neurotransmitter systems. Imaging data were obtained from the clinical trial NCT03019822, which explored the acute effects of lysergic acid diethylamide (LSD), d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers. The clinical trial employed a double-blind, placebo-controlled, crossover design. Herein, various resting-state connectivity measures were examined, including within-network connectivity (integrity), between-network connectivity (segregation), seed-based connectivity of resting-state networks, and global connectivity. Differences between placebo and the active conditions were assessed using repeated-measures ANOVA, followed by post-hoc pairwise t-tests. Changes in voxel-wise seed-based connectivity were correlated with serotonin 2 A receptor density maps. Compared to placebo, all substances reduced integrity in several networks, indicating both common and unique effects. While LSD uniquely reduced integrity in the default-mode network (DMN), the amphetamines, in contrast to our expectations, reduced integrity in more networks than LSD. However, LSD exhibited more pronounced segregation effects, characterized solely by decreases, in contrast to the amphetamines, which also induced increases. Across all substances, seed-based connectivity mostly increased between networks, with LSD demonstrating more pronounced effects than both amphetamines. Finally, while all substances decreased global connectivity in visual areas, compared to placebo, LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings advance our understanding of the distinctive neurobiological effects of psychedelics, prompting further exploration of their therapeutic potential.” Authors: Mihai Avram, Lydia Fortea, Lea Wollner, Ricarda Coenen, Alexandra Korda, Helena Rogg, Friederike Holze, Patrick Vizeli, Laura Ley, Joaquim Radua, Felix Müller, Matthias E. Liechti & Stefan Bordwardt Read the Full Article

Abstract “This study aims to estimate the lower, middle, and upper bounds of potential demand for psilocybin-assisted therapy (PSIL-AT) for major depressive disorder (MDD) and treatment-resistant depression (TRD) in the United States. We calculated potential PSIL-AT demand for MDD and TRD by estimating the number of U.S. patients with MDD, identifying those in treatment, and determining who qualifies as having TRD. We established a range of estimates using the exclusion criteria from the largest trials to date on PSIL-AT for MDD or TRD. Estimates ranged from lower-bound through stringent criteria, mid-range by focusing on likely real-world scenarios, to upper-bound by accounting for double counting for patients with multiple comorbidities. A significant portion of patients with MDD and TRD is ineligible for PSILAT due to disqualifying conditions. Percentage of patients who are eligible are 24% (lower-bound), 56% (mid-range), and 62% (upperbound). Variance was largely influenced by the removal of alcohol and substance use disorders as exclusion criteria, as well as removing the double counting from comorbid psychiatric and cardiovascular conditions. The analysis outlines the public health implications of providing PSIL-AT for MDD and TRD, emphasizing that the effective demand will be shaped by insurance coverage, state-level regulations, and the availability of trained providers. These findings suggest the need for careful policy planning and resource allocation to ensure equitable access and effective implementation of PSIL-AT across diverse populations and regions.” Authors: Syed F. Rab, Charles L. Raison & Elliot Marseille

Abstract “This study aims to estimate the lower, middle, and upper bounds of potential demand for psilocybin-assisted therapy (PSIL-AT) for major depressive disorder (MDD) and treatment-resistant depression (TRD) in the United States. We calculated potential PSIL-AT demand for MDD and TRD by estimating the number of U.S. patients with MDD, identifying those in treatment, and determining who qualifies as having TRD. We established a range of estimates using the exclusion criteria from the largest trials to date on PSIL-AT for MDD or TRD. Estimates ranged from lower-bound through stringent criteria, mid-range by focusing on likely real-world scenarios, to upper-bound by accounting for double counting for patients with multiple comorbidities. A significant portion of patients with MDD and TRD is ineligible for PSILAT due to disqualifying conditions. Percentage of patients who are eligible are 24% (lower-bound), 56% (mid-range), and 62% (upperbound). Variance was largely influenced by the removal of alcohol and substance use disorders as exclusion criteria, as well as removing the double counting from comorbid psychiatric and cardiovascular conditions. The analysis outlines the public health implications of providing PSIL-AT for MDD and TRD, emphasizing that the effective demand will be shaped by insurance coverage, state-level regulations, and the availability of trained providers. These findings suggest the need for careful policy planning and resource allocation to ensure equitable access and effective implementation of PSIL-AT across diverse populations and regions.” Authors: Syed F. Rab, Charles L. Raison & Elliot Marseille

Abstract “Current pharmacological treatments for major depressive disorder (MDD) are often only partially effective, with many patients experiencing no significant benefit, leading to treatment-resistant depression (TRD). Psilocybin, a classical serotonergic psychedelic, has emerged as a notable emerging treatment for such disorders. The aim of this systematic review and meta-analysis is to summarize and discuss the most recent evidence about the therapeutic effects of single-dose and two-dose psilocybin administration on the severity of depressive symptoms, as well as compare the efficacy of these interventions among patients with a primary diagnosis of MDD or TRD. Articles were collected from EBSCOhost and PubMed following the PRISMA guidelines, yielding 425 articles with 138 duplicates. After screening 287 records, 12 studies met the eligibility criteria and were included in the review. A quantitative analysis of the studies indicates that psilocybin is highly effective in reducing depressive symptoms severity among patients with primary MDD or TRD. Both single-dose and two-dose psilocybin treatments significantly reduced depressive symptoms severity, with two-dose administration sometimes yielding more pronounced and lasting effects. However, it is unclear if this was solely due to dosage or other factors. Future research should include standardized trials comparing these dosing strategies to better inform clinical practice.” Authors: Gianmarco Salvetti, Daniele Saccenti, Andrea S. Moro, Jacopo Lamanna & Mattia Ferrov

Abstract “Current pharmacological treatments for major depressive disorder (MDD) are often only partially effective, with many patients experiencing no significant benefit, leading to treatment-resistant depression (TRD). Psilocybin, a classical serotonergic psychedelic, has emerged as a notable emerging treatment for such disorders. The aim of this systematic review and meta-analysis is to summarize and discuss the most recent evidence about the therapeutic effects of single-dose and two-dose psilocybin administration on the severity of depressive symptoms, as well as compare the efficacy of these interventions among patients with a primary diagnosis of MDD or TRD. Articles were collected from EBSCOhost and PubMed following the PRISMA guidelines, yielding 425 articles with 138 duplicates. After screening 287 records, 12 studies met the eligibility criteria and were included in the review. A quantitative analysis of the studies indicates that psilocybin is highly effective in reducing depressive symptoms severity among patients with primary MDD or TRD. Both single-dose and two-dose psilocybin treatments significantly reduced depressive symptoms severity, with two-dose administration sometimes yielding more pronounced and lasting effects. However, it is unclear if this was solely due to dosage or other factors. Future research should include standardized trials comparing these dosing strategies to better inform clinical practice.” Authors: Gianmarco Salvetti, Daniele Saccenti, Andrea S. Moro, Jacopo Lamanna & Mattia Ferrov

Abstract “The administration of classic psychedelics has been associated with well-being and mental health benefits as well as risks and adverse events. The acute subjective effects of psychedelics might have a causal role in these risks and therapeutic benefits, but inconsistencies and limitations in the conceptualization and measurement of these acute subjective effects hinder research and clinical advances. In this Review, we outline current characterizations and psychometric examinations of the acute subjective effects of psychedelics, evaluate the construct validity of commonly used measures and describe findings showing that specific acute subjective effects predict certain outcomes. We discuss how to balance the limitations of existing measures with methodological advances in practice and elaborate on well-known methods and other psychological processes that can help inform the creation of new measures. We suggest actionable recommendations for how the field can transcend current conceptualizations and provide guidance on best practices until the next generation of measures is validated.” Authors: David B. Yaden, Sean P. Goldy, Brandon Weiss & Roland R. Griffiths Read the Full Article

Abstract “Importance A clear and comprehensive understanding of risks associated with psychedelic-assisted therapy is necessary as investigators extend its application to new populations and indications. Objective To assess adverse events (AEs) associated with classic psychedelics, particularly serious AEs (SAEs) and nonserious AEs (NSAEs) requiring medical or psychiatric evaluation. Data Sources The search for potentially eligible studies was conducted in the Scopus, MEDLINE, PsycINFO, and Web of Science databases from inception through February 8, 2024. Study Selection Two independent reviewers screened articles of classic psychedelics (lysergic acid diethylamide [LSD], psilocybin, dimethyltryptamine [DMT], and 5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) involving administration in clinical or research contexts. Data Extraction and Synthesis AE data were extracted and synthesized by 2 reviewers and were used for random-effects meta-analysis of AE frequency and heterogeneity. Risk of bias assessment focused on AE ascertainment (eg, systematic assessment and quality of follow-up). Main Outcomes and Measures A hybrid approach was used for capture of all reported AEs following high-dose classic psychedelic exposure and confirmatory capture of AEs of special interest, including suicidality, psychotic disorder, manic symptoms, cardiovascular events, and hallucinogen persisting perception disorder. AEs were stratified by timescale and study population type. Forest plots of common AEs were generated, and the proportions of participants affected by SAEs or NSAEs requiring medical intervention were summarized descriptively. Results A total of 214 unique studies were included, of which 114 (53.3%) reported analyzable AE data for 3504 total participants. SAEs were reported for no healthy participants and for approximately 4% of participants with preexisting neuropsychiatric disorders; among these SAEs were worsening depression, suicidal behavior, psychosis, and convulsive episodes. NSAEs requiring medical intervention (eg, paranoia, headache) were similarly rare. In contemporary research settings, there were no reports of deaths by suicide, persistent psychotic disorders, or hallucinogen persisting perception disorders following administration of high-dose classic psychedelics. However, there was significant heterogeneity in the quality of AE monitoring and reporting. Of 68 analyzed studies published since 2005, only 16 (23.5%) described systematic approaches to AE assessment, and 20 studies (29.4%) reported all AEs, as opposed to only adverse drug reactions. Meta-analyses of prevalence for common AEs (eg, headache, anxiety, nausea, fatigue, and dizziness) yielded comparable results for psilocybin and LSD. Conclusions and Relevance In this systematic review and meta-analysis, classic psychedelics were generally well tolerated in clinical or research settings according to the existing literature, although SAEs did occur. These results provide estimates of common AE frequencies and indicate that certain catastrophic events reported in recreational or nonclinical contexts have yet to be reported in contemporary trial participants. Careful, ongoing, and improved pharmacovigilance is required to understand the risk and benefit.” Authors: Jared T. Hinkle, Marianna Graziosi, Sandeep M. Nayak & David B. Yaden Read the Full Article

Abstract “Background Psilocybin, a serotonin 2A receptor agonist with psychedelic properties, shows promise as a novel treatment for alcohol use disorder (AUD). While current studies involve two dosing sessions, the effects a single dose have not been investigated. Aims To investigate the pharmacokinetics, feasibility, safety, and efficacy of single-dose psilocybin therapy in AUD. Methods This open-label, single-group study investigated single-dose psilocybin therapy in ten treatment-seeking adults (eight men and two women; median age 44 years) with severe AUD. The treatment involved two preparation sessions, a high-dose psilocybin session (25 mg), and two integration sessions. Pharmacokinetics were determined by noncompartmental analysis, and changes in alcohol consumption, craving and self-efficacy, were assessed with a linear mixed model. Results Notable between-participant pharmacokinetic variations were observed, with peak plasma psilocin concentrations ranging from 14-59 µg/L. Alcohol consumption significantly decreased over the 12 weeks following psilocybin administration. Heavy drinking days were reduced by 37.5 percentage points (95% CI, -61.1, -13.9, p = 0.005), and drinks per day decreased by 3.4 units (95% CI: -6.5, -0.3), p = 0.035). This was corroborated by reports of rapid and sustained reductions in craving and increases in self-efficacy. Conclusions Despite pharmacokinetic variations, a single 25 mg psilocybin dose was safe and effective in reducing alcohol consumption in AUD patients. Larger randomised, placebo-controlled, single-dose AUD trials are warranted.” Authors: Mathias E. Jensen, Dea S. Stenbæk, Catharina D. Messell, Emil D. Poulsen, Tibor V. Varga, Patrick M. Fisher, Marie K. Klose Nielsen, Sys S. Johansen, Nora D. Volkow, Gitte M. Knudsen & Anders F. Fink-Jensen Read the Full Article

Abstract “Background Psilocybin, a serotonin 2A receptor agonist with psychedelic properties, shows promise as a novel treatment for alcohol use disorder (AUD). While current studies involve two dosing sessions, the effects a single dose have not been investigated. Aims To investigate the pharmacokinetics, feasibility, safety, and efficacy of single-dose psilocybin therapy in AUD. Methods This open-label, single-group study investigated single-dose psilocybin therapy in ten treatment-seeking adults (eight men and two women; median age 44 years) with severe AUD. The treatment involved two preparation sessions, a high-dose psilocybin session (25 mg), and two integration sessions. Pharmacokinetics were determined by noncompartmental analysis, and changes in alcohol consumption, craving and self-efficacy, were assessed with a linear mixed model. Results Notable between-participant pharmacokinetic variations were observed, with peak plasma psilocin concentrations ranging from 14-59 µg/L. Alcohol consumption significantly decreased over the 12 weeks following psilocybin administration. Heavy drinking days were reduced by 37.5 percentage points (95% CI, -61.1, -13.9, p = 0.005), and drinks per day decreased by 3.4 units (95% CI: -6.5, -0.3), p = 0.035). This was corroborated by reports of rapid and sustained reductions in craving and increases in self-efficacy. Conclusions Despite pharmacokinetic variations, a single 25 mg psilocybin dose was safe and effective in reducing alcohol consumption in AUD patients. Larger randomised, placebo-controlled, single-dose AUD trials are warranted.” Authors: Mathias E. Jensen, Dea S. Stenbæk, Catharina D. Messell, Emil D. Poulsen, Tibor V. Varga, Patrick M. Fisher, Marie K. Klose Nielsen, Sys S. Johansen, Nora D. Volkow, Gitte M. Knudsen & Anders F. Fink-Jensen Read the Full Article

Abstract “Introduction: Despite widespread popular interest in the use of low doses of Lysergic acid diethylamide (LSD) to improve mood, little is known about how these doses affect emotional processing in the brain. In this study, we tested the effect of a single low dose of LSD (26 µg) compared with placebo on electroencephalogram (EEG) event-related potentials (ERP: N170, P300 and Mismatch Negativity) in healthy adults, while participants viewed angry, happy, and neutral faces. We hypothesized that the drug might affect either neutral faces, which are sometimes perceived as threatening, or emotional faces. Methods: Healthy young adults (n = 39) received LSD (26 µg or placebo sublingually) before completing an oddball task with emotional facial expressions during EEG recording. The N170 and P300 evoked potentials were recorded using EEG. LSD and placebo were administered in double-blind, randomized order separated by at least 7 days. During the oddball task, three emotional faces were presented infrequently (angry, happy, neutral) in a block design, and a cartoon face was presented frequently. Results: LSD significantly reduced the amplitude of the occipitotemporal N170 ERP to Neutral faces, but not angry or happy faces. LSD also reduced the amplitude of the midline posterior parietal P300 ERP to neutral and happy faces, but not angry faces. Discussion: These differential effects of LSD on the amplitude of the N170 and P300 to neutral and emotional faces add to our understanding of how low doses of LSD might affect the brain response to social and emotional information.” Authors: Connor J. Haggarty, Hanna M. Molla, James Glazer, Ilaria Tare, Alex Rains, Harriet de Wit & Royce Lee Read the Full Article

Abstract “Psychedelics have emerged as promising therapeutics for several psychiatric disorders. Hypotheses around their mechanisms have revolved around their partial agonism at the serotonin 2 A receptor, leading to enhanced neuroplasticity and brain connectivity changes that underlie positive mindset shifts. However, these accounts fail to recognise that the gut microbiota, acting via the gut-brain axis, may also have a role in mediating the positive effects of psychedelics on behaviour. In this review, we present existing evidence that the composition of the gut microbiota may be responsive to psychedelic drugs, and in turn, that the effect of psychedelics could be modulated by microbial metabolism. We discuss various alternative mechanistic models and emphasize the importance of incorporating hypotheses that address the contributions of the microbiome in future research. Awareness of the microbial contribution to psychedelic action has the potential to significantly shape clinical practice, for example, by allowing personalised psychedelic therapies based on the heterogeneity of the gut microbiota.” Authors: Giorgia Caspani, Simon G.D. Ruffell, WaiFung Tsang, Nigel Netzband, Cyrus Rohani-Shukla, Jonathan R. Swann & Wilfred A. Jefferies Read the Full Article

Abstract “Introduction: The positive results of MDMA from Phase 2 and 3 clinical trials in MDMA-assisted therapy (MDMA-AT) for the treatment of post-traumatic stress disorder (PTSD) call for a critical evaluation of its regulatory status within the European mental healthcare system. This is driven by the recent submission of MDMA-AT for FDA approval in the United States. Unless coordinated efforts in the European regulatory landscape start, there may be potential divergences in national regulatory strategies. Gaining insights from researchers and clinicians involved in the application of MDMA-AT may be useful in guiding the discussion of factors involved in its implementation. Method: A comprehensive invitation-only survey was sent to researchers and clinicians involved in MDMA-AT clinical trials and contributors to the scientific literature on MDMA-AT from around the globe. This study aimed to collect opinions on clinical practices, training, and regulation worldwide, examining the global best practices and pitfalls to outline strategies for possible European implementation of MDMA-AT. Results: The survey, which included responses from 68 experts, yielded a range of opinions where a large majority endorsed the need for training and standardization, emphasizing equity and access, stressing impediments in the national approval processes, and reflecting critically on anticipated spill-over effects of MDMA-AT in clinical settings. Conclusion: The experts highlight the need for science-informed policy development, active regulatory involvement, and international cooperation to incorporate MDMA-AT into the European mental healthcare system in general and the treatment of PTSD in particular. The study emphasizes the importance of ongoing research, open professional discourse, and collaborative engagement to facilitate MDMA-AT’s ethical and effective implementation.” Authors: Jerome Herpers, Natalie Maximets, Noah N. N. van Dongen, Josjan Zijlmans, Eric Vermetten Read the Full Article

Abstract “As a proposed mediator between stigma-related stressors and negative mental health outcomes, HIV-related shame has been predictive of increased rates of substance use and difficulties adhering to antiretroviral treatment among people with HIV. These downstream manifestations have ultimately impeded progress toward national goals to End the HIV Epidemic, in part due to limited success of conventional psychotherapies in addressing HIV-related shame. In a pilot clinical trial (N = 12), receipt of psilocybin-assisted group therapy was associated with a large pre-post decrease in HIV-related shame as measured by the HIV and Abuse Related Shame Inventory, with a median (IQR) change of − 5.5 (− 6.5, − 3.5) points from baseline to 3-months follow-up (Z = − 2.6, p = 0.009, r = − 0.75). A paradoxical exacerbation of sexual abuse-related shame experienced by two participants following receipt of psilocybin raises critical questions regarding the use of psilocybin therapy among patients with trauma. These preliminary findings carry potential significance for the future of HIV care.” Authors: Nicky J. Mehtani, Mallory O. Johnson, Peter S. Hendricks, Jennifer Mitchell & Brian T. Anderson Read the Full Article

Abstract “Recent clinical trials have found that the serotonergic psychedelic psilocybin effectively alleviates anxiodepressive symptoms in patients with life-threatening illnesses when given in a supportive environment. These outcomes prompted Canada to establish legal pathways for therapeutic access to psilocybin, coupled with psychological support. Despite over one-hundred Canadians receiving compassionate access since 2020, there has been little examination of these ‘real-world’ patients. We conducted a prospective longitudinal survey which focused on Canadians who were granted Section 56 exemptions for legal psilocybin-assisted psychotherapy. Surveys assessing various symptom dimensions were conducted at baseline, two weeks following the session (endpoint), and optionally one day post-session. Participant characteristics were examined using descriptive statistics, and paired sample t-tests were used to quantify changes from baseline to the two-week post-treatment endpoint. Eight participants with Section 56 exemptions (four females, Mage = 52.3 years), all with cancer diagnoses, fully completed baseline and endpoint surveys. Significant improvements in anxiety and depression symptoms, pain, fear of COVID-19, quality of life, and spiritual well-being were observed. Attitudes towards death, medical assistance in dying, and desire for hastened death remained unchanged. While most participants found the psilocybin sessions highly meaningful, if challenging, one reported a substantial decrease in well-being due to the experience. These preliminary data are amongst the first to suggest that psilocybin-assisted psychotherapy can produce psychiatric benefits in real-world patients akin to those observed in clinical trials. Limited enrollment and individual reports of negative experiences indicate the need for formal real-world evaluation programs to surveil the ongoing expansion of legal access to psychedelics.” Authors: Sara de la Salle, Hannes Kettner, Julien Thibault Lévesque, Nicolas Garel, Shannon Dames, Ryan Patchett-Marble, Soham Rej, Sara Gloeckler, David Erritzoe, Robin L. Carhart-Harris & Kyle T. Greenway Read the Full Article

Abstract “Background: Anxiety disorders are a major public health burden with limited treatment options. Aims: We investigated the long-term safety and efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with anxiety with or without life-threatening illness. Method: This study was an a priori-planned long-term follow-up of an investigator-initiated, two-centre trial that used a double-blind, placebo-controlled, two-period, random-order, crossover design with two sessions with either oral LSD (200 μg) or placebo per period. Participants (n = 39) were followed up 1 year after the end-of-study visit to assess symptoms of anxiety, depression and long-term effects of psychedelics using Spielberger’s State-Trait Anxiety Inventory–Global (STAI-G), the Beck Depression Inventory (BDI), the Persisting Effects Questionnaire and measures of personality traits using the NEO-Five-Factor Inventory. Results: Participants reported a sustained reduction of STAI-G scores compared with baseline (least square means (95% CI) = −21.6 (−32.7, −10.4), d = 1.04, P < 0.001, for those who received LSD in the first period (94 weeks after the last LSD treatment) and −16.5 (−26.2, −6.8), d = 1.02, P < 0.05, for those who received LSD in the second period (68 weeks after the last LSD treatment)). Similar effects were observed for comorbid depression with change from baseline BDI scores of −8.1 (−13.2, −3.1), d = 0.71, P < 0.01, and −8.9 (−12.9, −4.9), d = 1.21, P < 0.01, for the LSD-first and placebo-first groups, respectively. Personality trait neuroticism decreased (P < 0.0001) and trait extraversion increased (P < 0.01) compared with study inclusion. Individuals attributed positive long-term effects to the psychedelic experience. Conclusions: Patients reported sustained long-term effects of LSD-assisted therapy for anxiety.” Authors: Friederike Holze, Peter Gasser, Felix Müller, Manuel Strebel & Matthias E. Liechti Read the Full Article

Abstract “Science on methylenedioxymethamphetamine (MDMA) and MDMA-like substances is faced with the unique situation that this class of psychoactive agents is referred to with two basic names for its effects on the mind: empathogens and entactogens. Empathogen usually refers to the prosocial, empathetic, and openness properties of MDMA, while entactogen usually refers to the introspective and self-awareness properties of this substance. We review the origin and usage of the two terms, and also review recent findings that support that MDMA is an empathogen and an entactogen. Mostly no specified reasons can be detected whether research groups employ the term “entactogenic,” “empathogenic,” both, or neither, in their publications. A case is made that the use of two basic names for the effects on the mind for the same class of psychoactive substances is not warranted because a holistic principle underlies empathogenic and entactogenic properties of MDMA: an intense feeling of connection. Entactogenic characterizes being deeply connected to oneself, and empathogenic being deeply connected to others. We therefore suggest the name connectogen as the new basic name for the mind effects of MDMA and MDMA-like substances, a term having the connotation of producing a joining together/producing a connection. Thus, MDMA is basically a connectogen with at least the two major connective properties: entactogenic (intrapersonal) and empathogenic (interpersonal). Furthermore, first evidence shows that MDMA might also have further connectogenic properties such as a strong sense of connection with the here-and-now, the body, the world, and with spiritual principles. Finally, we compare connectogenic properties of MDMA with connectogenic properties of classic psychedelics, and lay out some future research in this regard.” Authors: Kurt Stocker & Matthias E. Liechti Read the Full Article

Abstract “Background: Alcohol use disorder (AUD) is a major public health issue, posing harmful consequences for individuals and society. Recent advances in addiction research have highlighted the therapeutic potential of ketamine-assisted therapy for AUD. However, the exact mechanisms underlying its effectiveness remain unknown. Aims: This double-blind, pilot study aimed to investigate esketamine combined with mindfulness-based intervention (MBI) to examine whether esketamine enhances engagement in MBI for individuals with alcohol misuse problems and whether enhanced engagement has any impact on alcohol-related outcomes. Methods: In all, 28 individuals with alcohol problems were randomly assigned to receive sublingual esketamine hydrochloride (AWKN002: 115.1 mg) or vitamin C (placebo) in an oral thin film and took part in 2 weeks of daily MBI. Participants were assessed on various self-report measures, including mindfulness, engagement in MBI (physical and psychological), alcohol cravings and consumption. Results: Esketamine enhanced psychological engagement with a daily MBI, compared to placebo, and led to transient decreases in alcohol cravings. Esketamine also resulted in significantly greater mystical experiences and dissociative states compared to placebo. Conclusions: The findings suggest that esketamine may improve treatment outcomes when combined with mindfulness-based therapies through its ability to increase engagement with meditative practice.” Authors: Emily M. Gent, Joshua W. Bryan, Maisy A. Cleary, Tegan I. Clarke, Harry D. Holmwood, Rania O. Nassereddine, Chris Salway, Simon Depla, Sarah Statton, Joy Krecké & Celia J. A. Morgan Read the Full Article

Abstract “Background: Alcohol use disorder (AUD) is a major public health issue, posing harmful consequences for individuals and society. Recent advances in addiction research have highlighted the therapeutic potential of ketamine-assisted therapy for AUD. However, the exact mechanisms underlying its effectiveness remain unknown. Aims: This double-blind, pilot study aimed to investigate esketamine combined with mindfulness-based intervention (MBI) to examine whether esketamine enhances engagement in MBI for individuals with alcohol misuse problems and whether enhanced engagement has any impact on alcohol-related outcomes. Methods: In all, 28 individuals with alcohol problems were randomly assigned to receive sublingual esketamine hydrochloride (AWKN002: 115.1 mg) or vitamin C (placebo) in an oral thin film and took part in 2 weeks of daily MBI. Participants were assessed on various self-report measures, including mindfulness, engagement in MBI (physical and psychological), alcohol cravings and consumption. Results: Esketamine enhanced psychological engagement with a daily MBI, compared to placebo, and led to transient decreases in alcohol cravings. Esketamine also resulted in significantly greater mystical experiences and dissociative states compared to placebo. Conclusions: The findings suggest that esketamine may improve treatment outcomes when combined with mindfulness-based therapies through its ability to increase engagement with meditative practice.” Authors: Emily M. Gent, Joshua W. Bryan, Maisy A. Cleary, Tegan I. Clarke, Harry D. Holmwood, Rania O. Nassereddine, Chris Salway, Simon Depla, Sarah Statton, Joy Krecké & Celia J. A. Morgan Read the Full Article

Abstract “The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine’s effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine’s temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine’s antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.” Authors: Elizabeth D. Ballard, Deanna Greenstein, Philip T. Reiss, Ciprian M. Crainiceanu, Erjia Cui, Wallace C. Duncan Jr., Nadia S. Hejazi & Carlos A. Zarate Jr. Read the Full Article

Abstract “The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine’s effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine’s temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine’s antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.” Authors: Elizabeth D. Ballard, Deanna Greenstein, Philip T. Reiss, Ciprian M. Crainiceanu, Erjia Cui, Wallace C. Duncan Jr., Nadia S. Hejazi & Carlos A. Zarate Jr. Read the Full Article

Abstract “Serotonergic psychedelics hold promise as a treatment modality for various psychiatric disorders and are currently applied in psychedelic-assisted psychotherapy. We investigated the learning effects of the serotonin receptor agonist psilocybin in a probabilistic cue-reward task with emotional cues in the form of neutral or fearful faces, presented either consciously or subconsciously. This study represents the first investigation into reinforcement learning with psilocybin. Across different dosages, psilocybin preserved learning effects and was statistically noninferior compared to placebo, while suggesting a higher exploratory behavior. Notably, the 20 mg group exhibited significantly better learning rates against the placebo group. Psilocybin induced inferior results with subconscious cues compared to placebo, and better results with conscious neutral cues in some conditions. These findings suggest that modulating serotonin signaling in the brain with psilocybin sufficiently preservers reinforcement learning.” Authors: Andrea F. Casanova, Andres Ort, John W. Smallridge, Katrin H. Preller, Erich Seifritz & Franz X. Vollenweider Read the Full Article

Abstract “For a new clinical trial testing a group retreat-based format of psilocybin-assisted therapy, our research team created an initial set of practice guidelines that aimed to describe facilitator use of touch in a way that is ethical, supportive, and minimizes harm. In our first three retreats, however, we had two unexpected experiences with touch that led us to iterate our initial guidelines into a new version of guidelines. In this Technical Report, we describe our evolving guidelines specifying acceptable practices for facilitator use of touch to ensure a safe, supportive, and therapeutic participant experience. Our primary goal with these guidelines is to create a haptic experience during the psilocybin session that reinforces the participants’ sense of safety and supports their own experience during the psilocybin session. Our secondary goal is to allow the facilitator team to notice and maintain therapeutic boundaries and to respond to participant experiences with empathy and openness in the context of those boundaries.” Authors: Anthony Back, Susanna Myers, John Guy, Juliana Perez, Leslie Lazar Thorn & Bonnie McGregor Read the Full Article

Abstract “Background: Ketamine, an NMDA receptor antagonist, provides rapid antidepressant effects. Although much research has focused on neural and molecular mechanisms of action, it is critical to also consider psychological mechanisms that may contribute to its therapeutic efficacy. The construct of an awe-inducing experience, which is a well-validated psychological phenomenon tied to emotional well-being, had not been applied previously in ketamine research. Methods: One hundred sixteen participants with depression, 77 of whom received a ketamine infusion (0.5 mg/kg over 40 minutes) and 39 patients who received saline placebo, completed a validated measure of awe (the Awe Experience Scale [AWE-S]) at 40 minutes postinfusion. AWE-S scores were examined as potential mediators of depression outcomes (% improvement in Montgomery–Åsberg Depression Rating Scale score) at 5 postinfusion time points (24 hours and 5, 12, 21, and 30 days). Dissociative effects, measured by Clinician-Administered Dissociative States Scale scores, were tested in parallel mediation models for comparison. Results: We found that the psychological experience of awe was strongly reported by participants during ketamine infusion, but not saline infusion, and there were significant associations between total AWE-S scores and Montgomery–Åsberg Depression Rating Scale score improvement (% change) in the ketamine arm at all 5 time points. Furthermore, at all 5 time points, total AWE-S scores statistically mediated the relationship between ketamine and Montgomery–Åsberg Depression Rating Scale scores. By contrast, Clinician-Administered Dissociative States Scale scores did not mediate outcomes at any time point. Conclusions: Ketamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression outcomes over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.” Authors: Julia Aepfelbacher, Benjamin Panny & Rebecca B. Price Read the Full Article

Abstract “Background: Under a risk evaluation and mitigation strategy program, esketamine nasal spray CIII requires self administration at a certified treatment center. Our objective was to identify factors associated with esketamine initiation and continuation. Methods: A retrospective observational cohort study was conducted among US adults who met treatment-resistant depression (TRD) criteria. Cases (n = 966) initiated esketamine between October 11, 2019, and February 28, 2022, and were compared to controls (n = 39,219) with TRD but no esketamine use. Outcomes included initiation, induction (8 administrations within 45 days), and interruptions (30-day treatment gap). Comorbid psychiatric conditions were identified using International Classification of Diseases, Tenth Revision, Clinical Modification, codes. Results: Cases resided significantly closer to treatment centers (8.9 vs 20.3 miles). Compared to 0–9 miles, initiation rate decreased by 11.9%, 50.8%, 68.1%, 75.9%, and 92.8% for individuals residing 10–19, 20–29, 30–39, 40–49, and 50+ miles from a center. After adjustment, factors associated with increased likelihood of initiation were posttraumatic stress disorder, major depressive disorder with suicidal ideation, and male sex, while increasing distance, substance use disorder, Medicaid, Charlson Comorbidity Index (CCI), and older age were associated with lower likelihood. Factors associated with lower likelihood of completing induction were Medicaid, low socioeconomic status (SES), CCI, and Hispanic communities. Factors associated with increased likelihood of interruption were alcohol use disorder, distance, and minority communities, while generalized anxiety disorder and Medicaid were associated with lower likelihood. Conclusions: Travel distance, insurance, low SES, and minority communities are potential barriers to treatment. Alternative care models may be needed to ensure adequate access to care.” Authors: Kruti Joshi, Joshua N. Liberman, Purva Parab, Jonathan D. Darer, & Lisa Harding Read the Full Article

Abstract “Background: Ketamine, an NMDA receptor antagonist, provides rapid antidepressant effects. Although much research has focused on neural and molecular mechanisms of action, it is critical to also consider psychological mechanisms that may contribute to its therapeutic efficacy. The construct of an awe-inducing experience, which is a well-validated psychological phenomenon tied to emotional well-being, had not been applied previously in ketamine research. Methods: One hundred sixteen participants with depression, 77 of whom received a ketamine infusion (0.5 mg/kg over 40 minutes) and 39 patients who received saline placebo, completed a validated measure of awe (the Awe Experience Scale [AWE-S]) at 40 minutes postinfusion. AWE-S scores were examined as potential mediators of depression outcomes (% improvement in Montgomery–Åsberg Depression Rating Scale score) at 5 postinfusion time points (24 hours and 5, 12, 21, and 30 days). Dissociative effects, measured by Clinician-Administered Dissociative States Scale scores, were tested in parallel mediation models for comparison. Results: We found that the psychological experience of awe was strongly reported by participants during ketamine infusion, but not saline infusion, and there were significant associations between total AWE-S scores and Montgomery–Åsberg Depression Rating Scale score improvement (% change) in the ketamine arm at all 5 time points. Furthermore, at all 5 time points, total AWE-S scores statistically mediated the relationship between ketamine and Montgomery–Åsberg Depression Rating Scale scores. By contrast, Clinician-Administered Dissociative States Scale scores did not mediate outcomes at any time point. Conclusions: Ketamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression outcomes over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.” Authors: Julia Aepfelbacher, Benjamin Panny & Rebecca B. Price Read the Full Article

Abstract “Background: Under a risk evaluation and mitigation strategy program, esketamine nasal spray CIII requires self administration at a certified treatment center. Our objective was to identify factors associated with esketamine initiation and continuation. Methods: A retrospective observational cohort study was conducted among US adults who met treatment-resistant depression (TRD) criteria. Cases (n = 966) initiated esketamine between October 11, 2019, and February 28, 2022, and were compared to controls (n = 39,219) with TRD but no esketamine use. Outcomes included initiation, induction (8 administrations within 45 days), and interruptions (30-day treatment gap). Comorbid psychiatric conditions were identified using International Classification of Diseases, Tenth Revision, Clinical Modification, codes. Results: Cases resided significantly closer to treatment centers (8.9 vs 20.3 miles). Compared to 0–9 miles, initiation rate decreased by 11.9%, 50.8%, 68.1%, 75.9%, and 92.8% for individuals residing 10–19, 20–29, 30–39, 40–49, and 50+ miles from a center. After adjustment, factors associated with increased likelihood of initiation were posttraumatic stress disorder, major depressive disorder with suicidal ideation, and male sex, while increasing distance, substance use disorder, Medicaid, Charlson Comorbidity Index (CCI), and older age were associated with lower likelihood. Factors associated with lower likelihood of completing induction were Medicaid, low socioeconomic status (SES), CCI, and Hispanic communities. Factors associated with increased likelihood of interruption were alcohol use disorder, distance, and minority communities, while generalized anxiety disorder and Medicaid were associated with lower likelihood. Conclusions: Travel distance, insurance, low SES, and minority communities are potential barriers to treatment. Alternative care models may be needed to ensure adequate access to care.” Authors: Kruti Joshi, Joshua N. Liberman, Purva Parab, Jonathan D. Darer, & Lisa Harding Read the Full Article

Abstract “Background: Traditional treatments for Post-Traumatic Stress Disorder (PTSD) often show limited success with high dropout. Ketamine, an N-methyl-D-aspartate antagonist known for rapid antidepressant effects, has decreased PTSD symptoms in some studies but not others.mAdministering ketamine in ways that parallel psychedelic-assisted treatments—including preparatory, integration, sensory immersion, and psychotherapy sessions—could decrease PTSD symptoms meaningfully. Methods: A sample of 117 screened outpatients with elevated scores on the PTSD Checklist for DSM-5 (PCL-5) received intravenous ketamine in highly supportive environments. The protocol included sessions focusing on preparation, setting intentions, and integration for each of at least six administrations. Administration sessions included eye shades and evocative music in ways that paralleled facets of MDMA trials for PTSD. Results: Mean PCL scores decreased from 52.39 (SD = 11.90) to 29.42 (SD = 16.52; Cohen’s d = 1.60). Patients tolerated treatment well, with no serious adverse events. Covariates, including age, gender, days between PCL assessments, number of psychiatric medications, and suicidal ideation were not significant moderators; concomitant psychotherapy did reach significance, d = 0.42. Conclusion: Intravenous ketamine in supportive environments, with hallmarks of psychedelic therapy, preceded large reductions in PTSD symptoms. These results highlight ketamine’s potential when delivered in this manner, suggesting that environmental factors might account for some of the variation that has appeared in previous work. Given the molecule’s cost, minimal interaction with other psychiatric medications, and legal status, intravenous ketamine in a psychedelic paradigm may be a promising new option for PTSD that has not responded to other treatments.” Authors: Henry A. MacConnel, Mitchell Earleywine & Steven Radowitz Read the Full Article

Abstract “Evidence suggests that MDMA-assisted psychotherapy (MDMA-AP) has therapeutic potential for treatment of psychiatric illness. We conducted the first comprehensive systematic review and meta-analysis of the side effects of MDMA-AP across indications. We also assessed the quality of side effects-reporting in published trials of MDMA-AP. PubMed, EMBASE, PsycINFO, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched. Phase 2 and 3 MDMA-AP studies were included; Phase 1 studies, which assessed MDMA without psychotherapy, were not. Quality of side effects-reporting was assessed against the CONSORT Harms 2022 guidelines. We also compared numbers of adverse events reported in publications to those recorded in ClinicalTrial.gov registers. Thirteen studies were included, with eight contributing to the meta-analysis. In Phase 2 studies, MDMA-AP was associated with increased odds of any side effect during medication sessions (OR = 1.67, 95%CI (1.12, 2.49)) and in the 7 days following (OR = 1.59, 95%CI (1.12, 2.24)) relative to control conditions. In Phase 3 studies, MDMA-AP was associated with increased odds of any adverse event during the treatment period relative to placebo-assisted psychotherapy (OR = 3.51, 95%CI (2.76, 4.46)). The majority of RCTs were rated as having high risk of bias. Certainty of the evidence was rated as very low to moderate according to the GRADE framework. No included RCT had adequate adherence to the CONSORT Harms 2022 recommendations and reporting rates were also low. Compared to placebo, MDMA-AP was associated with increased odds of side effects, which were largely transient and mild or moderate in severity. However, identified limitations in existing evidence indicate that further investigation is needed to better characterize the safety profile of MDMA-AP and guide implementation.” Authors: Julia Colcott, Alexandre A. Guerin, Olivia Carter, Sally Meikle & Gillinder Bedi Read the Full Article

Abstract “Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within a manualized psychotherapy that incorporated principles of Acceptance and Commitment Therapy. Depression severity, psychological flexibility, mindfulness, and values-congruent living were measured over a 16-weeks study period. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved following psilocybin and were maintained through week 16. Additionally, improvements in psychological flexibility and experiential acceptance were strongly associated with reductions in depression severity following psilocybin. These findings support the theoretical premise of integrating psilocybin treatment with psychotherapeutic platforms that target psychological flexibility and add to emerging evidence that increasing psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for MDD and potentially, other mental health conditions.” Authors: Jordan Sloshower, Richard J. Zeifman, Jeffrey Guss, Robert Krause, Hamideh Safi-Aghdam, Surbhi Pathania, Brian Pittman & Deepak Cyril D’Souza Read the Full Article

Abstract “Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within a manualized psychotherapy that incorporated principles of Acceptance and Commitment Therapy. Depression severity, psychological flexibility, mindfulness, and values-congruent living were measured over a 16-weeks study period. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved following psilocybin and were maintained through week 16. Additionally, improvements in psychological flexibility and experiential acceptance were strongly associated with reductions in depression severity following psilocybin. These findings support the theoretical premise of integrating psilocybin treatment with psychotherapeutic platforms that target psychological flexibility and add to emerging evidence that increasing psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for MDD and potentially, other mental health conditions.” Authors: Jordan Sloshower, Richard J. Zeifman, Jeffrey Guss, Robert Krause, Hamideh Safi-Aghdam, Surbhi Pathania, Brian Pittman & Deepak Cyril D’Souza Read the Full Article

Abstract “Traumatic events (TEs) play a causal role in the etiology of psychopathologies such as depression and posttraumatic stress disorder (PTSD). Recent research has highlighted the therapeutic potential of psychoactive substances and especially 3,4-methylenedioxymethamphetamine (MDMA), in alleviating trauma symptoms in chronic patients. However, little is known regarding the consequences of trauma that is acutely experienced under the influence of psychoactive substances. Here we investigated the acute experiences and peritraumatic processing of 657 survivors from the high-casualty terror attack at the Supernova music festival in Israel on October 7th, 2023. Data were collected four to twelve weeks following the TE. Approximately two-thirds of survivors were under the influence of psychoactive substances at the time of the TE, offering a tragic and unique natural experiment on the impact of psychoactive compounds on TE processing. Our findings reveal that individuals who experienced the trauma while under the influence of MDMA demonstrated significantly improved intermediate outcomes compared to those who were under the influence of other substances or no substances at all. Specifically, the MDMA group reported increased feelings of social support, more social interactions and enhanced quality of sleep during the peritraumatic period, yielding reduced levels of mental distress and reduced PTSD symptom severity. These novel findings suggest that the influence of MDMA during the TE may carry protective effects into the peritraumatic period, possibly mediated through the known effects of MDMA in reducing negative emotions and elevating prosociality. These protective effects in turn may mitigate the development of early psychopathology-related symptoms. Current preliminary results underscore the need for further understanding of the cognitive and physiological processes by which psychedelic substances intersect with trauma recovery processes.” Authors: Ophir Netzer, Noa Magal, Yonatan Stern, Tzuk Polinsky, Raz Gross, Roee Admon & Roy Salomon Read the Full Article

Abstract “Background: MDMA-assisted therapy (MDMA-AT) is an emerging treatment modality, with recent phase 3 trials indicating its potential for regulatory approval. Central to this therapy is the role of touch, yet its empirical evaluation in MDMA-AT, and psychotherapy in general, remains limited. The use of touch in combination with MDMA raises concerns about power imbalances and ethical boundaries. Methods: This article reviews existing literature on therapeutic touch and introduces the Touch Outcomes Measurement Inventory (TOMI). The TOMI is developed to assess client perceptions of touch in MDMA-AT, addressing a critical gap in the current research landscape. Results: The main outcome of this research is the creation of TOMI, a tool aimed at evaluating the impact of touch on clients in MDMA-AT. The review highlights the lack of empirical evidence in this area and the necessity for such a measure. Discussion: With the increasing likelihood of MDMA-AT becoming a widely used therapy, understanding how therapeutic touch affects clients is imperative. This article emphasizes the need for evidence-based and ethical guidelines for the use of touch in MDMA-AT. The development of TOMI is a step towards achieving this, providing a means for researchers and program evaluators to assess the implications of touch in MDMA-AT and psychedelic-assisted therapy more generally.” Authors: Jason Luoma, Luke R. Allen, Veronika Gold & Christopher Stauffer Read the Full Article

Abstract “Background: Reference to an intrinsic healing mechanism or an ‘inner healer’ is commonplace amongst psychedelic drug-using cultures. The ‘inner healer’ refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical body, for example, after sickness or injury. Aims: Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived ‘inner healing’ effects. Methods: The item was issued to 59 patients after a single high (25 mg, n = 30) or ‘placebo’ (1 mg, n = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression. Results: Inner healer scores were higher after the high versus placebo dose of psilocybin (t = 3.88, p < 0.001). Within the high-dose sub-sample only, inner healer scores predicted improved depressive symptomatology at 2 weeks post-dosing. Conclusions: The principle of activating inner healing mechanisms via psychedelics is scientifically nascent; however, this study takes a positivist and pragmatic step forward, asking whether it warrants further examination.” Authors: Joseph Peill, Miriam Marguilho, David Erritzoe, Tommaso Barba, Kyle T Greenway, Fernando Rosas, Christopher Timmermann & Robin Carhart-Harris Read the Full Article

Abstract “Background: There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling. Aims: Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes. Methods: Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. Results/outcomes: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found. Conclusion: Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.” Authors: David Erritzoe, Tommaso Barba, Meg J. Spriggs, Fernando E. Rosas, David J. Nutt & Robin L. Carhart-Harris Read the Full Article

Abstract “Background: There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling. Aims: Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes. Methods: Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. Results/outcomes: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found. Conclusion: Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.” Authors: David Erritzoe, Tommaso Barba, Meg J. Spriggs, Fernando E. Rosas, David J. Nutt & Robin L. Carhart-Harris Read the Full Article

Abstract “Background: Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period. Methods: Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466). Findings: Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge’s g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline. Conclusions: PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity. Funding: This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.” Authors: Joshua D. Rosenblat, Shakila Meshkat, Zoe Doyle, Erica Kaczmarek, Ryan M. Brudner, Kevin Kratiuk, Rodrigo B. Mansur, Christian Schulz-Quach, Rickinder Sethi, Amanda Abate, Shaun Ali, Jordan Bawks, Marc G. Blainey, Elisa Brietzke, Victoria Cronin, Jessica Danilewitz, Shalini Dhawan, Anthony Di Fonzo, Melissa Di Fonzo, Pawel Drzadzewski, William Dunlop, Hajnalka Fiszter, Fabiano A. Gomes, Smrita Grewal, Marisa Leon-Carlyle, Marilyn McCallum, Niki Mofidi, Hilary Offman, Jeremy Riva-Cambrin, Joel Schmidt, Mark Smolkin, Joan M. Quinn, Andrea Zumrova, Michelle Marlborough & Roger S. McIntyre Read the Full Article

Abstract “Background: Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period. Methods: Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466). Findings: Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge’s g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline. Conclusions: PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity. Funding: This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.” Authors: Joshua D. Rosenblat, Shakila Meshkat, Zoe Doyle, Erica Kaczmarek, Ryan M. Brudner, Kevin Kratiuk, Rodrigo B. Mansur, Christian Schulz-Quach, Rickinder Sethi, Amanda Abate, Shaun Ali, Jordan Bawks, Marc G. Blainey, Elisa Brietzke, Victoria Cronin, Jessica Danilewitz, Shalini Dhawan, Anthony Di Fonzo, Melissa Di Fonzo, Pawel Drzadzewski, William Dunlop, Hajnalka Fiszter, Fabiano A. Gomes, Smrita Grewal, Marisa Leon-Carlyle, Marilyn McCallum, Niki Mofidi, Hilary Offman, Jeremy Riva-Cambrin, Joel Schmidt, Mark Smolkin, Joan M. Quinn, Andrea Zumrova, Michelle Marlborough & Roger S. McIntyre Read the Full Article

Abstract "This pilot study investigated psilocybin-induced changes in neural reactivity to alcohol and emotional cues in patients with alcohol use disorder (AUD). Participants were recruited from a phase II, randomized, double-blind, placebo-controlled clinical trial investigating psilocybin-assisted therapy (PAT) for the treatment of AUD (NCT02061293). Eleven adult patients completed task-based blood oxygen dependent functional magnetic resonance imaging (fMRI) approximately 3 days before and 2 days after receiving 25 mg of psilocybin (n = 5) or 50 mg of diphenhydramine (n = 6). Visual alcohol and emotionally valanced (positive, negative, or neutral) stimuli were presented in block design. Across both alcohol and emotional cues, psilocybin increased activity in the medial and lateral prefrontal cortex (PFC) and left caudate, and decreased activity in the insular, motor, temporal, parietal, and occipital cortices, and cerebellum. Unique to negative cues, psilocybin increased supramarginal gyrus activity; unique to positive cues, psilocybin increased right hippocampus activity and decreased left hippocampus activity. Greater PFC and caudate engagement and concomitant insula, motor, and cerebellar disengagement suggests enhanced goal-directed action, improved emotional regulation, and diminished craving. The robust changes in brain activity observed in this pilot study warrant larger neuroimaging studies to elucidate neural mechanisms of PAT.” Authors: Broc A. Pagni, Petros D. Petridis, Samantha K. Podrebarac, Jack Grinband, E. D. Claus & Michael P. Bogenschutz Read the Full Article

Abstract "This pilot study investigated psilocybin-induced changes in neural reactivity to alcohol and emotional cues in patients with alcohol use disorder (AUD). Participants were recruited from a phase II, randomized, double-blind, placebo-controlled clinical trial investigating psilocybin-assisted therapy (PAT) for the treatment of AUD (NCT02061293). Eleven adult patients completed task-based blood oxygen dependent functional magnetic resonance imaging (fMRI) approximately 3 days before and 2 days after receiving 25 mg of psilocybin (n = 5) or 50 mg of diphenhydramine (n = 6). Visual alcohol and emotionally valanced (positive, negative, or neutral) stimuli were presented in block design. Across both alcohol and emotional cues, psilocybin increased activity in the medial and lateral prefrontal cortex (PFC) and left caudate, and decreased activity in the insular, motor, temporal, parietal, and occipital cortices, and cerebellum. Unique to negative cues, psilocybin increased supramarginal gyrus activity; unique to positive cues, psilocybin increased right hippocampus activity and decreased left hippocampus activity. Greater PFC and caudate engagement and concomitant insula, motor, and cerebellar disengagement suggests enhanced goal-directed action, improved emotional regulation, and diminished craving. The robust changes in brain activity observed in this pilot study warrant larger neuroimaging studies to elucidate neural mechanisms of PAT.” Authors: Broc A. Pagni, Petros D. Petridis, Samantha K. Podrebarac, Jack Grinband, E. D. Claus & Michael P. Bogenschutz Read the Full Article

Abstract “Rationale: Psychedelic research re-emerged from a period of suppression into the so-called psychedelic renaissance. In parallel, most media reporting has shifted from the overstatement of the risks of psychedelics to overly positive hype. As the empirical evidence is more equivocal than frequently portrayed, the conclusions about the effectiveness of psychedelics should be considered preliminary. Poor science communication about psychedelics’ therapeutic potential may lead potential participants or patients to feel misled and policy decisions to be misinformed. An evidence-informed characterization of their risks and benefits is needed. Objectives: This article assesses the state of psychedelic research for treating depression and the effect sizes of psychedelics on therapeutic outcomes, the risk of bias, and the prevalence of adverse effects. We review research on the risks and benefits of psychedelics and discuss how the following depression treatments have shown decreasing effect sizes over time: (1) cognitive behavioral therapy, (2) mindfulness interventions, (3) selective serotonin reuptake inhibitors, and (4) ketamine. We speculate that a similar trend may occur for psychedelic treatments. Results and conclusions: It is likely that larger and better-controlled psychedelic trials will demonstrate smaller effect sizes that are more comparable to other conventional and emerging treatments for mood disorders. Clear science communication is critical for setting public expectations and psychedelic policy. With this evidence-based assessment, we aim to cut through the misinformation about the benefits, risks, and future prospects of psychedelic treatments.” Authors: Daniel Meling, Rebecca Ehrenkranz, Sandeep M. Nayak, Helena D. Aicher, Xaver Funk, Michiel van Elk, Marianna Graziosi, Prisca R. Bauer, Milan Scheidegger & David B. Yaden Read the Full Article

Abstract “Background: Reference to an intrinsic healing mechanism or an ‘inner healer’ is commonplace amongst psychedelic drug-using cultures. The ‘inner healer’ refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical body, for example, after sickness or injury. Aims: Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived ‘inner healing’ effects. Methods: The item was issued to 59 patients after a single high (25 mg, n = 30) or ‘placebo’ (1 mg, n = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression. Results: Inner healer scores were higher after the high versus placebo dose of psilocybin (t = 3.88, p < 0.001). Within the high-dose sub-sample only, inner healer scores predicted improved depressive symptomatology at 2 weeks post-dosing. Conclusions: The principle of activating inner healing mechanisms via psychedelics is scientifically nascent; however, this study takes a positivist and pragmatic step forward, asking whether it warrants further examination.” Authors: Joseph Peill, Miriam Marguilho, David Erritzoe, Tommaso Barba, Kyle T Greenway, Fernando Rosas, Christopher Timmermann & Robin Carhart-Harris Read the Full Article

Abstract “Background: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. Methods: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. Results: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d’ = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. Discussion: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment.” Authors: Emmanuelle A. D. Schindler, R. Andrew Sewell, Christopher H. Gottschalk, L. Taylor Flynn, Yutong Zhu, Brian P. Pittman, Nicholas V. Cozzi & Deepak C. D’Souza Read the Full Article

Abstract “Introduction: We investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. Material and methods: Patients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. Results: Twenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (−5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01). Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. Discussion: Our results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.” Authors: M. Colla, B. Offenhammer, H. Scheerer, G. Kronenberg, S. Vetter, J. Mutschler, T. Mikoteit, A. Bankwitz, A. Adank, L. Schaekel, C. Eicher, A.B. Brühl & E. Seifritz Read the Full Article

Abstract “Introduction: We investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. Material and methods: Patients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. Results: Twenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (−5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01). Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. Discussion: Our results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.” Authors: M. Colla, B. Offenhammer, H. Scheerer, G. Kronenberg, S. Vetter, J. Mutschler, T. Mikoteit, A. Bankwitz, A. Adank, L. Schaekel, C. Eicher, A.B. Brühl & E. Seifritz Read the Full Article

Abstract “Background: Ketamine and esketamine offer a novel approach in the pharmacological treatment of major depressive disorder (MDD). This meta-analysis aimed to investigate the placebo response in double-blind, randomized controlled studies (RCTs) on patients with MDD receiving ketamine or esketamine. Methods: For this systematic review and meta-analysis Medline (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), PsycInfo and Embase databases were systematically searched for citations published up to March 17, 2023. A total number of 5017 abstracts was identified. Quality of the included trials was assessed with the Cochrane risk-of-bias tool. The meta-analysis was performed using a restricted maximum likelihood model. This study is registered with PROSPERO, number CRD42022377591. Results: A total number of 14 studies and 1100 participants (593 in the medication group and 507 in the placebo group) meeting the inclusion criteria were selected. We estimated the pooled effect sizes of the overall placebo (d pl = -1.85 [CI 95%: -2.9 to -0.79] and overall treatment (dtr = -2.57; [CI 95% -3.36 to -1.78]) response. The overall placebo response accounts for up to 72% of the overall treatment response. Furthermore, we performed subgroup analysis of 8 studies for the for the 7 days post-intervention timepoint. Seven days post-intervention the placebo response (d pl 7d = -1.98 [CI 95%: -3.26 to -0.69]) accounts for 66% of the treatment response (d tr 7d = – 3.01 [CI 95%, -4.28 to -1.74]). Conclusion: Ketamine and esketamine show large antidepressant effects. However, our findings suggest that the placebo response plays a significant role in the antidepressant response and should be used for the benefit of the patients in clinical practice.” Authors: Alexandros Matsingos, Marcel Wilhelm, Laila Noor, Cüneyt Yildiz, Winfried Rief, Stefan G. Hofmann, Irina Falkenberg & Tilo Kircher Read the Full Article

Abstract “Background: Ketamine and esketamine offer a novel approach in the pharmacological treatment of major depressive disorder (MDD). This meta-analysis aimed to investigate the placebo response in double-blind, randomized controlled studies (RCTs) on patients with MDD receiving ketamine or esketamine. Methods: For this systematic review and meta-analysis Medline (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), PsycInfo and Embase databases were systematically searched for citations published up to March 17, 2023. A total number of 5017 abstracts was identified. Quality of the included trials was assessed with the Cochrane risk-of-bias tool. The meta-analysis was performed using a restricted maximum likelihood model. This study is registered with PROSPERO, number CRD42022377591. Results: A total number of 14 studies and 1100 participants (593 in the medication group and 507 in the placebo group) meeting the inclusion criteria were selected. We estimated the pooled effect sizes of the overall placebo (d pl = -1.85 [CI 95%: -2.9 to -0.79] and overall treatment (dtr = -2.57; [CI 95% -3.36 to -1.78]) response. The overall placebo response accounts for up to 72% of the overall treatment response. Furthermore, we performed subgroup analysis of 8 studies for the for the 7 days post-intervention timepoint. Seven days post-intervention the placebo response (d pl 7d = -1.98 [CI 95%: -3.26 to -0.69]) accounts for 66% of the treatment response (d tr 7d = – 3.01 [CI 95%, -4.28 to -1.74]). Conclusion: Ketamine and esketamine show large antidepressant effects. However, our findings suggest that the placebo response plays a significant role in the antidepressant response and should be used for the benefit of the patients in clinical practice.” Authors: Alexandros Matsingos, Marcel Wilhelm, Laila Noor, Cüneyt Yildiz, Winfried Rief, Stefan G. Hofmann, Irina Falkenberg & Tilo Kircher Read the Full Article

Abstract “The mechanisms by which Psilocybin Therapy (PT) improves depression remain an important object of study, with scientists actively exploring acute psychological experiences and neurobiological processes as candidates. In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we investigated whether acute psychological experiences could meaningfully account for the unique efficacy of PT versus Escitalopram Treatment over a core 6-week trial period. An exploratory-factor-analysis-derived single-factor of depression was used as the outcome. Among a comprehensive set of acute experiences related to psilocybin, so-called “mystical experience” and “ego dissolution” were unique in mediating the effect of treatment condition on depressive response with high specificity. Higher reported levels of mystical experience, emotional breakthrough, and intense responses to music-listening were furthermore associated with greater antidepressant response. These results provide qualified support for the causal mechanistic role of acute psychological experiences in the treatment of depression via PT.” Authors: Brandon Weiss, Leor Roseman, Bruna Giribaldi, David J. Nutt, Robin L. Carhart-Harris & David Erritzoe Read the Full Article

Abstract “The mechanisms by which Psilocybin Therapy (PT) improves depression remain an important object of study, with scientists actively exploring acute psychological experiences and neurobiological processes as candidates. In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we investigated whether acute psychological experiences could meaningfully account for the unique efficacy of PT versus Escitalopram Treatment over a core 6-week trial period. An exploratory-factor-analysis-derived single-factor of depression was used as the outcome. Among a comprehensive set of acute experiences related to psilocybin, so-called “mystical experience” and “ego dissolution” were unique in mediating the effect of treatment condition on depressive response with high specificity. Higher reported levels of mystical experience, emotional breakthrough, and intense responses to music-listening were furthermore associated with greater antidepressant response. These results provide qualified support for the causal mechanistic role of acute psychological experiences in the treatment of depression via PT.” Authors: Brandon Weiss, Leor Roseman, Bruna Giribaldi, David J. Nutt, Robin L. Carhart-Harris & David Erritzoe Read the Full Article

Abstract “We examined if the therapeutic alliance between study participants and intervention facilitators in a psilocybin-assisted therapy (PAT) trial changed over time and whether there were relationships between alliance, acute psilocybin experiences, and depression outcomes. In a randomized, waiting list-controlled clinical trial for major depressive disorder in adults (N = 24), participants were randomized to an immediate (N = 13) or delayed (N = 11) condition with two oral doses of psilocybin (20mg/70kg and 30mg/70kg). Ratings of therapeutic alliance significantly increased from the final preparation session to one-week post-intervention (p = .03, d = .43). A stronger total alliance at the final preparation session predicted depression scores at 4 weeks (r = -.65, p = .002), 6 months (r = -.47, p = .036), and 12 months (r = -.54, p = .014) post-intervention. A stronger total alliance in the final preparation session was correlated with higher peak ratings of mystical experiences (r = .49, p = .027) and psychological insight (r = .52, p = .040), and peak ratings of mystical experience and psychological insight were correlated with depression scores at 4 weeks (r = -.45, p = .030 for mystical; r = -.75, p < .001 for insight). Stronger total alliance one week after the final psilocybin session predicted depression scores at 4 weeks (r = -.85, p < .001), 3 months (r = -.52, p = .010), 6 months (r = -.77, p < .001), and 12 months (r = -.61, p = .001) post-intervention. These findings highlight the importance of the therapeutic relationship in PAT. Future research should explore therapist and participant characteristics which maximize the therapeutic alliance and evaluate its relationship to treatment outcomes.” Authors: Adam W. Levin, Rafaelle Lancelotta, Nathan D. Sepeda, Natalie Gukasyan, Sandeep Nayak, Theodore L. Wagener, Frederick S. Barrett, Roland R. Griffiths & Alan K. Davis Read the Full Article

Abstract “We examined if the therapeutic alliance between study participants and intervention facilitators in a psilocybin-assisted therapy (PAT) trial changed over time and whether there were relationships between alliance, acute psilocybin experiences, and depression outcomes. In a randomized, waiting list-controlled clinical trial for major depressive disorder in adults (N = 24), participants were randomized to an immediate (N = 13) or delayed (N = 11) condition with two oral doses of psilocybin (20mg/70kg and 30mg/70kg). Ratings of therapeutic alliance significantly increased from the final preparation session to one-week post-intervention (p = .03, d = .43). A stronger total alliance at the final preparation session predicted depression scores at 4 weeks (r = -.65, p = .002), 6 months (r = -.47, p = .036), and 12 months (r = -.54, p = .014) post-intervention. A stronger total alliance in the final preparation session was correlated with higher peak ratings of mystical experiences (r = .49, p = .027) and psychological insight (r = .52, p = .040), and peak ratings of mystical experience and psychological insight were correlated with depression scores at 4 weeks (r = -.45, p = .030 for mystical; r = -.75, p < .001 for insight). Stronger total alliance one week after the final psilocybin session predicted depression scores at 4 weeks (r = -.85, p < .001), 3 months (r = -.52, p = .010), 6 months (r = -.77, p < .001), and 12 months (r = -.61, p = .001) post-intervention. These findings highlight the importance of the therapeutic relationship in PAT. Future research should explore therapist and participant characteristics which maximize the therapeutic alliance and evaluate its relationship to treatment outcomes.” Authors: Adam W. Levin, Rafaelle Lancelotta, Nathan D. Sepeda, Natalie Gukasyan, Sandeep Nayak, Theodore L. Wagener, Frederick S. Barrett, Roland R. Griffiths & Alan K. Davis Read the Full Article

Abstract “Psilocybin is being studied for its therapeutic potential in various mental health disorders, such as depression, anxiety, and addiction. Initial studies suggested that psilocybin is generally safe when used under controlled conditions, but more research is needed to better understand its safety profile. We report safety pharmacology data from a pooled analysis of three randomized crossover studies that included 85 healthy participants and 113 single-dose administrations of psilocybin. Single oral doses included 15 mg, 20 mg, 25 mg, and 30 mg psilocybin dihydrate. We investigated subjective effects, blood pressure, heart rate, body temperature, acute and subacute adverse effects, reports of flashbacks, and liver and kidney function before and after the studies. The 20, 25, and 30 mg doses of psilocybin produced stronger effects than the 15 mg dose. Psilocybin at all doses induced higher “good drug effects” than “bad drug effects.” Only the 25 and 30 mg doses increased anxiety. Psilocybin elevated autonomic effects only moderately. Tachycardia (>100 beats/min) was observed with 7% of all psilocybin administrations. Body temperature >38° was reached in 7%, 9%, 17%, and 32% of the participants with the 15, 20, 25, and 30 mg doses, respectively. Kidney and liver function parameters were unaltered at the end of the study. Five participants (6%) reported transient flashback phenomena. No serious adverse reactions occurred. These findings suggest that a single administration of psilocybin is safe with regard to acute psychological and physical harm in healthy participants in a controlled research setting.” Authors: Isabelle Straumann, Friederike Holze, Anna M. Becker, Laura Ley, Nepomuk Halter & Matthias E. Liechti Read the Full Article

Abstract “There are profound methodological challenges facing microdosing research. One way we can address some of these methodological issues is by understanding how psilocybin microdosing fits in the broader existential context of people’s lives. We recruited participants who underwent psilocybin microdosing on their own and consented to being monitored for harm mitigation purposes. We combined momentary ecological assessment and detailed retrospective interviews. Participants reported loosening of mental structures (i.e., less intense strength of thoughts, tangential stream of consciousness), increased salience of external stimuli (varyingly associated with greater interest in otherwise mundane activities, as well as sensory overload), an increase in flexible cognition, a decrease in stable cognition, and various ego-dystonic contents Highly structured environments were conducive to positive appraisal of experience and vice versa). Momentary ecological assessment and retrospective interviews yielded diametrically opposite accounts of microdosing experience. We relate our findings to stable and cognitive cognition, as well as the notion of salience. We point out the necessity for systematic mixed methods studies to better characterize the lived experience of psilocybin microdosing.” Authors: Aleš Oblak, Liam Korošec Hudnik, Anja Levačić, Kristian Elersič, Peter Pregelj & Jurij Bon Read the Full Article

Abstract “Individuals with major depressive disorder and treatment resistant depression (MDD-TRD) have limited and sometimes poorly tolerated therapeutic options. Low dose ketamine has presented promising and potent antidepressant effects in this population. To support the existent literature, we conducted a longitudinal study examining five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for MDD-TRD outpatients. For this study we collected demographic information, clinical scale scores, side effects and dropout data. The data was analyzed using descriptive statistics, effect size using Cohen’s D analysis, and multivariate ANOVA (MANOVA) to determine the impact of sociodemographic variables. 71 outpatients (50.28 years old, SD: 14.26; female 74.65%) were included in the analysis. The results showed a significant reduction in depressive symptoms and suicide ideation (SI) by treatment endpoint. 54.93% of patients responded to the treatment, 78.26% experienced transient and mild side effects, and 11.27% of dropped out of the treatment. Multivariate analysis showed that the demographic variables did not impact treatment effect or tolerability. The results of this study suggest that IV low dose ketamine treatment is effective, fast-acting, and well tolerated for the management of depressive symptoms and SI in patients with MDD-TRD in naturalistic clinical practice.” Authors: Gilmar Gutierrez, Melody J. Y. Kang & Gustavo Vazquez Read the Full Article

Abstract “Individuals with major depressive disorder and treatment resistant depression (MDD-TRD) have limited and sometimes poorly tolerated therapeutic options. Low dose ketamine has presented promising and potent antidepressant effects in this population. To support the existent literature, we conducted a longitudinal study examining five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for MDD-TRD outpatients. For this study we collected demographic information, clinical scale scores, side effects and dropout data. The data was analyzed using descriptive statistics, effect size using Cohen’s D analysis, and multivariate ANOVA (MANOVA) to determine the impact of sociodemographic variables. 71 outpatients (50.28 years old, SD: 14.26; female 74.65%) were included in the analysis. The results showed a significant reduction in depressive symptoms and suicide ideation (SI) by treatment endpoint. 54.93% of patients responded to the treatment, 78.26% experienced transient and mild side effects, and 11.27% of dropped out of the treatment. Multivariate analysis showed that the demographic variables did not impact treatment effect or tolerability. The results of this study suggest that IV low dose ketamine treatment is effective, fast-acting, and well tolerated for the management of depressive symptoms and SI in patients with MDD-TRD in naturalistic clinical practice.” Authors: Gilmar Gutierrez, Melody J. Y. Kang & Gustavo Vazquez Read the Full Article

Abstract “Objective: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. Methods: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity. Results: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms. Conclusions: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.” Authors: Thomas Knuijver, Rob Ter Heine, Arnt F. A. Schellekens, Paniz Heydari, Luc Lucas, Sjoerd Westra, Maarten Belgers, Toon Van Oosteren, Robbert Jan Verkes & Cornelis Kramers Read the Full Article

Abstract “Objective: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. Methods: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity. Results: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms. Conclusions: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.” Authors: Thomas Knuijver, Rob Ter Heine, Arnt F. A. Schellekens, Paniz Heydari, Luc Lucas, Sjoerd Westra, Maarten Belgers, Toon Van Oosteren, Robbert Jan Verkes & Cornelis Kramers Read the Full Article

Abstract “Challenging experiences in ayahuasca use, childhood trauma, and posttraumatic growth have not been investigated systematically. This study aimed to explore whether a self-reported history of childhood trauma was associated with challenging experiences during acute ayahuasca effects and whether such challenging experiences were associated with beneficial long-term outcomes measured by posttraumatic growth. For this study, 231 individuals (mean age 40.29, 48% women) completed an online survey about traumatic experiences in childhood, challenges during acute ayahuasca effects, and perceived benefits of those challenges. This study found that people with histories of childhood trauma were not at greater risk of adverse or challenging experiences during acute ayahuasca effects than people without histories of childhood trauma ( r = .080, p = .281, 95% CI [–.066, .223]). Additionally, there was no difference in posttraumatic growth among those who had history of childhood trauma versus those who did not ( r = –.016, p = .837, 95% CI [–.166, .135]). People who have experienced more challenges during acute ayahuasca effects did not experience more ayahuasca-related posttraumatic growth ( r = .137, p = .076, 95% CI [–.014, .281]). These findings are important, as they may indicate that childhood trauma exposure does not pose the same risk for a poor treatment response to ayahuasca, as it predicts in other forms of intervention.” Authors: Ksenia Cassidy, Cj Healy, Eva Henje & Wendy D’Andrea Read the Full Article

Abstract "About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference −6.0, 95% CI −7.71 to −4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.” Authors: Sanne Y. Smith-Apeldoorn, Jolien K. E. Veraart, Jeanine Kamphuis, Jan Spijker, Annemarie van der Meij, Antoinette D. I. van Asselt, Marije aan het Rot & Robert A. Schoevers Read the Full Article

Abstract “Objective: To evaluate the effectiveness of repeated at-home ketamine treatments for depression, generalized anxiety, and social anxiety and assess safety in terms of adverse effects and tendency towards long-term use. Methods: This retrospective analysis included patients with depression, generalized anxiety, and/or social anxiety who received ketamine treatment (delivered at-home via low-dose, sublingual lozenges) through a private telehealth provider. Data was collected between May 2022 and April 2023. The primary outcome was change in depression, generalized anxiety, and social anxiety symptoms from baseline to three follow-up time points, measured via Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Assessment (GAD-7), and Social Anxiety Disorder Severity Scale (SAD-D-10), with analysis subgroups established based on baseline diagnosis. Secondary outcomes included side effects, adverse events, long-term use, well-being improvements, and comparison of outcomes between treatment-resistant and non-resistant depression cases. Results: Of 431 patients (mean [SD] age, 43.6 [10.9] years; 49.2% women), 81 (18.8%) reported minor side effects resolving within 24 hours, and 397 concluded treatment in ≤ 6 months. Statistically significant improvement on the primary outcome was observed at all follow-ups in all three subgroups (p < 0.001). No significant differences were found between treatment-resistant and non-resistant depression outcomes. Conclusions: Repeated sublingual ketamine significantly reduced depression, generalized anxiety, and social anxiety with no major adverse events and minimal tendency towards long-term use observed. These findings prompt further exploration of ketamine as an alternative or adjunct to medications such as SSRIs and benzodiazepines to minimize response delays and dependence risk.” Authors: Lauren N. Swanson, Lila S. Jones, Jose Muñoz Aycart, Zhipeng Zhu, David M. Rabin & Taylor Kuhn Read the Full Article

Abstract "Psilocybin is the most researched classic psychedelic for Treatment-Resistant Depression (TRD). While optimizing set and setting are considered essential for efficacy and safety, patient perspectives on these aspects have rarely been investigated. To address this knowledge gap, the current paper explored the experiences of 11 TRD patients (8 women, 3 men) participating in a double-blind randomized clinical trial with a single session of oral (1, 10 or 25 mg) psilocybin treatment. After qualitative analysis, three major themes were identified: (1) challenges with trust-building and expectation management; (2) navigating the experience; and (3) the need for a more comprehensive treatment. Subthemes of the first theme include a general distrust in mental healthcare, trust in study therapists, limited time for preparation, and managing expectations. The second theme included the following subthemes: trusting to surrender, profound and overwhelming experiences, and music as a guide. The third theme addressed a desire for multiple psilocybin sessions, and challenges with sensemaking. Patients' perspectives provided important insights into potential optimization of psilocybin treatment of TRD, including individualized preparation, investment in trust-building, offering additional psilocybin sessions, providing access to sustained (psycho)therapy with trusted therapists, and personalizing treatment approaches, which may also enhance real-world adaption of these treatments." Authors: Joost J. Breeksema, Alistair Niemeijer, Erwin Krediet, Tilman Karsten, Jeanine Kamphuis, Eric Vermetten, Wim van den Brink & Robert Schoevers Read the Full Article

Abstract "About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference −6.0, 95% CI −7.71 to −4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.” Authors: Sanne Y. Smith-Apeldoorn, Jolien K. E. Veraart, Jeanine Kamphuis, Jan Spijker, Annemarie van der Meij, Antoinette D. I. van Asselt, Marije aan het Rot & Robert A. Schoevers Read the Full Article

“Objective: To evaluate the effectiveness of repeated at-home ketamine treatments for depression, generalized anxiety, and social anxiety and assess safety in terms of adverse effects and tendency towards long-term use. Methods: This retrospective analysis included patients with depression, generalized anxiety, and/or social anxiety who received ketamine treatment (delivered at-home via low-dose, sublingual lozenges) through a private telehealth provider. Data was collected between May 2022 and April 2023. The primary outcome was change in depression, generalized anxiety, and social anxiety symptoms from baseline to three follow-up time points, measured via Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Assessment (GAD-7), and Social Anxiety Disorder Severity Scale (SAD-D-10), with analysis subgroups established based on baseline diagnosis. Secondary outcomes included side effects, adverse events, long-term use, well-being improvements, and comparison of outcomes between treatment-resistant and non-resistant depression cases. Results: Of 431 patients (mean [SD] age, 43.6 [10.9] years; 49.2% women), 81 (18.8%) reported minor side effects resolving within 24 hours, and 397 concluded treatment in ≤ 6 months. Statistically significant improvement on the primary outcome was observed at all follow-ups in all three subgroups (p < 0.001). No significant differences were found between treatment-resistant and non-resistant depression outcomes. Conclusions: Repeated sublingual ketamine significantly reduced depression, generalized anxiety, and social anxiety with no major adverse events and minimal tendency towards long-term use observed. These findings prompt further exploration of ketamine as an alternative or adjunct to medications such as SSRIs and benzodiazepines to minimize response delays and dependence risk.” Authors: Lauren N. Swanson, Lila S. Jones, Jose Muñoz Aycart, Zhipeng Zhu, David M. Rabin & Taylor Kuhn Click Here to Read the Full Article

Abstract “Background: Psilocybin is a serotonergic psychedelic drug under assessment as a potential therapy for treatment-resistant and major depression. Heterogeneous treatment responses raise interest in predicting the outcome from baseline data. Methods: A machine learning pipeline was implemented to investigate baseline resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI) as a predictor of symptom severity in psilocybin monotherapy for treatment-resistant depression (16 patients administered two 5 mg capsules followed by 25 mg, separated by one week). Generalizability was tested in a sample of 22 patients who participated in a psilocybin vs. escitalopram trial for moderate-to-severe major depression (two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo vs. two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram). The analysis was repeated using both samples combined. Results: Functional connectivity of visual, default mode and executive networks predicted early symptom improvement, while the salience network predicted responders up to 24 weeks after treatment (accuracy≈0.9). Generalization performance was borderline significant. Consistent results were obtained from the combined sample analysis. Fronto-occipital and fronto-temporal coupling predicted early and late symptom reduction, respectively. Limitations: The number of participants and differences between the two datasets limit the generalizability of the findings, while the lack of a placebo arm limits their specificity. Conclusions: Baseline neurophysiological measurements can predict the outcome of psilocybin treatment for depression. Future research based on larger datasets should strive to assess the generalizability of these predictions.” Authors: Débora Copa, David Erritzoe, Bruna Giribaldi, David J. Nutt, Robin L. Carhart-Harris & Enzo Tagliazucchi Read the Full Article

Abstract "Psilocybin is the most researched classic psychedelic for Treatment-Resistant Depression (TRD). While optimizing set and setting are considered essential for efficacy and safety, patient perspectives on these aspects have rarely been investigated. To address this knowledge gap, the current paper explored the experiences of 11 TRD patients (8 women, 3 men) participating in a double-blind randomized clinical trial with a single session of oral (1, 10 or 25 mg) psilocybin treatment. After qualitative analysis, three major themes were identified: (1) challenges with trust-building and expectation management; (2) navigating the experience; and (3) the need for a more comprehensive treatment. Subthemes of the first theme include a general distrust in mental healthcare, trust in study therapists, limited time for preparation, and managing expectations. The second theme included the following subthemes: trusting to surrender, profound and overwhelming experiences, and music as a guide. The third theme addressed a desire for multiple psilocybin sessions, and challenges with sensemaking. Patients' perspectives provided important insights into potential optimization of psilocybin treatment of TRD, including individualized preparation, investment in trust-building, offering additional psilocybin sessions, providing access to sustained (psycho)therapy with trusted therapists, and personalizing treatment approaches, which may also enhance real-world adaption of these treatments." Authors: Joost J. Breeksema, Alistair Niemeijer, Erwin Krediet, Tilman Karsten, Jeanine Kamphuis, Eric Vermetten, Wim van den Brink & Robert Schoevers Read the Full Article

Abstract The mechanisms by which Psilocybin Therapy (PT) improves depression remain an important object of study, with scientists actively exploring acute psychological experiences and neurobiological processes as candidates. In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we investigated whether acute psychological experiences could meaningfully account for the unique efficacy of PT versus Escitalopram Treatment over a core 6-week trial period. An exploratory-factor-analysis-derived single-factor of depression was used as the outcome. Among a comprehensive set of acute experiences related to psilocybin, so-called "mystical experience" and "ego dissolution" were unique in mediating the effect of treatment condition on depressive response with high specificity. Higher reported levels of mystical experience, emotional breakthrough, and intense responses to music-listening were furthermore associated with greater antidepressant response. These results provide qualified support for the causal mechanistic role of acute psychological experiences in the treatment of depression via PTA growing body of research supports the importance of psychological experiences, pertaining to the acute psychoactive effects of psychedelic compounds, for subsequent positive mental health changes. The purpose of this study was to examine whether such psychological experiences measured in relation to Psilocybin Therapy (PT) could account for greater therapeutic responses. This was done in a double-blind randomized controlled trial (DB-RCT) of patients with major depressive disorder (MDD) undergoing PT versus Escitalopram Treatment (ET), the combination of escitalopram, a common selective serotonin reuptake inhibitor (SSRI), plus psychological support. The role of subjective experience is central to debates within clinical psychiatry concerning the therapeutic mechanisms of action of psychedelic therapies, and how these mechanisms may be distinctive from conventional treatments such as evidence-based psychotherapy or chronic antidepressant pharmacotherapy. Using mediational analyses and comparisons of a PT condition to a placebo (or placebo-like low-dose psilocybin) condition, two double-blind cross-over studies have previously demonstrated a significant indirect effect of acute psychedelic experience, namely, so-called "mystical experiences" (Barrett et al., 2015; Kangaslampi, 2023) on clinical outcomes (i.e., depression and anxiety related to terminal cancer) (Griffiths et al., 2016; Ross et al., 2016). The construct of mystical experience refers to states of consciousness involving (1) a sense of undifferentiated unity with a larger whole; (2) positive sentiment and mood, e.g., awe and peace; (3) ineffability; and (4) perturbations to ordinary spatio-temporal sensing. In these studies, a moderate dose of psilocybin was associated with substantially higher mystical experience scores, and patients' level of mystical experience was associated with better therapeutic response. Notably, in Griffiths et al.'s (2016) study, the indirect effect of mystical experience retained its significance while controlling for the intensity of the drug experience, suggesting some therapeutic specificity to the mystical experience itself beyond mere generic drug effects. Such mediation-based designs are considered to provide stronger mechanistic evidence because they are able to demonstrate that the mechanism is unique to the experimental condition (Hayes & Rockwood, 2017; Kazdin, 2007). In addition, moderation-based designs examining whether higher levels of acute experiences are associated with greater therapeutic response are also valuable for demonstrating mechanisms of change, as one would expect that an increased level of a genuine mechanism would accompany improved response (Kazdin, 2007). A number of studies have demonstrated such evidence. Within clinical trials, mystical experience, and a related construct, oceanic boundlessness (Studerus et al., 2010), have demonstrated moderate to large associations with multiple clinical outcomes including smoking craving (r=−0.61, Johnson et al., 2014), smoking abstinence, and depression (r=−0.41, Davis et al., 2021a, 2021b; r=−0.50, Roseman et al., 2018a, 2018b). Outside of clinical trials, the relevance of acute experiences to positive mental health outcomes post-psychedelic use has found additional support. Not only mystical experiences, but also experiences of emotional breakthrough (Roseman et al., 2019), cognitive reappraisal (Agin-Liebes et al., 2022), insight (Davis et al., 2021a, 2021b), psychological flexibility (Agin-Liebes et al., 2022; Close et al., 2020; Zeifman et al., 2020), and communitas (or experiences of perceived togetherness) (Kettner et al., 2021) have demonstrated associations with adaptive changes in negative emotionality and well-being. Indeed, evidence has been found that emotional breakthrough and psychological insight are especially strong moderators of improved mental health outcomes post-psychedelic use (Peill et al., 2022). Notwithstanding these supportive findings, some biocentric scientists aver that the acute experience may constitute epiphenomenal psychological correlates of primarily causal neuroplasticity-based reparative processes (Olson, 2020). Used to support this point of view is evidence from rodent models in which synthesized 5-HT2A receptor agonists - that are argued (but not demonstrated) to be psychoactively inert in humans - have been linked to adaptive behavioral outcomes in mice that are assumed to approximate the alleviation of internalizing symptoms in humans (Cameron et al., 2021). Previous research is indicative that psychedelic compounds stimulate neurotrophic mechanisms, including glutamaturgic cascades, leading to spinogenic neuroplasticity, or the proliferation of dendritic spines (Ly et al., 2018; Vargas et al., 2023). This viewpoint is at least plausible in view of recent Positron Emission Tomography findings showing that greater 5HT2A receptor occupancy covaries with acute subjective intensity (R2=0.35); that is, greater receptor binding could amplify therapeutic biological processes while epiphenomenally generating psychological experience (Madsen et al., 2019).Footnote1 A number of clinical scientists regard a biopsychosocial mechanistic model to be more compelling, however (Carhart-Harris & Goodwin, 2017; Kočárová et al., 2021; Yaden & Griffiths, 2020; Yaden et al., 2022), primarily noting uncertainty regarding the translation between rodent and human models (Carhart-Harris, 2023), on which the biological causation (centered) theory is based. First, some remain circumspect that head-twitch serves as a valid index of psychoactive experience in rodents, and await human trials before concluding that "non-hallucinogenic psychedelics" in fact do not elicit psychoactivity (Carhart-Harris, 2023; Nutt et al., 2022; c.f., Karst et al., 2010). Second, far smaller weight-adjusted dosages have been used in human clinical trials versus dosages associated with neuroplastic effects in rodents, raising some concern that comparable neuroplasticity-mediated psychological effects are less plausible in humans (De Vos et al., 2021). Finally, the efficacy of antidepressant pharmacology has shown significant limitations despite there being demonstrated neuroplastic mechanisms involved (Harmer et al., 2017; Tardito et al., 2006). Distinctive lipophilic-mediated intra-cellular receptor binding may account for improved neurotrophic activity from psychedelic compounds (versus serotonin), but it remains unclear whether such improvements will show meaningfully greater functional benefit (Vargas et al., 2023). In addition, propositions that biological (but not psychological) processes are capable of being "causal" ignores the strong possibility of entanglement and mutual dependency between phenomenological and physiological levels of function. The idea of dissociating psychedelic-induced biological effects from experience has been proposed, i.e., where a suppression of (psychedelic) experience but preserved anti-depressive response might be interpreted as evidence against the causal role of experience (Yaden & Griffiths, 2020). Special care must be taken with such work however, as (1) the anesthetic may suppress all of the core action of the psychedelic drug, (2) certain anesthetics have been known to produce neural plasticity and antidepressant effects themselves (Lii et al., 2023), (3) pre- and post-psychological support plus other non-pharmacological factors could confound matters given they are also known to be causal of therapeutic response, and (4) salient variables such as "blinding integrity" and "positive expectancy" should be measured in all studies if inferences are to be made on their causal contribution to outcomes (Lii et al., 2023). In humans, evidence is currently stronger for mechanistic models that accommodate a mutual dependency between psychological and physiological levels of function. Arguably the most compelling biopsychological account of the action of psychedelic therapy takes inspiration from recent functional magnetic resonance imaging findings of decreased brain network modularity after Psilocybin Therapy for depression in two independent datasets and cohorts, where the decreases correlated with improved symptom severity in both samples (Daws et al., 2022). These results that have been characterized as remediation, "flattening" or "relaxation" of overly reinforced or "canalized" attractor patterns (in the isomorphic brain and mind (Carhart-Harris et al., 2022)) have since been partially supported by another study finding a consistent relationship between decreased brain network modularity and improved mental health sub-acutely after psilocybin (Lyons et al., in review). Acute alterations in between-region connectivity consistent with decreased modularity have been linked to acute experience, such as ego dissolution, in previous work (Carhart-Harris et al., 2016; Lebedev et al., 2015). Complementing these findings, we have also seen that acute increases in the signal complexity of spontaneous brain activity recorded via electroencephalography (EEG) and indexed by the data compressibility algorithm Lempel-Ziv (LZc) - an effect that is reliable for serotonin 2A receptor agonist psychedelics and correlated with psychological measures of acute experiential richness (Schartner et al., 2017; Timmermann et al., 2023) - is significantly predictive of 1-month later improvements in generic mental health, both directly and indirectly, via a moderating role from psychological insight (Lyons et al., in review). Other research has observed altered emotional processing and modulation of amygdala response to facial affect stimuli 1 day (Roseman et al., 2018a, 2018b) and 1 week (Barrett et al., 2020) post-psilocybin. Future work is needed to examine how the psychological constructs focused on in this paper relate to these potentially important (if not fundamental) biological effects. Read the Full Article

Abstract The mechanisms by which Psilocybin Therapy (PT) improves depression remain an important object of study, with scientists actively exploring acute psychological experiences and neurobiological processes as candidates. In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we investigated whether acute psychological experiences could meaningfully account for the unique efficacy of PT versus Escitalopram Treatment over a core 6-week trial period. An exploratory-factor-analysis-derived single-factor of depression was used as the outcome. Among a comprehensive set of acute experiences related to psilocybin, so-called "mystical experience" and "ego dissolution" were unique in mediating the effect of treatment condition on depressive response with high specificity. Higher reported levels of mystical experience, emotional breakthrough, and intense responses to music-listening were furthermore associated with greater antidepressant response. These results provide qualified support for the causal mechanistic role of acute psychological experiences in the treatment of depression via PTA growing body of research supports the importance of psychological experiences, pertaining to the acute psychoactive effects of psychedelic compounds, for subsequent positive mental health changes. The purpose of this study was to examine whether such psychological experiences measured in relation to Psilocybin Therapy (PT) could account for greater therapeutic responses. This was done in a double-blind randomized controlled trial (DB-RCT) of patients with major depressive disorder (MDD) undergoing PT versus Escitalopram Treatment (ET), the combination of escitalopram, a common selective serotonin reuptake inhibitor (SSRI), plus psychological support. The role of subjective experience is central to debates within clinical psychiatry concerning the therapeutic mechanisms of action of psychedelic therapies, and how these mechanisms may be distinctive from conventional treatments such as evidence-based psychotherapy or chronic antidepressant pharmacotherapy. Using mediational analyses and comparisons of a PT condition to a placebo (or placebo-like low-dose psilocybin) condition, two double-blind cross-over studies have previously demonstrated a significant indirect effect of acute psychedelic experience, namely, so-called "mystical experiences" (Barrett et al., 2015; Kangaslampi, 2023) on clinical outcomes (i.e., depression and anxiety related to terminal cancer) (Griffiths et al., 2016; Ross et al., 2016). The construct of mystical experience refers to states of consciousness involving (1) a sense of undifferentiated unity with a larger whole; (2) positive sentiment and mood, e.g., awe and peace; (3) ineffability; and (4) perturbations to ordinary spatio-temporal sensing. In these studies, a moderate dose of psilocybin was associated with substantially higher mystical experience scores, and patients' level of mystical experience was associated with better therapeutic response. Notably, in Griffiths et al.'s (2016) study, the indirect effect of mystical experience retained its significance while controlling for the intensity of the drug experience, suggesting some therapeutic specificity to the mystical experience itself beyond mere generic drug effects. Such mediation-based designs are considered to provide stronger mechanistic evidence because they are able to demonstrate that the mechanism is unique to the experimental condition (Hayes & Rockwood, 2017; Kazdin, 2007). In addition, moderation-based designs examining whether higher levels of acute experiences are associated with greater therapeutic response are also valuable for demonstrating mechanisms of change, as one would expect that an increased level of a genuine mechanism would accompany improved response (Kazdin, 2007). A number of studies have demonstrated such evidence. Within clinical trials, mystical experience, and a related construct, oceanic boundlessness (Studerus et al., 2010), have demonstrated moderate to large associations with multiple clinical outcomes including smoking craving (r=−0.61, Johnson et al., 2014), smoking abstinence, and depression (r=−0.41, Davis et al., 2021a, 2021b; r=−0.50, Roseman et al., 2018a, 2018b). Outside of clinical trials, the relevance of acute experiences to positive mental health outcomes post-psychedelic use has found additional support. Not only mystical experiences, but also experiences of emotional breakthrough (Roseman et al., 2019), cognitive reappraisal (Agin-Liebes et al., 2022), insight (Davis et al., 2021a, 2021b), psychological flexibility (Agin-Liebes et al., 2022; Close et al., 2020; Zeifman et al., 2020), and communitas (or experiences of perceived togetherness) (Kettner et al., 2021) have demonstrated associations with adaptive changes in negative emotionality and well-being. Indeed, evidence has been found that emotional breakthrough and psychological insight are especially strong moderators of improved mental health outcomes post-psychedelic use (Peill et al., 2022). Notwithstanding these supportive findings, some biocentric scientists aver that the acute experience may constitute epiphenomenal psychological correlates of primarily causal neuroplasticity-based reparative processes (Olson, 2020). Used to support this point of view is evidence from rodent models in which synthesized 5-HT2A receptor agonists - that are argued (but not demonstrated) to be psychoactively inert in humans - have been linked to adaptive behavioral outcomes in mice that are assumed to approximate the alleviation of internalizing symptoms in humans (Cameron et al., 2021). Previous research is indicative that psychedelic compounds stimulate neurotrophic mechanisms, including glutamaturgic cascades, leading to spinogenic neuroplasticity, or the proliferation of dendritic spines (Ly et al., 2018; Vargas et al., 2023). This viewpoint is at least plausible in view of recent Positron Emission Tomography findings showing that greater 5HT2A receptor occupancy covaries with acute subjective intensity (R2=0.35); that is, greater receptor binding could amplify therapeutic biological processes while epiphenomenally generating psychological experience (Madsen et al., 2019).Footnote1 A number of clinical scientists regard a biopsychosocial mechanistic model to be more compelling, however (Carhart-Harris & Goodwin, 2017; Kočárová et al., 2021; Yaden & Griffiths, 2020; Yaden et al., 2022), primarily noting uncertainty regarding the translation between rodent and human models (Carhart-Harris, 2023), on which the biological causation (centered) theory is based. First, some remain circumspect that head-twitch serves as a valid index of psychoactive experience in rodents, and await human trials before concluding that "non-hallucinogenic psychedelics" in fact do not elicit psychoactivity (Carhart-Harris, 2023; Nutt et al., 2022; c.f., Karst et al., 2010). Second, far smaller weight-adjusted dosages have been used in human clinical trials versus dosages associated with neuroplastic effects in rodents, raising some concern that comparable neuroplasticity-mediated psychological effects are less plausible in humans (De Vos et al., 2021). Finally, the efficacy of antidepressant pharmacology has shown significant limitations despite there being demonstrated neuroplastic mechanisms involved (Harmer et al., 2017; Tardito et al., 2006). Distinctive lipophilic-mediated intra-cellular receptor binding may account for improved neurotrophic activity from psychedelic compounds (versus serotonin), but it remains unclear whether such improvements will show meaningfully greater functional benefit (Vargas et al., 2023). In addition, propositions that biological (but not psychological) processes are capable of being "causal" ignores the strong possibility of entanglement and mutual dependency between phenomenological and physiological levels of function. The idea of dissociating psychedelic-induced biological effects from experience has been proposed, i.e., where a suppression of (psychedelic) experience but preserved anti-depressive response might be interpreted as evidence against the causal role of experience (Yaden & Griffiths, 2020). Special care must be taken with such work however, as (1) the anesthetic may suppress all of the core action of the psychedelic drug, (2) certain anesthetics have been known to produce neural plasticity and antidepressant effects themselves (Lii et al., 2023), (3) pre- and post-psychological support plus other non-pharmacological factors could confound matters given they are also known to be causal of therapeutic response, and (4) salient variables such as "blinding integrity" and "positive expectancy" should be measured in all studies if inferences are to be made on their causal contribution to outcomes (Lii et al., 2023). In humans, evidence is currently stronger for mechanistic models that accommodate a mutual dependency between psychological and physiological levels of function. Arguably the most compelling biopsychological account of the action of psychedelic therapy takes inspiration from recent functional magnetic resonance imaging findings of decreased brain network modularity after Psilocybin Therapy for depression in two independent datasets and cohorts, where the decreases correlated with improved symptom severity in both samples (Daws et al., 2022). These results that have been characterized as remediation, "flattening" or "relaxation" of overly reinforced or "canalized" attractor patterns (in the isomorphic brain and mind (Carhart-Harris et al., 2022)) have since been partially supported by another study finding a consistent relationship between decreased brain network modularity and improved mental health sub-acutely after psilocybin (Lyons et al., in review). Acute alterations in between-region connectivity consistent with decreased modularity have been linked to acute experience, such as ego dissolution, in previous work (Carhart-Harris et al., 2016; Lebedev et al., 2015). Complementing these findings, we have also seen that acute increases in the signal complexity of spontaneous brain activity recorded via electroencephalography (EEG) and indexed by the data compressibility algorithm Lempel-Ziv (LZc) - an effect that is reliable for serotonin 2A receptor agonist psychedelics and correlated with psychological measures of acute experiential richness (Schartner et al., 2017; Timmermann et al., 2023) - is significantly predictive of 1-month later improvements in generic mental health, both directly and indirectly, via a moderating role from psychological insight (Lyons et al., in review). Other research has observed altered emotional processing and modulation of amygdala response to facial affect stimuli 1 day (Roseman et al., 2018a, 2018b) and 1 week (Barrett et al., 2020) post-psilocybin. Future work is needed to examine how the psychological constructs focused on in this paper relate to these potentially important (if not fundamental) biological effects. Read the Full Article

"Psychiatry is in a growth phase in which several psychedelic medicines have entered its arena with great promise. Of these, presently, ketamine is the only medicine that may be legally prescribed. We hypothesize that at subanesthetic doses, ketamine produces a unique spectrum of altered states, ranging from psychoactive to deep ego-dissolving experiences, that are intrinsic to ketamine's therapeutic effects. When these experiences are embedded in a therapeutic relationship-a setting-that fosters an amplification of the recipient's subjective consciousness, personal growth, inner healing, greater clarity, and better relationships may well ensue. While much of the literature on ketamine labels its dissociative effects as 'side effects', alteration of consciousness is a component and unavoidable 'effect' of its therapeutic impact. From its inception in the clinical trials of the 1960s, ketamine was recognized for producing dissociative, psychedelic effects on consciousness in subjects as they emerged from ketamine-induced anesthesia. Unanticipated and unintegrated, these experiences of 'emergence phenomena' were felt to be disturbing. Accordingly, such experiences have been typically labeled as dissociative side effects. However, in a conducive set and settings, these experiences have been demonstrated to be of positive use in psychiatry and psychotherapy, providing a time-out from usual states of mind to facilitate a reshaping of self-experience along with symptomatic relief. In this way, ketamine-assisted psychotherapy (KAP) offers a new potential in psychiatry and psychotherapy that is powerfully valanced toward recognizing experience, individuality, and imagination. Essential to a successful therapeutic experience and outcome with KAP is close attention to the subjective experience, its expression by the recipient and integration of the ketamine experience as a healing opportunity." Click Here to Read the Full Article

Abstract:  "Background: MDMA-assisted psychotherapy (MDMA-AP) is a combined psychotherapeutic and pharmacologic intervention that shows promise in the treatment of posttraumatic stress disorder (PTSD). Although therapeutic alliance has been established as a key predictor across psychotherapies and is emphasised within MDMA-AP treatment manuals, research has not yet examined the relationship between therapeutic alliance and MDMA-AP treatment outcomes. Objective: Examine whether therapeutic alliance predicts changes in PTSD symptoms following MDMA-AP. Method: Twenty-three individuals with chronic PTSD participated in a MDMA-AP clinical trial that included a randomised (MDMA vs. placebo) and open-label phase. The present analyses focused on participants who were administered MDMA over the course of the randomised and open-label phases (n=22). Therapeutic alliance was assessed using the Working Alliance Inventory at sessions baseline (pre-session 3) and sessions 4 and 9. PTSD symptoms were assessed using the Clinician Administered PTSD Scale and the Impact of Events Scale-Revised. Results: Controlling for baseline clinician-assessed PTSD severity, therapeutic alliance at sessions 4 and 9 (but not baseline) significantly predicted post-MDMA-AP clinician-assessed PTSD severity. Controlling for baseline self-reported PTSD severity, therapeutic alliance at baseline (although this did not survive correction for multiple comparisons) and sessions 4 and 9 predicted post-MDMA-AP self-reported PTSD severity. Conclusions: The present results provide the first preliminary evidence for the relationship between the therapeutic alliance and treatment outcomes within MDMA-AP for PTSD. These findings highlight the important role of psychotherapy, and common psychotherapeutic factors, within MDMA-AP. Replication in studies with larger and more diverse clinical samples remain necessary." Authors: Richard J. Zeifman, Hannes Kettner, Stephen Ross, Brandon Weiss, Michael C. Mithoefer, Ann T. Mithoefer & Anne C. Wagner Click Here to Read the Full Article

Abstract: "Background: PTSD is a significant mental health problem worldwide. Current evi ence-based interventions suffer various limitations. Ketamine is a novel agent that is hoped to be incrementally better than extant interventions. Objective: Several randomized control trials (RCTs) of ketamine interventions for PTSD have now been published. We sought to systematically review and meta-analyse results from these trials to evaluate preliminary evidence for ketamine's incremental benefit above-and-beyond control interventions in PTSD treatment. Results: Omnibus findings from 52 effect sizes extracted across six studies (n=221) yielded a small advantage for ketamine over control conditions at reducing PTSD symptoms (g=0.27, 95% CI=0.03, 0.51). However, bias-correction estimates attenuated this effect (adjusted g=0.20, 95%, CI=−0.08, 0.48). Bias estimates indicated smaller studies reported larger effect sizes favouring ketamine. The only consistent timepoint assessed across RCTs was 24-hours post-initial infusion. Effects at 24-hours post-initial infusion suggest ketamine has a small relative advantage over controls (g=0.35, 95% CI=0.06, 0.64). Post-hoc analyses at 24-hours post-initial infusion indicated that ketamine was significantly better than passive controls (g=0.44, 95% CI=0.03, 0.85), but not active controls (g=0.24, 95% CI=−0.30, 0.78). Comparisons one-week into intervention suggested no meaningful group differences (g=0.24, 95% CI=0.00, 0.48). No significant differences were evident for RCTs that examined effects two-weeks post initial infusion (g=0.17, 95% CI=−0.10, 0.44). Conclusions: Altogether, ketamine-for-PTSD RCTs reveal a nominal initial therapeutic advantage relative to controls. However, bias and heterogeneity appear problematic. While rapid acting effects were observed, all control agents (including saline) also evidenced rapid acting effects. We argue blind penetration to be a serious concern, and that placebo is the likely mechanism behind reported therapeutic effects." Authors: Nicholas C. Borgogna, Tyler Owen, Jacob Vaughn, David A. L. Johnson, Stephen L. Aita & Benjamin D. Hill Click Here to Read the Full Article

Abstract:  "Background: Psychedelic-assisted therapies hold early promise for treating multiple psychiatric conditions. However, absent standards for the care, teams providing psychedelic-assisted therapy pose a major roadblock to safe administration. Psychedelics often produce spiritually and existentially meaningful experiences, and spiritual health practitioners have been involved in administering psychedelic-assisted therapies in multiple settings, suggesting important qualifications for delivering these therapies. However, the roles and competencies of spiritual health practitioners in psychedelic-assisted therapies have not been described in research. Method: This study examined interviews with 15 spiritual health practitioners who have facilitated psychedelic-assisted therapy. Thematic analyses focused on their contributions, application of expertise and professional background, and roles in administering these therapies. Results: Seven themes emerged, comprising two domains: unique and general contributions. Unique contributions included: competency to work with spiritual material, awareness of power dynamics, familiarity with non-ordinary states of consciousness, holding space, and offer a counterbalance to biomedical perspectives. General contributions included use of generalizable therapeutic repertoire when conducting PAT, and contributing to interdisciplinary collaboration. Implications: Spiritual health practitioners bring unique and specific expertise to psychedelic-assisted therapy based on their training and professional experience. They are skilled at interprofessional collaboration in a way that complements other clinical team members. Psychedelic-assisted therapy teams may benefit from including spiritual health practitioners. In order to ensure rigorous standards and quality care, further efforts to delineate the roles and necessary qualifications and training of spiritual health clinicians for psychedelic-assisted therapy are needed." Authors: Caroline Peacock, Jennifer S. Mascaro, Erin Brauer, Ali J. Zarrabi, Boadie W. Dunlop, Jessica L. Maples-Keller, George H. Grant, Charles L. Raison, Fayzan Rab & Roman Palitsky. Click Here to Read the Full Article

Abstract: "Introduction N,N-Dimethyltryptamine (DMT), a naturally occurring psychedelic tryptamine contained in the indigenous ayahuasca brew has shown antidepressant effects. This Phase 2a clinical trial investigates for the first time the efficacy of isolated DMT in treatment-resistant depression (TRD). Methods Six TRD patients participated in an open-label, fixed-order, dose-escalation study, receiving a lower (15 mg) and then a higher (60 mg) dose of vaporized DMT in a single-day session. Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Patient Health Questionnaire-9 (PHQ-9) up to one-month post-dosing. Results Significant reductions in MADRS and PHQ-9 scores were noted from Day 1 to M1. The mean MADRS score variation from baseline to D7 was −22 points and −17 points at M1. PHQ-9 scores also showed significant decreases, mirroring the MADRS results. By D7, 83.33% of patients responded to treatment, with 66.67% achieving remission. At M1, 66.67% maintained response, and 50% maintained remission. Discussion The rapid onset and sustained antidepressant effects of vaporized DMT align with the paradigm of rapid-acting antidepressants to be used in the scope of interventional psychiatry. The non-invasive route and short-acting nature of DMT offer practical advantages, potentially enhancing accessibility to psychedelic treatments." Authors: Marcelo Falchi-Carvalho, Handersson Barros, Raynara Bolcont, Sophie Laborde, Isabel Wießner, Sérgio Ruschi B. Silva, Daniel Montanini, David C. Barbosa, Ewerton Teixeira, Rodrigo Florence-Vilela, Raissa Almeida, Rosana K. A. de Macedo, Flávia Arichelle, Érica J. Pantrigo, Emerson Arcoverde, Nicole Galvão-Coelho, Draulio B. Araujo & Fernanda Palhano-Fontes Click Here to Read the Full Article

Abstract: "Introduction N,N-Dimethyltryptamine (DMT), a naturally occurring psychedelic tryptamine contained in the indigenous ayahuasca brew has shown antidepressant effects. This Phase 2a clinical trial investigates for the first time the efficacy of isolated DMT in treatment-resistant depression (TRD). Methods Six TRD patients participated in an open-label, fixed-order, dose-escalation study, receiving a lower (15 mg) and then a higher (60 mg) dose of vaporized DMT in a single-day session. Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Patient Health Questionnaire-9 (PHQ-9) up to one-month post-dosing. Results Significant reductions in MADRS and PHQ-9 scores were noted from Day 1 to M1. The mean MADRS score variation from baseline to D7 was −22 points and −17 points at M1. PHQ-9 scores also showed significant decreases, mirroring the MADRS results. By D7, 83.33% of patients responded to treatment, with 66.67% achieving remission. At M1, 66.67% maintained response, and 50% maintained remission. Discussion The rapid onset and sustained antidepressant effects of vaporized DMT align with the paradigm of rapid-acting antidepressants to be used in the scope of interventional psychiatry. The non-invasive route and short-acting nature of DMT offer practical advantages, potentially enhancing accessibility to psychedelic treatments." Authors: Marcelo Falchi-Carvalho, Handersson Barros, Raynara Bolcont, Sophie Laborde, Isabel Wießner, Sérgio Ruschi B. Silva, Daniel Montanini, David C. Barbosa, Ewerton Teixeira, Rodrigo Florence-Vilela, Raissa Almeida, Rosana K. A. de Macedo, Flávia Arichelle, Érica J. Pantrigo, Emerson Arcoverde, Nicole Galvão-Coelho, Draulio B. Araujo & Fernanda Palhano-Fontes Click Here to Read the Full Article

Abstract: "Introduction Intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS) are effective in the acute treatment of Treatment-Resistant Depression (TRD). Studies comparing KET-IV and ESK-NS concerning their action, safety, and tolerability are currently lacking. Materials and methods We combined patients' data from two unipolar TRD cohorts that received KET-IV (n=171) at the Canadian Rapid Treatment Center of Excellence in Toronto, Canada, or ESK-NS (n=140) at several TRD clinics in Italy. The Quick Inventory for Depression Symptomatology-Self-Report-16/QIDS-SR16 in the KET-IV group and Montgomery-Ã…sberg Depression Rating Scale/MADRS in the ESK-NS group measured depressive symptoms at baseline (T0) and after the acute treatment phase (T1) (i.e., four infusions of KET-IV and eight administrations of ESK-NS). As different scales were used, the primary outcome was to compare the improvement in depression severity in the two cohorts by measuring effect sizes, response and remission rates. Finally, we compare side effects and discontinuation rates. Results At T1, KET-IV and ESK-NS significantly reduced depressive symptoms (respectively: QIDS-SR16 mean reduction=5.65, p<0.001; MADRS mean reduction=11.41, p=0.025). KET-IV showed larger effect sizes compared to ESK-NS (1.666 vs. 1.244). KET-IV had higher response rates (36% vs. 25%; p=0.042) but not superior remission rates (13% vs. 12%; p=0.845) than ESK-NS at T1. Despite more reported side effects, KET-IV did not cause more discontinuations for adverse events (4.6% vs. 2.12%; p=0.228) than ESK-NS. Conclusion KET-IV showed a higher short-term antidepressant effect, whereas ESK-NS exhibited lower side effects. Both were generally well tolerated. Future head-to-head studies should consider the long-term efficacy of these treatments." Authors: Giacomo d'Andrea, Mauro Pettorruso, Giorgio Di Lorenzo, Taeho Greg Rhee, Stefania Chiappini, Rosalba Carullo, Stefano Barlati, Raffaella Zanardi, Gianluca Rosso, Marco Di Nicola, Ileana Andriola, Matteo Marcatili, Massimo Clerici, Bernardo Maria Dell'Osso, Stefano L. Sensi, Rodrigo B. Mansur, Joshua D. Rosenblat, Giovanni Martinotti, Roger S. McIntyre Click Here to Read the Full Article

Abstract: "Introduction Intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS) are effective in the acute treatment of Treatment-Resistant Depression (TRD). Studies comparing KET-IV and ESK-NS concerning their action, safety, and tolerability are currently lacking. Materials and methods We combined patients' data from two unipolar TRD cohorts that received KET-IV (n=171) at the Canadian Rapid Treatment Center of Excellence in Toronto, Canada, or ESK-NS (n=140) at several TRD clinics in Italy. The Quick Inventory for Depression Symptomatology-Self-Report-16/QIDS-SR16 in the KET-IV group and Montgomery-Ã…sberg Depression Rating Scale/MADRS in the ESK-NS group measured depressive symptoms at baseline (T0) and after the acute treatment phase (T1) (i.e., four infusions of KET-IV and eight administrations of ESK-NS). As different scales were used, the primary outcome was to compare the improvement in depression severity in the two cohorts by measuring effect sizes, response and remission rates. Finally, we compare side effects and discontinuation rates. Results At T1, KET-IV and ESK-NS significantly reduced depressive symptoms (respectively: QIDS-SR16 mean reduction=5.65, p<0.001; MADRS mean reduction=11.41, p=0.025). KET-IV showed larger effect sizes compared to ESK-NS (1.666 vs. 1.244). KET-IV had higher response rates (36% vs. 25%; p=0.042) but not superior remission rates (13% vs. 12%; p=0.845) than ESK-NS at T1. Despite more reported side effects, KET-IV did not cause more discontinuations for adverse events (4.6% vs. 2.12%; p=0.228) than ESK-NS. Conclusion KET-IV showed a higher short-term antidepressant effect, whereas ESK-NS exhibited lower side effects. Both were generally well tolerated. Future head-to-head studies should consider the long-term efficacy of these treatments." Authors: Giacomo d'Andrea, Mauro Pettorruso, Giorgio Di Lorenzo, Taeho Greg Rhee, Stefania Chiappini, Rosalba Carullo, Stefano Barlati, Raffaella Zanardi, Gianluca Rosso, Marco Di Nicola, Ileana Andriola, Matteo Marcatili, Massimo Clerici, Bernardo Maria Dell'Osso, Stefano L. Sensi, Rodrigo B. Mansur, Joshua D. Rosenblat, Giovanni Martinotti, Roger S. McIntyre Click Here to Read the Full Article

Maria Helha Fernandes-Nascimento, André Brooking Negrão, Karine Viana Ferreira, Bruno Daniel Rasmussen Chaves & Yuan-Pang Wang (2023) Three Decades of Research on the Development of Ibogaine Treatment of Substance Use Disorders: A Scientometric Analysis, Journal of Psychoactive Drugs, DOI: https://doi.org/10.1080/02791072.2023.2276230 Abstract:  "Ibogaine is a natural psychoactive drug that has been investigated for its potential role in the treatment of substance use disorders since the mid-1960s. To evaluate the interest in ibogaine's use as a therapeutic agent, we performed a scientometric analysis covering the last three decades (1993-2002, 2003-2012, and 2013-2022). A complementary analysis was performed to select and describe published clinical trials and meta-analyses. A total of 1523 references were found. Linear growth of publications in the first and third decades were identified, and the average number of publications from 1993 to 2002 was lower than that in the other two decades. Researchers from five continents were identified. Globally, academic research centers in the United States and Canada were the most productive. Cocaine, tobacco, morphine, and alcohol prevailed as major keywords in the first two decades and opioids and psychedelics were included in the third decade. A few key authors were the most co-referenced. One preclinical meta-analysis and no meta-analysis in humans were found. Research trends for ibogaine are widespread, growing, and consonant with current attentiveness in drug abuse. Our findings support the pressing need for rigorous clinical research on ibogaine to evaluate its efficacy and safety." Click Here to Read the Full Article

Maria Helha Fernandes-Nascimento, André Brooking Negrão, Karine Viana Ferreira, Bruno Daniel Rasmussen Chaves & Yuan-Pang Wang (2023) Three Decades of Research on the Development of Ibogaine Treatment of Substance Use Disorders: A Scientometric Analysis, Journal of Psychoactive Drugs, DOI: https://doi.org/10.1080/02791072.2023.2276230 Abstract:  "Ibogaine is a natural psychoactive drug that has been investigated for its potential role in the treatment of substance use disorders since the mid-1960s. To evaluate the interest in ibogaine's use as a therapeutic agent, we performed a scientometric analysis covering the last three decades (1993-2002, 2003-2012, and 2013-2022). A complementary analysis was performed to select and describe published clinical trials and meta-analyses. A total of 1523 references were found. Linear growth of publications in the first and third decades were identified, and the average number of publications from 1993 to 2002 was lower than that in the other two decades. Researchers from five continents were identified. Globally, academic research centers in the United States and Canada were the most productive. Cocaine, tobacco, morphine, and alcohol prevailed as major keywords in the first two decades and opioids and psychedelics were included in the third decade. A few key authors were the most co-referenced. One preclinical meta-analysis and no meta-analysis in humans were found. Research trends for ibogaine are widespread, growing, and consonant with current attentiveness in drug abuse. Our findings support the pressing need for rigorous clinical research on ibogaine to evaluate its efficacy and safety." Click Here to Read the Full Article

Abstract:  "Rationale: Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for mental health conditions, such as substance use disorders and depression. The current model for PAP emphasizes the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical study concerning the "psychotherapy" in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered.Objectives: As clinical trials for psychedelic compounds begin the transition from demonstrating safety and feasibility to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and ensure safety.Results: The present paper first reviews the current status of psychotherapy in the PAP literature, overviewing both published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments, identifying mechanisms of change, and optimizing clinical trial designs. Throughout this review, we underscore the need for increased research on the psychotherapeutic component of treatment in PAP.Conclusions: PAP is a highly unique and transdisciplinary intervention, and future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration." Click Here to Read the Full Paper

Abstract: Post-traumatic stress disorder (PTSD) is a debilitating mental health disorder that causes significant dysfunction in individuals. Currently, there are many approved pharmacotherapy and psychotherapy treatment options for PTSD, but unfortunately, half of the patients do not respond to traditional therapies. In this article, we review clinical trials and research on 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in PTSD patients, its pharmacokinetics, and current treatment guidelines for PTSD. Our findings are based on the results of the efficacy of MDMA-assisted psychotherapy from six phase II randomized controlled trials. MDMA-assisted psychotherapy for PTSD has received the "breakthrough therapy" designation from the FDA. MDMA can reduce PTSD symptoms even in treatment-resistant cases by increasing certain neurohormones, i.e., dopamine, serotonin, norepinephrine, and oxytocin. It also modulates activities in the brain regions involved in fear and anxiety. Future research is needed to show whether the advantages outweigh the disadvantages and whether its use can be integrated into available treatment options for PTSD. Click Here to Read the Full Article Riaz K, Suneel S, Hamza Bin Abdul Malik M, Kashif T, Ullah I, Waris A, Di Nicola M, Mazza M, Sani G, Martinotti G, et al. MDMA-Based Psychotherapy in Treatment-Resistant Post-Traumatic Stress Disorder (PTSD): A Brief Narrative Overview of Current Evidence. Diseases. 2023; 11(4):159. https://doi.org/10.3390/diseases11040159

Abstract:  "Eating disorders (EDs) are difficult conditions to resolve, necessitating novel treatments. Ayahuasca, a psychedelic plant medicine originating in Indigenous Amazonian communities, is being investigated. Aspects of ceremonial ayahuasca use (purging, dietary restrictions) appear similar to ED behaviors, raising questions about ayahuasca's suitability as an intervention for individuals with EDs. This study explored the perspectives of ayahuasca ceremony leaders on these and other considerations for ceremonial ayahuasca drinking among individuals with EDs. A qualitative content analysis of interviews was undertaken with 15 ayahuasca ceremony leaders, the majority of whom were from the West/Global North. Screening for EDs, purging and dietary restrictions, potential risks and dangers, and complementarity with conventional ED treatment emerged as categories. The findings offer ideas, including careful screening and extra support, to promote safe and beneficial ceremony experiences for ceremony participants with EDs. More research is needed to clarify the impacts of ceremony-related purging and preparatory diets. To evolve conventional models of treatment, the ED field could consider Indigenous approaches to mental health whereby ayahuasca ceremony leaders and ED researchers and clinicians collaborate in a decolonizing, bidirectional bridging process between Western and Indigenous paradigms of healing." Authors: Meris Williams, Annie Kingston Miller & Adele Lafrance Meris Williams, Annie Kingston Miller & Adele Lafrance (2023) Ayahuasca ceremony leaders' perspectives on special considerations for eating disorders, Eating Disorders, DOI: https://doi.org/10.1080/10640266.2023.2271201 Click Here to Read the Full Article

Abstract: "The growing interest in and prevalence of the use of psychedelics, as well as the potential benefits and negative consequences associated with psychedelic experiences, create a need for mental health specialists to be able to provide adequate and effective intervention regarding the content and consequences of these experiences, that is, psychedelic integration. At the same time, current graduate training in psychiatry, psychology, psychotherapy, counseling, etc., fails to adequately prepare professionals for such interventions. In order to fill this gap, an international, bottom-up project was established to attempt developing guidelines. This project was conducted by means of literature reviews as well as roundtable discussions among project participants, leading to a consensus on the guidelines' final scope and content. Drawing from the outcomes of this project, this article presents proposed comprehensive guidelines covering both theoretical and practical aspects of psychedelic integration, that are intended to serve as a resource for various mental health specialists who may encounter individuals in need of support considering their psychedelic experiences. These guidelines encompass clinician-friendly information on the effects of psychedelics, a definition of psychedelic integration, the general theoretical considerations linked to utilization of psychedelic experiences in clinical practice, a simple model organizing the course of psychedelic integration practice, as well as an overview of the current models of psychedelic integration, along with a selective presentation of basic and specific interventions derived from various psychotherapeutic approaches that can be employed in the practice of psychedelic integration." Authors: Jakub GreÅ„, Filip TylÅ¡, MichaÅ‚ Lasocik & Csaba Kiraly Click Here to Read the Full Article

Abstract: "Introduction Serotonergic psychedelics such as ayahuasca are reported to promote both structural and functional neural plasticity via partial 5-HT2A agonism. However, little is known about how these molecular mechanisms may extend to repeated psychedelic administration in humans, let alone neuroanatomy. While early evidence suggests localised changes to cortical thickness in long-term ayahuasca users, it is unknown how such findings may be reflected by large-scale anatomical brain networks comprising cytoarchitecturally complex regions. Methods Here, we examined the relationship between cortical gene expression markers of psychedelic action and brain morphometric change following repeated ayahuasca usage, using high-field 7 Tesla neuroimaging data derived from 24 members of an ayahuasca-using church (Santo Daime) and case-matched controls. Results Using a morphometric similarity network (MSN) analysis, repeated ayahuasca use was associated with a spatially distributed cortical patterning of both structural differentiation in sensorimotor areas and de-differentiation in transmodal areas. Cortical MSN remodelling was found to be spatially correlated with dysregulation of 5-HT2A gene expression as well as a broader set of genes encoding target receptors pertinent to ayahuasca's effects. Furthermore, these associations were similarly interrelated with altered gene expression of specific transcriptional factors and immediate early genes previously identified in preclinical assays as relevant to psychedelic-induced neuroplasticity. Conclusion Taken together, these findings provide preliminary evidence that the molecular mechanisms of psychedelic action may scale up to a macroscale level of brain organisation in vivo. Closer attention to the role of cortical transcriptomics in structural-functional coupling may help account for the behavioural differences observed in experienced psychedelic users." Authors: Pablo Mallaroni, Natasha L. Mason, Lilian Kloft, Johannes T. Reckweg, Kim van Oorsouw & Johannes G. Ramaekers Mallaroni, P., Mason, N. L., Kloft, L., Reckweg, J. T., Van Oorsouw, K., & Ramaekers, J. G. (2023). Cortical structural differences following repeated ayahuasca use hold molecular signatures. Frontiers in Neuroscience, 17. Click Here to Read the Full Article

Abstract: IntroductionSexual health, an integral component of overall well-being, is frequently compromised by common yet underdiagnosed sexual dysfunctions. Traditional interventions encompass pharmaceutical and psychological treatments. Unconventional therapies, like MDMA, offer hope for sexual dysfunction. This review delves into MDMA's effects on sexual responsiveness and its potential role in treating sexual dysfunction.ObjectivesThe purpose of this review is to elucidate effects of MDMA on different domains of the female and male sexual response cycles.MethodsWe conducted a systematic review on the effects of MDMA on each domain of the female and male sexual response cycles. PubMed, MEDLINE, and EMBASE were queried, and results were screened using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search terms utilized were "MDMA" or "ecstasy" in combination with "desire," "arousal," "lubrication," "orgasm," "pleasure," "libido," "erection," and "ejaculation." Inclusion criteria for this review were MDMA use by study subjects and sexual outcomes in at least 1 domain of the female and/or male sexual response cycles were described and measured. Randomized controlled trials, cohort studies (both prospective and retrospective), surveys, and literature reviews published between January 2000 and June 2022 were included. Case reports and studies that did not address conditions of interest were excluded from analysis. Duplicated search results were screened out. The remaining studies were then read in full text to ensure they met inclusion and exclusion criteria for analysis.ResultsWe identified 181 studies, of which 6 met criteria for assessment of the female sexual response cycle and 8 met criteria for assessment of the male sexual response cycle. Four of 6 studies reported increased sexual desire with MDMA use among women. Arousal and lubrication were improved with MDMA use in 3 of 4 studies, but they were not affected in 1 randomized control study. In men, 7 studies evaluated the effects of MDMA on desire and/or arousal, 5 studies measured impact on erection, 3 on orgasm, and 2 on ejaculation. Sixty percent of interview-based studies reported increased sexual desire in men, while 40% reported mixed or no effect. Two studies reported impairment of erection, 2 reported mixed effects, and 1 reported fear of erection impairment. In both men and women, all studies evaluating orgasm reported delay in achieving orgasm but increased intensity and pleasure if achieved. Primary outcome measures were variable and largely qualitative.ConclusionOur findings suggest that MDMA generally increases sexual desire and intensifies orgasm when achieved. While producing conflicting evidence on sexual arousal in both sexes, MDMA may impair erectile and ejaculatory function in men.Ava Wexler, Alexandra Dubinskaya, Julie Suyama, Barry R Komisaruk, Jennifer Anger, Karyn Eilber, Does MDMA have treatment potential in sexual dysfunction? A systematic review of outcomes across the female and male sexual response cycles, Sexual Medicine Reviews, 2023;, qead046, https://doi.org/10.1093/sxmrev/qead046Click Here to Read the Full Article

Abstract: "In this paper, the case study of ketamine as a new treatment for severe depression is used to outline the challenges of repurposing established medicines and we suggest potential solutions. The antidepressant effects of generic racemic ketamine were identified over 20years ago, but there were insufficient incentives for commercial entities to pursue its registration, or support for non-commercial entities to fill this gap. As a result, the evaluation of generic ketamine was delayed, piecemeal, uncoordinated, and insufficient to gain approval. Meanwhile, substantial commercial investment enabled the widespread registration of a patented, intranasal s-enantiomeric ketamine formulation (Spravato®) for depression. However, Spravato is priced at $600-$900/dose compared to ~$5/dose for generic ketamine, and the ~AUD$100 million annual government investment requested in Australia (to cover drug costs alone) has been rejected twice, leaving this treatment largely inaccessible for Australian patients 2years after Therapeutic Goods Administration approval. Moreover, emerging evidence indicates that generic racemic ketamine is at least as effective as Spravato, but no comparative trials were required for regulatory approval and have not been conducted. Without action, this story will repeat regularly in the next decade with a new wave of psychedelic-assisted psychotherapy treatments, for which the original off-patent molecules could be available at low-cost and reduce the overall cost of treatment. Several systemic reforms are required to ensure that affordable, effective options become accessible; these include commercial incentives, public and public-private funding schemes, reduced regulatory barriers and more coordinated international public funding schemes to support translational research." Authors: Anthony Rodgers, Dilara Bahceci, Christopher G. Davey, Mary Lou Chatterton, Nick Glozier, Malcolm Hopwood & Colleen Loo Click Here to Read the Full Article

Abstract: "Background In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. Methods In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Ã…sberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. Results Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P=0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. Conclusions In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8." Authors: Andreas Reif, Istvan Bitter, Jozefien Buyze, Kerstin Cebulla, Richard Frey, Dong-Jing Fu, Tetsuro Ito, Yerkebulan Kambarov, Pierre-Michel Llorca, Albino J. Oliveira-Maia, Thomas Messer & Siobhán Mulhern-Haughey Click Here to Read the Full Article

Abstract: "Background In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. Methods In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Ã…sberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. Results Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P=0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. Conclusions In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8." Authors: Andreas Reif, Istvan Bitter, Jozefien Buyze, Kerstin Cebulla, Richard Frey, Dong-Jing Fu, Tetsuro Ito, Yerkebulan Kambarov, Pierre-Michel Llorca, Albino J. Oliveira-Maia, Thomas Messer & Siobhán Mulhern-Haughey Click Here to Read the Full Article

Abstract: "Introduction: Predictors of treatment response to intravenous ketamine remain unclear in patients with treatment-resistant depression (TRD); therefore, this study aimed to clarify these predictors using the US National Institutes of Health database of clinical trials. Methods: Data from a placebo-controlled, double-blind, randomized controlled trial were used to assess the efficacy of intravenous ketamine in adult patients with TRD (NCT01920555). For the analysis, data were used from the participants who had received therapeutic doses of intravenous ketamine (i.e., 0.5 and 1.0mg/kg). Logistic and multivariable regression analyses were conducted to explore the demographic and clinical factors associated with response to treatment or changes in the Hamilton Depression Rating Scale 6 items (HAM-D-6) total score. Results: This study included 31 patients with TRD (13 women; mean±standard deviation age, 48.4±10.9 years). Logistic regression analysis showed that the age of onset was positively correlated with treatment response after three days of ketamine administration (β=0.08, p=0.037); however, no association was observed between treatment response and age, sex, baseline HAM-D-6 total score, or dissociative score assessed with the Clinician-Administered Dissociative States Scale 40 min after ketamine infusion. Multiple regression analysis showed that no factors were correlated significantly with the percentage change in the HAM-D-6 total score three days after ketamine administration. Discussion: Later disease onset correlates with a better treatment response three days after ketamine infusion in patients with TRD. Glutamatergic signal transmission may be impaired in patients with an earlier onset of depression, resulting in decreased neuroplasticity, which diminishes ketamine response." Authors: Kengo Yonezawa, Hiroyuki Uchida, Taisuke Yatomi, Yohei Ohtani, Kie Nomoto-Takahashi, Shinichiro Nakajima, Masaru Mimura & Hideaki Tani Click Here to Read the Full Article

Abstract: "Introduction: Predictors of treatment response to intravenous ketamine remain unclear in patients with treatment-resistant depression (TRD); therefore, this study aimed to clarify these predictors using the US National Institutes of Health database of clinical trials. Methods: Data from a placebo-controlled, double-blind, randomized controlled trial were used to assess the efficacy of intravenous ketamine in adult patients with TRD (NCT01920555). For the analysis, data were used from the participants who had received therapeutic doses of intravenous ketamine (i.e., 0.5 and 1.0mg/kg). Logistic and multivariable regression analyses were conducted to explore the demographic and clinical factors associated with response to treatment or changes in the Hamilton Depression Rating Scale 6 items (HAM-D-6) total score. Results: This study included 31 patients with TRD (13 women; mean±standard deviation age, 48.4±10.9 years). Logistic regression analysis showed that the age of onset was positively correlated with treatment response after three days of ketamine administration (β=0.08, p=0.037); however, no association was observed between treatment response and age, sex, baseline HAM-D-6 total score, or dissociative score assessed with the Clinician-Administered Dissociative States Scale 40 min after ketamine infusion. Multiple regression analysis showed that no factors were correlated significantly with the percentage change in the HAM-D-6 total score three days after ketamine administration. Discussion: Later disease onset correlates with a better treatment response three days after ketamine infusion in patients with TRD. Glutamatergic signal transmission may be impaired in patients with an earlier onset of depression, resulting in decreased neuroplasticity, which diminishes ketamine response." Authors: Kengo Yonezawa, Hiroyuki Uchida, Taisuke Yatomi, Yohei Ohtani, Kie Nomoto-Takahashi, Shinichiro Nakajima, Masaru Mimura & Hideaki Tani Click Here to Read the Full Article

Abstract: "Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain's affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05mg/kg ketamine, and 0.5mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals." Authors: Laura M. Hack, Xue Zhang, Boris D. Heifets, Trisha Suppes, Peter J. van Roessel, Jerome A. Yesavage, Nancy J. Gray, Rachel Hilton, Claire Bertrand, Carolyn I. Rodriguez, Karl Deisseroth, Brian Knutson & Leanne M. Williams Hack, L. M., Zhang, X., Heifets, B. D., Suppes, T., van Roessel, P. J., Yesavage, J. A., ... & Williams, L. M. (2023). Ketamine's acute effects on negative brain states are mediated through distinct altered states of consciousness in humans. Nature Communications, 14(1), 1-11. Click Here to Read the Full Article

Abstract: "Psychedelic substances are known to facilitate mystical-type experiences which can include metaphysical beliefs about the fundamental nature of reality. Such insights have been criticized as being incompatible with naturalism and therefore false. This leads to two problems. The easy problem is to elaborate on what is meant by the "fundamental nature of reality", and whether mystical-type conceptions of it are compatible with naturalism. The hard problem is to show how mystical-type insights, which from the naturalistic perspective are brain processes, could afford insight into the nature of reality beyond the brain. I argue that naturalism is less restrictive than commonly assumed, allowing that reality can be more than what science can convey. I propose that what the mystic refers to as the ultimate nature of reality can be considered as its representation- and observation-independent nature, and that mystical-type conceptions of it can be compatible with science. However, showing why the claims of the mystic would be true requires answering the hard problem. I argue that we can in fact directly know the fundamental nature of one specific part of reality, namely our own consciousness. Psychedelics may amplify our awareness of what consciousness is in itself, beyond our conceptual models about it, and may thus yield a glimpse into the fundamental nature of reality. Moreover, psychedelics may aid us to become aware of the limits of our models of reality. However, it is far from clear how mystical-type experience could afford access to the fundamental nature of all of reality. I conclude that mystical-type conceptions about reality may be compatible with naturalism, but not verifiable, as is the case with most metaphysical theses about reality." Authors: Jussi Jylkkä Jylkkä, J. (2023, October 10). Naturalism and the hard problem of mysticism in psychedelic science. https://doi.org/10.31234/osf.io/gxuv6 Click Here to Read the Full Article

Abstract: "Widespread executive function deficits impair daily functioning in psychiatric disorders. In this group, reduced frontal-midline-theta neurofeedback responsiveness may be related to impaired neural plasticity. In our pioneering study, we investigated the feasibility and practicality of integrating a neuroplasticity agent by psilocybin-assisted neurofeedback. Thirty-seven participants were divided into an experimental and a passive control group. The experimental group received three microdose sessions followed by three psilocybin-assisted neurofeedback sessions. Our results showed changes in self-regulatory frontal-midline theta from session-to-session approaching significance. Importantly, placebo ratings and expectations did not differ between the two groups. There were no immediate improvements in the experimental tasks assessing executive functions. However significant improvements were observed in self-reported executive functions in daily life. Participants reported improvements in working memory, shifting, monitoring and inhibition with high effect sizes. In addition, the experimental group reported positive changes in their priority areas, which included cognition, presence and mood. These results suggest that psilocybin-assisted neurofeedback shows promise for a potential transdiagnostic treatment. Future research should investigate the optimal timing and duration of this pharmacological and neuroscientific combination. Overall, our study highlights the feasibility and potential of this innovative approach, emphasizing the potential for enhanced neuroplasticity that may amplify the impact of neurofeedback." Authors: Stefanie Enriquez-Geppert, Jaroslav Krc, Fiachra O'Higgins & Morten P. Lietz Enriquez-Geppert, S., Krc, J., O'Higgins, F., & Lietz, M. P. (2023, October 11). Psilocybin-assisted neurofeedback for the improvement of executive functions: a semi-naturalistic-lab feasibility study. https://doi.org/10.31234/osf.io/jqasf Click Here to Read the Full Article

Abstract: "The aim of this review was to determine the effect of psilocybin on depressive symptoms in patients diagnosed with life-threatening illnesses or major depressive disorder. Systematic searches were conducted to search for randomized clinical trials and open-label trials that evaluated depression symptoms after psilocybin therapy. Data was pooled using a random-effects model. The primary outcome was the standardized mean difference (SMD) in depression severity, determined by calculating the change in depression ratings from baseline to the primary endpoint in the psilocybin arm versus the control arm. The literature search yielded 1734 studies, and 13 studies (n = 686) were included in either qualitative and/or quantitative analyses. The meta-analysis included 9 studies (pooled n = 596) and yielded a large effect size in favour of psilocybin (SMD = -0.78; p<0.001). Risk ratios for response and remission were large and significant in favour of psilocybin. A review of open-label trials showed robust decreases in depressive symptoms following psilocybin administration. These findings provide preliminary evidence for antidepressant efficacy with psilocybin-assisted psychotherapy, however, further studies are needed to evaluate safety and efficacy and to optimize treatment protocols." Authors: Sipan Haikazian, David C.J. Chen-Li, Danica E. Johnson, Farhan Fancy, Anastasia Levinta, M. Ishrat Husain, Rodrigo B. Mansur, Roger S. McIntyre & Joshua D. Rosenblat Click Here to Read the Full Article

Abstract: "The aim of this review was to determine the effect of psilocybin on depressive symptoms in patients diagnosed with life-threatening illnesses or major depressive disorder. Systematic searches were conducted to search for randomized clinical trials and open-label trials that evaluated depression symptoms after psilocybin therapy. Data was pooled using a random-effects model. The primary outcome was the standardized mean difference (SMD) in depression severity, determined by calculating the change in depression ratings from baseline to the primary endpoint in the psilocybin arm versus the control arm. The literature search yielded 1734 studies, and 13 studies (n = 686) were included in either qualitative and/or quantitative analyses. The meta-analysis included 9 studies (pooled n = 596) and yielded a large effect size in favour of psilocybin (SMD = -0.78; p<0.001). Risk ratios for response and remission were large and significant in favour of psilocybin. A review of open-label trials showed robust decreases in depressive symptoms following psilocybin administration. These findings provide preliminary evidence for antidepressant efficacy with psilocybin-assisted psychotherapy, however, further studies are needed to evaluate safety and efficacy and to optimize treatment protocols." Authors: Sipan Haikazian, David C.J. Chen-Li, Danica E. Johnson, Farhan Fancy, Anastasia Levinta, M. Ishrat Husain, Rodrigo B. Mansur, Roger S. McIntyre & Joshua D. Rosenblat Click Here to Read the Full Article

Abstract: "Research into the use of psilocybin for the treatment of psychiatric disorders is a growing field. Nevertheless, robust brain-behavior relationships linking psilocybin-induced brain changes to subjective drug-induced effects have not been established. Furthermore, it is unclear if the acute neural effects are dependent on individual heterogeneity in baseline characteristics. To address this, we assessed the effects of three oral doses of psilocybin vs. placebo on cerebral blood flow (CBF) using arterial spin labeling in healthy participants (N=70; n=31, 0.16 mg/kg; n=10, 0.2 mg/kg; n=29, 0.215 mg/kg). First, we quantified psilocybin-induced changes in relative and absolute CBF. Second, in an exploratory analysis, we assessed whether individual baseline characteristics and subjective psychedelic experience are associated with changes in CBF. Psychological and neurobiological baseline characteristics correlated with the psilocybin-induced reduction in relative CBF and the psilocybin-induced subjective experience. Furthermore, the psilocybin-induced subjective experience was associated with acute changes in relative and absolute CBF. The results demonstrated that inter-individual heterogeneity in the neural response to psilocybin is associated with baseline characteristics and shed light on the mechanisms underlying the psychedelic-induced altered state. Overall, these findings help guide the search for biomarkers, paving the way for a personalized medicine approach within the framework of psychedelic-assisted therapy." Authors: Nathalie M. Rieser, Ladina P. Gubser, Flora Moujaes, Patricia Duerler, Candace R. Lewis, Lars Michels, Franz X. Vollenweider & Katrin H. Preller Click Here to Read the Full Article

"Rationale Research on psychedelics has recently shown promising results in the treatment of various psychiatric disorders, but relatively little remains known about the psychiatric risks associated with naturalistic use of psychedelics. Objective The objective of the current study was to investigate associations between naturalistic psychedelic use and psychiatric risks. Methods Using a sample representative of the US adult population with regard to sex, age, and ethnicity (N=2822), this study investigated associations between lifetime naturalistic psychedelic use, lifetime unusual visual experiences, and past 2-week psychotic symptoms. Results Among respondents who reported lifetime psychedelic use (n=613), 1.3% reported having been told by a doctor or other medical professional that they had hallucinogen persisting perception disorder. In covariate-adjusted linear regression models, lifetime psychedelic use was associated with more unusual visual experiences at any point across the lifetime, but no association was observed between lifetime psychedelic use and past 2-week psychotic symptoms. There was an interaction between lifetime psychedelic use and family (but not personal) history of psychotic or bipolar disorders on past 2-week psychotic symptoms such that psychotic symptoms were highest among respondents who reported lifetime psychedelic use and a family history of psychotic or bipolar disorders and lowest among those who reported lifetime psychedelic use and no family history of psychotic or bipolar disorders. Conclusions Although the results in this study should be interpreted with caution, the findings suggest that lifetime naturalistic use of psychedelics might be associated with more unusual visual experiences across the lifetime, as well as more psychotic symptoms in the past 2 weeks for individuals with a family history of psychotic or bipolar disorders and the reverse for those without such a family history. Future research should distinguish between different psychotic and bipolar disorders and should also utilize other research designs (e.g., longitudinal) and variables (e.g., polygenic risk scores) to better understand potential cause-and-effect relationships." Authors: Otto Simonsson, Simon B. Goldberg, Richard Chambers, Walter Osika, Charlotta Simonsson & Peter S. Hendricks Click Here to Read Full Article

Abstract:  "Background: Resurgent psychedelic research has largely supported the safety and efficacy of psychedelic therapy for the treatment of various psychiatric disorders. As psychedelic use and therapy increases in prevalence, so does the importance of understanding associated risks. Cases of prolonged negative psychological responses to psychedelic therapy seem rare; however, studies are limited by biases and small sample sizes. The current analytical approach was motivated by the question of whether rare but significant adverse effects have been under-sampled in psychedelic research studies. Methods: A 'bottom margin analysis' approach was taken to focus on negative responders to psychedelic use in a pool of naturalistic, observational prospective studies (N=807). We define 'negative response' by a clinically meaningful decline in a generic index of mental health, i.e., a one standard error from the mean decrease in psychological well-being 4 weeks post psychedelic use (vs pre-use baseline). We then assessed whether a history of diagnosed mental illness can predict negative responses. Results: We find that 16% of the cohort fall into the 'negative responder' subset. Parsing the sample by self-reported history of psychiatric diagnoses, results revealed a disproportionate prevalence of negative responses among those reporting a prior personality disorder diagnosis (31%). One multivariate regression model indicated a greater than four-fold elevated risk of adverse psychological responses to psychedelics in the personality-disorder sub-sample (b = 1.425, p < 0.05). Conclusion: We infer that the presence of a personality disorder may represent an elevated risk for psychedelic use, and hypothesize that the importance of psychological support and good therapeutic alliance may be increased in this population." Authors: Alessia Marrocu, Hannes Kettner, Brandon Weiss, Richard J. Zeifman, David Erritzoe & Robin L. Carhart-Harris Click Here to Read the Full Article

Abstract "The effectiveness of the esketamine nasal spray (ESK-NS) for treatment-resistant depression (TRD) has been confirmed by real-world studies. Available evidence derived from clinician-rated assessments might differ from patients' perceptions about the helpfulness of treatments. We aimed to verify the effect of ESK-NS from patients' view in 25 TRD patients (56% males, 55.1 ± 10.9 years) treated with ESK-NS (mean dose: 78.4 ± 11.43 mg) for three months and evaluated at different time-points through clinician-rated and self-administered scales, assessing changes in depression, anhedonia, sleep, cognition, suicidality, and anxiety. We observed an overall early improvement that lasted over time (endpoint total score reduction in Montgomery-Ã…sberg Depression Rating Scale, p < 0.001, Beck Depression Inventory, p = 0.003). Patients reported a significant self-rated decrease in anhedonia at two months (Snaith-Hamilton Pleasure Scale, p = 0.04) and in suicide ideation at endpoint (BDI subitem 9, p = 0.039) vs. earlier improvements detected by clinicians (one-month reduction in MADRS subitem 8, p = 0.005, and subitem 10, p = 0.007). These findings confirm the effectiveness of a three-month treatment with ESK-NS in TRD patients, highlighting an overall overlapping response from patients' and clinicians' perspectives, although with some differential effects on specific symptoms at given time-points. Including patients' viewpoints in routine assessments could inform clinical practice, ensuring a better characterization of clinical phenotypes to deliver personalized interventions." Click Here to Read the Full Article

Abstract "The effectiveness of the esketamine nasal spray (ESK-NS) for treatment-resistant depression (TRD) has been confirmed by real-world studies. Available evidence derived from clinician-rated assessments might differ from patients' perceptions about the helpfulness of treatments. We aimed to verify the effect of ESK-NS from patients' view in 25 TRD patients (56% males, 55.1 ± 10.9 years) treated with ESK-NS (mean dose: 78.4 ± 11.43 mg) for three months and evaluated at different time-points through clinician-rated and self-administered scales, assessing changes in depression, anhedonia, sleep, cognition, suicidality, and anxiety. We observed an overall early improvement that lasted over time (endpoint total score reduction in Montgomery-Ã…sberg Depression Rating Scale, p < 0.001, Beck Depression Inventory, p = 0.003). Patients reported a significant self-rated decrease in anhedonia at two months (Snaith-Hamilton Pleasure Scale, p = 0.04) and in suicide ideation at endpoint (BDI subitem 9, p = 0.039) vs. earlier improvements detected by clinicians (one-month reduction in MADRS subitem 8, p = 0.005, and subitem 10, p = 0.007). These findings confirm the effectiveness of a three-month treatment with ESK-NS in TRD patients, highlighting an overall overlapping response from patients' and clinicians' perspectives, although with some differential effects on specific symptoms at given time-points. Including patients' viewpoints in routine assessments could inform clinical practice, ensuring a better characterization of clinical phenotypes to deliver personalized interventions." Click Here to Read the Full Article

Abstract: "The effectiveness of the esketamine nasal spray (ESK-NS) for treatment-resistant depression (TRD) has been confirmed by real-world studies. Available evidence derived from clinician-rated assessments might differ from patients' perceptions about the helpfulness of treatments. We aimed to verify the effect of ESK-NS from patients' view in 25 TRD patients (56% males, 55.1 ± 10.9 years) treated with ESK-NS (mean dose: 78.4 ± 11.43 mg) for three months and evaluated at different time-points through clinician-rated and self-administered scales, assessing changes in depression, anhedonia, sleep, cognition, suicidality, and anxiety. We observed an overall early improvement that lasted over time (endpoint total score reduction in Montgomery-Ã…sberg Depression Rating Scale, p < 0.001, Beck Depression Inventory, p = 0.003). Patients reported a significant self-rated decrease in anhedonia at two months (Snaith-Hamilton Pleasure Scale, p = 0.04) and in suicide ideation at endpoint (BDI subitem 9, p = 0.039) vs. earlier improvements detected by clinicians (one-month reduction in MADRS subitem 8, p = 0.005, and subitem 10, p = 0.007). These findings confirm the effectiveness of a three-month treatment with ESK-NS in TRD patients, highlighting an overall overlapping response from patients' and clinicians' perspectives, although with some differential effects on specific symptoms at given time-points. Including patients' viewpoints in routine assessments could inform clinical practice, ensuring a better characterization of clinical phenotypes to deliver personalized interventions." Authors: Maria Pepe, Giovanni Bartolucci, Ilaria Marcelli, Francesco Pesaresi, Andrea Brugnami, Romina Caso, Alessia Fischetti, Flavia Grisoni, Marianna Mazza, Giovanni Camardese, Marco Di Nicola & Gabriele Sani Pepe, M., Bartolucci, G., Marcelli, I., Pesaresi, F., Brugnami, A., Caso, R., ... & Sani, G. (2023). The Patient's Perspective on the Effects of Intranasal Esketamine in Treatment-Resistant Depression. Brain Sciences, 13(10), 1494.

Abstract: "The effectiveness of the esketamine nasal spray (ESK-NS) for treatment-resistant depression (TRD) has been confirmed by real-world studies. Available evidence derived from clinician-rated assessments might differ from patients' perceptions about the helpfulness of treatments. We aimed to verify the effect of ESK-NS from patients' view in 25 TRD patients (56% males, 55.1 ± 10.9 years) treated with ESK-NS (mean dose: 78.4 ± 11.43 mg) for three months and evaluated at different time-points through clinician-rated and self-administered scales, assessing changes in depression, anhedonia, sleep, cognition, suicidality, and anxiety. We observed an overall early improvement that lasted over time (endpoint total score reduction in Montgomery-Ã…sberg Depression Rating Scale, p < 0.001, Beck Depression Inventory, p = 0.003). Patients reported a significant self-rated decrease in anhedonia at two months (Snaith-Hamilton Pleasure Scale, p = 0.04) and in suicide ideation at endpoint (BDI subitem 9, p = 0.039) vs. earlier improvements detected by clinicians (one-month reduction in MADRS subitem 8, p = 0.005, and subitem 10, p = 0.007). These findings confirm the effectiveness of a three-month treatment with ESK-NS in TRD patients, highlighting an overall overlapping response from patients' and clinicians' perspectives, although with some differential effects on specific symptoms at given time-points. Including patients' viewpoints in routine assessments could inform clinical practice, ensuring a better characterization of clinical phenotypes to deliver personalized interventions." Authors: Maria Pepe, Giovanni Bartolucci, Ilaria Marcelli, Francesco Pesaresi, Andrea Brugnami, Romina Caso, Alessia Fischetti, Flavia Grisoni, Marianna Mazza, Giovanni Camardese, Marco Di Nicola & Gabriele Sani Pepe, M., Bartolucci, G., Marcelli, I., Pesaresi, F., Brugnami, A., Caso, R., ... & Sani, G. (2023). The Patient's Perspective on the Effects of Intranasal Esketamine in Treatment-Resistant Depression. Brain Sciences, 13(10), 1494.

Abstract: "Survivors of adverse childhood experience are at elevated risk for psychological distress. In recent years, renewed interest in psychedelic medicine has highlighted the therapeutic potential of psilocybin for those who have experienced childhood adversity. However, recreational psilocybin use remains illegal and access to approved therapies is difficult. Such use provides an opportunity to explore the therapeutic potential of psilocybin for psychological distress among people with adverse childhood experiences. Therefore, we conducted an online survey to assess interest in, acceptability of, and experiences with psilocybin. We further explored whether the association between Adverse Childhood Experiences Questionnaire (ACEQ) scores and psychological distress was lower among those who had used psilocybin in the past three months. Results showed high levels of interest in and acceptability of psilocybin that did not differ across ACEQ scores. Results also showed that the effect of adverse childhood experiences on psychological distress was lower for people who had recently used psilocybin (p=.019). Taken together, these findings suggest that psilocybin therapy may be potentially acceptable and may feasibly help in supporting survivors of adverse childhood experiences with particularly strong benefits to those with more severe childhood adversity." Authors: Kiffer G. Card, Ashmita Grewal, Kalysha Closson, Gina Martin, Laura Baracaldo, Sandra Allison, Daniel J. Kruger & Zach Walsh Click Here to Read the Full Article

LSD, lysergic acid diethylamide, microdose

Robin J. Murphy, Rachael Sumner, William Evans, Rhys Ponton, Sanya Ram, Kate Godfrey, Anna Forsyth, Alana Cavadino, Venkat Krishnamurthy Naga, Todd Smith, Nicholas R. Hoeh, David B. Menkes, Suresh Muthukumaraswamy, Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial, Biological Psychiatry, 2023, ISSN 0006-3223, https://doi.org/10.1016/j.biopsych.2023.03.013. (https://www.sciencedirect.com/science/article/pii/S0006322323011642) Abstract: Background: Microdosing psychedelic drugs is a widespread social phenomenon with diverse benefits claimed for mood and cognition. Randomized controlled trials have failed to support these claims, but the laboratory-based dosing in trials conducted to date may have limited ecological validity. Methods: Healthy male volunteers were randomized into lysergic acid diethylamide (LSD) (n = 40) and placebo (n = 40) groups and received 14 doses of either 10 μg LSD or an inactive placebo every 3 days for 6 weeks. First doses were given in a supervised laboratory setting, with other doses self-administered in a naturalistic setting. Results of safety data, blinding, daily questionnaires, expectancy, and pre-/postintervention psychometrics and cognitive tasks are presented here. Results: The most notable reported adverse event was treatment-related anxiety, which prompted the withdrawal of 4 participants from the LSD group. Daily questionnaires showed credible evidence (>99% posterior probability) of improved ratings of creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, and these effects remained when controlling for preintervention expectancy. No questionnaire or cognitive task showed a credible change between baseline and 6-week assessment time points. Conclusions: Microdosing LSD appears to be relatively safe in healthy adult men, notwithstanding a risk of anxiety. While microdosing elicited transient increases in scales associated with mood-elevating effects, it was not sufficient to promote enduring changes to overall mood or cognition in healthy adults. Future microdosing trials in clinical populations will require the use of active placebos to control for placebo effects and dose titration to adjust for interindividual variability in drug response.

Abstract: "Ayahuasca is a brew with psychoactive properties that has been used as an entheogen for centuries, with more recent studies suggesting it is a promising treatment for some clinical disorders. Although there is an emerging scientific literature on its effects, to the best of our knowledge no study has explored the self-reported experiences of first-time ayahuasca users with quantitative textual analysis tools. Accordingly, the current study aimed to analyze the subjective experience of naive individuals with depression and healthy controls after consuming ayahuasca. For this purpose, responses from a subsample of participants from a previous clinical trial to open-ended questions regarding their experience with ayahuasca underwent textual analysis. Data from nine patients with treatment-resistant depression and 20 healthy individuals were included, and quantitative textual analysis was performed using IRaMuTeQ 0.7 alpha 2 and R 3.1.2. The analysis identified five clusters: alterations in the state of consciousness, cognitive changes, somatic alterations, auditory experiences, and visual perceptual content. Additionally, findings suggest specific features of the experience of people with depression with ayahuasca, such as increased aversive bodily reactions. The results are consistent with previous findings indicating central axes of the psychedelic experience, and may inform therapeutic approaches using ayahuasca." Authors: Lucas Cruz, Bheatrix B. Favero, Fernanda Palhano-Fontes, Luís F. Tófoli, Dráulio B. Araújo & Daniel C. Mograbi Click Here to Read the Full Article

Abstract: "The application of MDMA in conjunction with psychotherapy has in recent years seen a resurgence of clinical, scientific, and public interest in the treatment of posttraumatic stress disorder (PTSD). Clinical trials have shown promising safety and efficacy, but the mechanisms underlying this treatment form remain largely unestablished. This article explores recent preclinical and clinical evidence suggesting that the treatment's efficacy may be influenced by the mnemonic effects of MDMA. We review data on the effects of MDMA on fear extinction and fear reconsolidation and the utility of these processes for PTSD treatment. We corroborate our findings by incorporating research from cognitive psychology and psychopharmacology and offer recommendations for future research." Authors: Mesud Sarmanlu, Kim P. C. Kuypers, Patrick Vizeli & Timo L. Kvamme Click Here to Read the Full Article

GaÅ‚uszko-WÄ™gielnik, M., Jakuszkowiak-Wojten, K., Wilkowska, A., & CubaÅ‚a, W. J. (2023). Short term ketamine treatment in patient with bipolar disorder with comorbidity with borderline personality disorder: focus on impulsivity. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 1-15. Advance online publication. https://doi.org/10.1080/15622975.2023.2227901 Abstract:  Objectives: Borderline personality disorder (BPD) and bipolar disorder (BD) often co-occur and frequently do not respond adequately to traditional antidepressant treatments. Ketamine has shown rapid antidepressant and anti-suicidal effects. However, there is limited literature on the safety and tolerance of using ketamine to treat patients with comorbid BD and BPD. Methods: This case presents a female patient diagnosed with both Bipolar Disorder (BD) and Borderline Personality Disorder (BPD) who received intravenous ketamine treatment to alleviate acute depressive symptoms. Results: Initially, ketamine ameliorated depressed symptoms. However, as the ketamine treatment continued, the patient showed an increase in nonsuicidal self-injury (NSSIs) and impulsive conduct with a aggravation of dissociative symptoms. As a result, intravenous ketamine was discontinued, and the patient received the medication, which proved helpful. Conclusions: Although ketamine presents antidepressant properties, reports on its impact on emotional dysregulation and impulsive conduct are unclear and not alike to its antidepressant effect. Therefore, there is a need for more studies investigating the effectiveness and safety of this rapid-acting medicine in this patient population. Click Here to Read the Full Article

Goodwin, G.M., Croal, M., Feifel, D. et al. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01648-7 Abstract:  "Psilocybin is being investigated as a treatment in adults with treatment-resistant depression (TRD). Withdrawal from serotonergic antidepressant drugs is a common prerequisite for taking part in trials of psilocybin due to the possibility of ongoing antidepressant drugs altering the psychedelic effect. This phase II, exploratory, international, fixed-dose, open-label study explored the safety, tolerability, and efficacy of a synthetic form of psilocybin (investigational drug COMP360) adjunct to a selective serotonin reuptake inhibitor in participants with TRD. Participants received a single 25 mg dose of psilocybin alongside psychological support and were followed-up for 3 weeks. The primary efficacy end point was change in the Montgomery-Ã…sberg Depression Rating Scale (MADRS) total score from Baseline at Week 3. Secondary end points were safety, including treatment-emergent adverse events (TEAEs), the proportion of responders and remitters at Week 3, and the change from Baseline to Week 3 in Clinical Global Impression-Severity (CGI-S) score. Nineteen participants were dosed and the mean Baseline MADRS total score was 31.7 (SD=5.77). Twelve (63.2%) participants had a TEAE, most of which were mild and resolved on the day of onset. There were no serious TEAEs or indication of increased suicidal ideation or behavior. At Week 3, mean change from Baseline in MADRS total score was −14.9 (95% CI, −20.7 to −9.2), and −1.3 (SD=1.29) in the CGI-S. Both response and remission were evident in 8 (42.1%) participants. Larger, comparator-controlled trials are necessary to understand if this paradigm can optimize treatment-outcome where antidepressant drug withdrawal would be problematic." Authors: Guy M. Goodwin, Megan Croal, David Feifel, John R. Kelly, Lindsey Marwood, Sunil Mistry, Veronica O'Keane, Stephanie Knatz Peck, Hollie Simmons, Claudia Sisa, Susan C. Stansfield, Joyce Tsai, Sam Williams & Ekaterina Malievskaia Click Here to Read the Full Article

Goodwin, G.M., Croal, M., Feifel, D. et al. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01648-7 Abstract:  "Psilocybin is being investigated as a treatment in adults with treatment-resistant depression (TRD). Withdrawal from serotonergic antidepressant drugs is a common prerequisite for taking part in trials of psilocybin due to the possibility of ongoing antidepressant drugs altering the psychedelic effect. This phase II, exploratory, international, fixed-dose, open-label study explored the safety, tolerability, and efficacy of a synthetic form of psilocybin (investigational drug COMP360) adjunct to a selective serotonin reuptake inhibitor in participants with TRD. Participants received a single 25 mg dose of psilocybin alongside psychological support and were followed-up for 3 weeks. The primary efficacy end point was change in the Montgomery-Ã…sberg Depression Rating Scale (MADRS) total score from Baseline at Week 3. Secondary end points were safety, including treatment-emergent adverse events (TEAEs), the proportion of responders and remitters at Week 3, and the change from Baseline to Week 3 in Clinical Global Impression-Severity (CGI-S) score. Nineteen participants were dosed and the mean Baseline MADRS total score was 31.7 (SD=5.77). Twelve (63.2%) participants had a TEAE, most of which were mild and resolved on the day of onset. There were no serious TEAEs or indication of increased suicidal ideation or behavior. At Week 3, mean change from Baseline in MADRS total score was −14.9 (95% CI, −20.7 to −9.2), and −1.3 (SD=1.29) in the CGI-S. Both response and remission were evident in 8 (42.1%) participants. Larger, comparator-controlled trials are necessary to understand if this paradigm can optimize treatment-outcome where antidepressant drug withdrawal would be problematic." Authors: Guy M. Goodwin, Megan Croal, David Feifel, John R. Kelly, Lindsey Marwood, Sunil Mistry, Veronica O'Keane, Stephanie Knatz Peck, Hollie Simmons, Claudia Sisa, Susan C. Stansfield, Joyce Tsai, Sam Williams & Ekaterina Malievskaia Click Here to Read the Full Article

Abstract:  "Post-traumatic stress disorder (PTSD) is a prevalent psychiatric condition that significantly impacts daily functioning in patients but lacks adequate treatment options. 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy for the treatment of PTSD has been studied increasingly for the last two decades and has shown promising results through quantitative data. However, few qualitative studies have been conducted to investigate patients' experiences who participate in these trials. This study intends to complement and clarify the quantitative findings resulting from a Phase-II clinical trial for assessing the safety and efficacy of MDMA-assisted psychotherapy for PTSD by using a qualitative approach based on available material of 4 recorded and transcripted integrative sessions per participant. An Interpretative Phenomenological Analysis (IPA) was conducted for 7 participants who met criteria for severe PTSD to develop a deeper understanding of the treatment and its efficacy. Analysis results provided real-life statements from participants that reflect perceived mechanisms of change and showed to what extent their proposed working mechanisms integrate into daily life." Authors: Macha Godes, Jasper Lucas & Eric Vermetten Click Here to Read the Full Article

depression, ketamine infusions

Artemis Zavaliangos-Petropulu, Shawn M. McClintock, Jacqueline Khalil, Shantanu H. Joshi, Brandon Taraku, Noor B. Al-Sharif, Randall T. Espinoza, Katherine L. Narr, Neurocognitive effects of subanesthetic serial ketamine infusions in treatment resistant depression, Journal of Affective Disorders, Volume 333, 2023, Pages 161-171, ISSN 0165-0327, https://doi.org/10.1016/j.jad.2023.04.015. (https://www.sciencedirect.com/science/article/pii/S0165032723004767) Abstract: Introduction: Ketamine treatment prompts a rapid antidepressant response in treatment-resistant depression (TRD). We performed an exploratory investigation of how ketamine treatment in TRD affects different cognitive domains and relates to antidepressant response. Methods: Patients with TRD (N = 66; 30 M/35F; age = 39.5 Â± 11.1 years) received four ketamine infusions (0.5 mg/kg). Neurocognitive function and depressive symptoms were assessed at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks following end of treatment. Mixed effect models tested for changes in seven neurocognitive domains and antidepressant response, with post-hoc pairwise comparisons between timepoints, including follow-up. Relationships between change in neurocognitive function and antidepressant response over the course of treatment were tested with Pearson's correlation and mediation analyses. Associations between baseline neurocognitive performance and antidepressant response were tested with Pearson's correlation. Results: Significant improvements in inhibition, working memory, processing speed, and overall fluid cognition were observed after the first and fourth ketamine infusion. Improvements in processing speed and overall fluid cognition persisted through follow-up. Significant improvements in depressive symptoms reverted towards baseline at follow-up. Baseline working memory and change in inhibition were moderately correlated with antidepressant response, however, improvements in neurocognitive performance were statistically independent from antidepressant response. Conclusion: Antidepressant ketamine leads to improved neurocognitive function, which persist for at least 5 weeks. Neurocognitive improvements observed appear independent of antidepressant response, suggesting ketamine may target overlapping but distinct functional brain systems. Limitations Research investigating repeated serial ketamine treatments is important to determine cognitive safety. This study is a naturalistic design and does not include placebo. Click Here to Read the Full Article

depression, Ketamine, Sleep

Sandor Kantor, Michael Lanigan, Lauren Giggins, Lisa Lione, Lilia Magomedova, Inés de Lannoy, Neil Upton, Mark Duxon, Ketamine supresses REM sleep and markedly increases EEG gamma oscillations in the Wistar Kyoto rat model of treatment-resistant depression, Behavioural Brain Research, Volume 449, 2023, 114473, ISSN 0166-4328, https://doi.org/10.1016/j.bbr.2023.114473. (https://www.sciencedirect.com/science/article/pii/S0166432823001912) Abstract: Wistar-Kyoto (WKY) rats exhibit depression-like characteristics and decreased sensitivity to monoamine-based antidepressants, making them a suitable model of treatment-resistant depression (TRD). Ketamine has emerged recently as a rapidly acting antidepressant with high efficacy in TRD. Our aim was to determine whether subanaesthetic doses of ketamine can correct sleep and electroencephalogram (EEG) alterations in WKY rats and whether any ketamine-induced changes differentially affect WKY rats compared to Sprague-Dawley (SD) rats. Thus, we surgically implanted 8 SD and 8 WKY adult male rats with telemetry transmitters and recorded their EEG, electromyogram, and locomotor activity after vehicle or ketamine (3, 5 or 10 mg/kg, s.c.) treatment. We also monitored the plasma concentration of ketamine and its metabolites, norketamine and hydroxynorketamine in satellite animals. We found that WKY rats have an increased amount of rapid eye movement (REM) sleep, fragmented sleep-wake pattern, and increased EEG delta power during non-REM sleep compared to SD rats. Ketamine suppressed REM sleep and increased EEG gamma power during wakefulness in both strains, but the gamma increase was almost twice as large in WKY rats than in SD rats. Ketamine also increased beta oscillations, but only in WKY rats. These differences in sleep and EEG are unlikely to be caused by dissimilarities in ketamine metabolism as the plasma concentrations of ketamine and its metabolites were similar in both strains. Our data suggest an enhanced antidepressant-like response to ketamine in WKY rats, and further support the predictive validity of acute REM sleep suppression as a measure of antidepressant responsiveness.Keywords: Wistar-Kyoto rats; Treatment-resistant depression; NMDA receptor antagonist; Ketamine; REM sleep; EEG gamma power

depression, Ketamine, Sleep

Sandor Kantor, Michael Lanigan, Lauren Giggins, Lisa Lione, Lilia Magomedova, Inés de Lannoy, Neil Upton, Mark Duxon, Ketamine supresses REM sleep and markedly increases EEG gamma oscillations in the Wistar Kyoto rat model of treatment-resistant depression, Behavioural Brain Research, Volume 449, 2023, 114473, ISSN 0166-4328, https://doi.org/10.1016/j.bbr.2023.114473. (https://www.sciencedirect.com/science/article/pii/S0166432823001912) Abstract: Wistar-Kyoto (WKY) rats exhibit depression-like characteristics and decreased sensitivity to monoamine-based antidepressants, making them a suitable model of treatment-resistant depression (TRD). Ketamine has emerged recently as a rapidly acting antidepressant with high efficacy in TRD. Our aim was to determine whether subanaesthetic doses of ketamine can correct sleep and electroencephalogram (EEG) alterations in WKY rats and whether any ketamine-induced changes differentially affect WKY rats compared to Sprague-Dawley (SD) rats. Thus, we surgically implanted 8 SD and 8 WKY adult male rats with telemetry transmitters and recorded their EEG, electromyogram, and locomotor activity after vehicle or ketamine (3, 5 or 10 mg/kg, s.c.) treatment. We also monitored the plasma concentration of ketamine and its metabolites, norketamine and hydroxynorketamine in satellite animals. We found that WKY rats have an increased amount of rapid eye movement (REM) sleep, fragmented sleep-wake pattern, and increased EEG delta power during non-REM sleep compared to SD rats. Ketamine suppressed REM sleep and increased EEG gamma power during wakefulness in both strains, but the gamma increase was almost twice as large in WKY rats than in SD rats. Ketamine also increased beta oscillations, but only in WKY rats. These differences in sleep and EEG are unlikely to be caused by dissimilarities in ketamine metabolism as the plasma concentrations of ketamine and its metabolites were similar in both strains. Our data suggest an enhanced antidepressant-like response to ketamine in WKY rats, and further support the predictive validity of acute REM sleep suppression as a measure of antidepressant responsiveness.Keywords: Wistar-Kyoto rats; Treatment-resistant depression; NMDA receptor antagonist; Ketamine; REM sleep; EEG gamma power

Abstract:  "Purpose To assess the effect of esketamine nasal spray on patient-reported outcomes (PROs) in patients with major depressive disorder having active suicidal ideation with intent (MDSI). Methods Patient-level data from two phase 3 studies (ASPIRE I; ASPIRE II) of esketamine+standard of care (SOC) in patients (aged 18-64 years) with MDSI, were pooled. PROs were evaluated from baseline through end of the double-blind treatment phase (day 25). Outcome assessments included: Beck Hopelessness Scale (BHS), Quality of Life (QoL) in Depression Scale (QLDS), European QoL Group-5-Dimension-5-Level (EQ-5D-5L), and 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9). Changes in BHS and QLDS scores (baseline to day 25) were analyzed using a mixed-effects model for repeated measures (MMRM). Results Pooled data for esketamine+SOC (n=226; mean age: 40.5 years, 59.3% females) and placebo+SOC (n=225; mean age: 39.6 years, 62.2% females) were analyzed. Mean±SD change from baseline to day 25, esketamine+SOC vs placebo+SOC (least-square mean difference [95% CI] based on MMRM): BHS total score,−7.4±6.7 vs−6.8±6.5 [−1.0 (−2.23, 0.21)]; QLDS score,−14.4±11.5 vs−12.2±10.8 [−3.1 (−5.21,−1.02)]. Relative risk (95% CI) of reporting perceived problems (slight to extreme) in EQ-5D-5L dimensions (day 25) in esketamine+SOC vs placebo+SOC: mobility [0.78 (0.50, 1.20)], self-care [0.83 (0.55, 1.27)], usual activities [0.87 (0.72, 1.05)], pain/discomfort [0.85 (0.69, 1.04)], and anxiety/depression [0.90 (0.80, 1.00)]. Mean±SD changes from baseline in esketamine+SOC vs placebo+SOC for health status index: 0.23±0.21 vs 0.19±0.22; and for EQ-Visual Analogue Scale: 24.0±27.2 vs 19.3±24.4. At day 25, mean±SD in domains of TSQM-9 scores in esketamine+SOC vs placebo+SOC were: effectiveness, 67.2±25.3 vs 56.2±26.8; global satisfaction, 69.9±25.2 vs 56.3±27.8; and convenience, 74.0±19.4 vs 75.4±18.7. Conclusion These PRO data support the patient perspective of the effect associated with esketamine+SOC in improving health-related QoL in patients with MDSI." Authors: Carol Jamieson, Carla M. Canuso, Dawn F. Ionescu, Rosanne Lane, Xin Qiu, Heather Rozjabek, Patricio Molero & Dong-Jing Fu Click Here to Read the Full Article

Abstract:  "Purpose To assess the effect of esketamine nasal spray on patient-reported outcomes (PROs) in patients with major depressive disorder having active suicidal ideation with intent (MDSI). Methods Patient-level data from two phase 3 studies (ASPIRE I; ASPIRE II) of esketamine+standard of care (SOC) in patients (aged 18-64 years) with MDSI, were pooled. PROs were evaluated from baseline through end of the double-blind treatment phase (day 25). Outcome assessments included: Beck Hopelessness Scale (BHS), Quality of Life (QoL) in Depression Scale (QLDS), European QoL Group-5-Dimension-5-Level (EQ-5D-5L), and 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9). Changes in BHS and QLDS scores (baseline to day 25) were analyzed using a mixed-effects model for repeated measures (MMRM). Results Pooled data for esketamine+SOC (n=226; mean age: 40.5 years, 59.3% females) and placebo+SOC (n=225; mean age: 39.6 years, 62.2% females) were analyzed. Mean±SD change from baseline to day 25, esketamine+SOC vs placebo+SOC (least-square mean difference [95% CI] based on MMRM): BHS total score,−7.4±6.7 vs−6.8±6.5 [−1.0 (−2.23, 0.21)]; QLDS score,−14.4±11.5 vs−12.2±10.8 [−3.1 (−5.21,−1.02)]. Relative risk (95% CI) of reporting perceived problems (slight to extreme) in EQ-5D-5L dimensions (day 25) in esketamine+SOC vs placebo+SOC: mobility [0.78 (0.50, 1.20)], self-care [0.83 (0.55, 1.27)], usual activities [0.87 (0.72, 1.05)], pain/discomfort [0.85 (0.69, 1.04)], and anxiety/depression [0.90 (0.80, 1.00)]. Mean±SD changes from baseline in esketamine+SOC vs placebo+SOC for health status index: 0.23±0.21 vs 0.19±0.22; and for EQ-Visual Analogue Scale: 24.0±27.2 vs 19.3±24.4. At day 25, mean±SD in domains of TSQM-9 scores in esketamine+SOC vs placebo+SOC were: effectiveness, 67.2±25.3 vs 56.2±26.8; global satisfaction, 69.9±25.2 vs 56.3±27.8; and convenience, 74.0±19.4 vs 75.4±18.7. Conclusion These PRO data support the patient perspective of the effect associated with esketamine+SOC in improving health-related QoL in patients with MDSI." Authors: Carol Jamieson, Carla M. Canuso, Dawn F. Ionescu, Rosanne Lane, Xin Qiu, Heather Rozjabek, Patricio Molero & Dong-Jing Fu Click Here to Read the Full Article

Abstract:  "Objective Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid antisuicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial of intravenous esketamine's safety and efficacy in this population. Method A total of 54 adolescents (aged 13-18) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive three infusions of esketamine (0.25 mg/kg) or midazolam (0.045 mg/kg) over 5 days, with routine inpatient care and treatment. Changes from baseline to 24 hours after the final infusion (Day 6) in the scores of the Columbia Suicide Severity Rating Scale (C-SSRS) Ideation and Intensity (primary outcome) and Montgomery-Ã…sberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. Additionally, the 4-week clinical treatment response was a key secondary outcome. Results The mean changes in C-SSRS Ideation and Intensity scores from baseline to Day 6 were significantly greater in the esketamine group than in the midazolam group (Ideation, -2.6 [SD=2.0] vs. -1.7 [SD=2.2], P=0.007; Intensity, -10.6 [SD=8.4] vs. -5.0 [SD=7.4], P=0.002), and the changes in MADRS scores from baseline to Day 6 were significantly greater in the esketamine group than in the midazolam group (-15.3 [SD=11.2] vs. -8.8 [SD=9.4], P=0.004). The rates of antisuicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and 52.5% and 52.5% after midazolam, respectively. The most common adverse events in the esketamine group were nausea, dissociation, dry mouth, sedation, headache and dizziness. Conclusion These preliminary findings indicate that three-dose intravenous esketamine, added to routine inpatient care and treatment, was an effective and well-tolerated therapy for treating adolescents with MDD and suicidal ideation." Authors: Yanling Zhou, Xiaofeng Lan, Chengyu Wang, Fan Zhang, Haiyan Liu, Ling Fu, Weicheng Li, Yanxiang Ye, Zhibo Hu, Ziyuan Chao & Yuping Ning Click Here to Read the Full Article

Abstract:  "Objective Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid antisuicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial of intravenous esketamine's safety and efficacy in this population. Method A total of 54 adolescents (aged 13-18) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive three infusions of esketamine (0.25 mg/kg) or midazolam (0.045 mg/kg) over 5 days, with routine inpatient care and treatment. Changes from baseline to 24 hours after the final infusion (Day 6) in the scores of the Columbia Suicide Severity Rating Scale (C-SSRS) Ideation and Intensity (primary outcome) and Montgomery-Ã…sberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. Additionally, the 4-week clinical treatment response was a key secondary outcome. Results The mean changes in C-SSRS Ideation and Intensity scores from baseline to Day 6 were significantly greater in the esketamine group than in the midazolam group (Ideation, -2.6 [SD=2.0] vs. -1.7 [SD=2.2], P=0.007; Intensity, -10.6 [SD=8.4] vs. -5.0 [SD=7.4], P=0.002), and the changes in MADRS scores from baseline to Day 6 were significantly greater in the esketamine group than in the midazolam group (-15.3 [SD=11.2] vs. -8.8 [SD=9.4], P=0.004). The rates of antisuicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and 52.5% and 52.5% after midazolam, respectively. The most common adverse events in the esketamine group were nausea, dissociation, dry mouth, sedation, headache and dizziness. Conclusion These preliminary findings indicate that three-dose intravenous esketamine, added to routine inpatient care and treatment, was an effective and well-tolerated therapy for treating adolescents with MDD and suicidal ideation." Authors: Yanling Zhou, Xiaofeng Lan, Chengyu Wang, Fan Zhang, Haiyan Liu, Ling Fu, Weicheng Li, Yanxiang Ye, Zhibo Hu, Ziyuan Chao & Yuping Ning Click Here to Read the Full Article

This article was published on June 9, 2023 in the Journal of Pain and Symptom Management. Due to restrictions, this article must be accessed off platform. Click the link below to access the full article.  Click Here to Read the Full Article

BACKGROUND Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was −10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, −0.9±1.1 in the ketamine group vs. −9.7±1.2 in the ECT group; scores range from −300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968..) Click Here to Read the Full Article

BACKGROUND Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was −10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, −0.9±1.1 in the ketamine group vs. −9.7±1.2 in the ECT group; scores range from −300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968..) Click Here to Read the Full Article

COVID, COVID-19, depression, Ketamine, suicidality, suicide

Sharma Meha, Satish Suhas, Naren P Rao, Successful use of ketamine to treat severe depression with suicidality post-COVID-19 - A case report, Psychiatry Research Case Reports, Volume 2, Issue 1, 2023, 100100, ISSN 2773-0212, https://doi.org/10.1016/j.psycr.2022.100100. (https://www.sciencedirect.com/science/article/pii/S277302122200092X) Abstract: Every second patient who suffers from COVID-19 experiences is at risk for depression. The treatment of severe depression with suicidal risk is challenging in patients with COVID-19 given the restrictions in access to and safety concerns with the use of electroconvulsive therapy during the COVID pandemic. Although ketamine is effective in treating depression, especially in presence of acute suicidality, to date, there are no reports on ketamine use to treat severe depression in the context of COVID-19. In this case report, we describe the success of ketamine to treat a person with severe depression and suicidality following COVID-19 infection.Keywords: Depression; Electroconvulsive therapy; Pharmacotherapy; Suicide; Treatment; Case report; Ketamine; COVID-19 Click Here to Read the Full Article

COVID, COVID-19, depression, Ketamine, suicidality, suicide

Sharma Meha, Satish Suhas, Naren P Rao, Successful use of ketamine to treat severe depression with suicidality post-COVID-19 - A case report, Psychiatry Research Case Reports, Volume 2, Issue 1, 2023, 100100, ISSN 2773-0212, https://doi.org/10.1016/j.psycr.2022.100100. (https://www.sciencedirect.com/science/article/pii/S277302122200092X) Abstract: Every second patient who suffers from COVID-19 experiences is at risk for depression. The treatment of severe depression with suicidal risk is challenging in patients with COVID-19 given the restrictions in access to and safety concerns with the use of electroconvulsive therapy during the COVID pandemic. Although ketamine is effective in treating depression, especially in presence of acute suicidality, to date, there are no reports on ketamine use to treat severe depression in the context of COVID-19. In this case report, we describe the success of ketamine to treat a person with severe depression and suicidality following COVID-19 infection.Keywords: Depression; Electroconvulsive therapy; Pharmacotherapy; Suicide; Treatment; Case report; Ketamine; COVID-19 Click Here to Read the Full Article

depression, Ketamine

Sahil Jamal, Sujita Kumar Kar, Amit Singh, Switching from parenteral to oral formulation of ketamine in the management of severe depressive episode, Psychiatry Research Case Reports, Volume 2, Issue 1, 2023, 100119, ISSN 2773-0212, https://doi.org/10.1016/j.psycr.2023.100119.(https://www.sciencedirect.com/science/article/pii/S2773021223000172) Abstract: Ketamine is a dissociative anaesthetic and a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors. In cases of Major Depressive Disorder (MDD) and Bipolar Depression, Ketamine may quickly alleviate depressive symptoms. Researchers discovered a comparable decline in suicidal thoughts among MDD patients receiving intravenous boluses in the emergency room. A patient with a severe depressive episode who had previously attempted suicide once and had suicidal thoughts was hospitalised in our department after exhibiting lithium toxicity symptoms and receiving treatment for two months. He received conservative treatment for lithium toxicity and was scheduled to administer Ketamine to reduce his depressive symptoms and suicidal thoughts quickly. Over the course of two weeks, ketamine administration six sessions (the first two intravenous and the latter four by oral route) were given. An excellent clinical response was noted a few hours after the initial session. This improvement was successfully maintained over the course of the next five sessions, reducing depressive symptoms and the risk of suicide. After six sessions, the Hamilton Depression Rating Scale score dropped from 24 to 10. Few side effects were present only during administration and disappeared completely after 2 hours. Findings suggest that Ketamine can be administered safely to a patient with major depressive disorder even in the background of lithium toxicity, to manage depressive symptoms and suicidal thoughts quickly. Venlafaxine and Ketamine are well tolerated when administered simultaneously. When necessary, oral ketamine administration can be used instead of intravenous infusion because it is non-invasive and well-accepted by the patient. Click Here to Read the Full Article

depression, Ketamine

Sahil Jamal, Sujita Kumar Kar, Amit Singh, Switching from parenteral to oral formulation of ketamine in the management of severe depressive episode, Psychiatry Research Case Reports, Volume 2, Issue 1, 2023, 100119, ISSN 2773-0212, https://doi.org/10.1016/j.psycr.2023.100119.(https://www.sciencedirect.com/science/article/pii/S2773021223000172) Abstract: Ketamine is a dissociative anaesthetic and a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors. In cases of Major Depressive Disorder (MDD) and Bipolar Depression, Ketamine may quickly alleviate depressive symptoms. Researchers discovered a comparable decline in suicidal thoughts among MDD patients receiving intravenous boluses in the emergency room. A patient with a severe depressive episode who had previously attempted suicide once and had suicidal thoughts was hospitalised in our department after exhibiting lithium toxicity symptoms and receiving treatment for two months. He received conservative treatment for lithium toxicity and was scheduled to administer Ketamine to reduce his depressive symptoms and suicidal thoughts quickly. Over the course of two weeks, ketamine administration six sessions (the first two intravenous and the latter four by oral route) were given. An excellent clinical response was noted a few hours after the initial session. This improvement was successfully maintained over the course of the next five sessions, reducing depressive symptoms and the risk of suicide. After six sessions, the Hamilton Depression Rating Scale score dropped from 24 to 10. Few side effects were present only during administration and disappeared completely after 2 hours. Findings suggest that Ketamine can be administered safely to a patient with major depressive disorder even in the background of lithium toxicity, to manage depressive symptoms and suicidal thoughts quickly. Venlafaxine and Ketamine are well tolerated when administered simultaneously. When necessary, oral ketamine administration can be used instead of intravenous infusion because it is non-invasive and well-accepted by the patient. Click Here to Read the Full Article

AUTHOR=Batievsky Daniella, Weiner Michelle, Kaplan Shari B., Thase Michael Edward, Maglione Domenick Nicholas, Vidot Denise Christina TITLE=Ketamine-assisted psychotherapy treatment of chronic pain and comorbid depression: a pilot study of two approaches JOURNAL=Frontiers in Pain Research VOLUME=4 YEAR=2023 URL=https://www.frontiersin.org/articles/10.3389/fpain.2023.1127863 DOI=10.3389/fpain.2023.1127863 ISSN=2673-561X ABSTRACT=Chronic pain and depression diagnoses are skyrocketing. There is an urgent need for more effective treatments. Ketamine was recently established to alleviate pain and depression, but many gaps remain in the scientific literature. This paper reports the findings of an observational preliminary study that explored the efficacy of ketamine-assisted psychotherapy (KAPT) for chronic pain/major depressive disorder (MDD) comorbidity. Researchers evaluated two KAPT approaches to determine optimal route of administration/dose. Ten individuals diagnosed with a chronic pain disorder and MDD receiving KAPT were recruited: five individuals pursuing the psychedelic approach (high doses administered intramuscularly 24 h before therapy) and five individuals pursuing the psycholytic approach (low doses administered sublingually via oral lozenges during therapy). To evaluate differences between altered states of consciousness each approach induces, participants completed the Mystical Experience Questionnaire (MEQ30) after their first (T-1), third (T-2) and sixth/final (T-3) treatment sessions. Primary outcomes were change in Beck Depression Inventory (BDI) scores and Brief Pain Inventory (BPI) Short Form scores from baseline (T0) to (T-1)–(T-3). Secondary outcomes were changes in Generalized Anxiety Disorder (GAD-7) Scale scores and Post-Traumatic Stress Disorder Checklist (PCL-5) scores at each timepoint. Statistically significant differences between each approach were not observed, but the small sample’s limited statistical power makes changes seen worth noting. All participants’ symptoms declined throughout treatment. Psychedelic treatment participants saw a larger, more consistent decrease. Researchers conclude that KAPT may be effective for treating chronic pain/MDD comorbidity, anxiety and Post-Traumatic Stress Disorder (PTSD). Findings imply that the psychedelic approach may be more effective. This pilot study serves as a basis for more extensive research that will inform how clinicians administer treatment to optimize outcomes. Click Here to Read the Full Article

Ketamine, ketamine-assisted psychotherapy, ketamine-assisted therapy

Kew, B. M., Porter, R. J., Douglas, K. M., Glue, P., Mentzel, C. L., & Beaglehole, B. (2023). Ketamine and psychotherapy for the treatment of psychiatric disorders: systematic review. BJPsych open, 9(3), e79. https://doi.org/10.1192/bjo.2023.53 BackgroundKetamine is an effective short-term treatment for a range of psychiatric disorders. A key question is whether the addition of psychotherapy to ketamine treatment improves outcomes or delays relapse. AimTo identify all studies combining psychotherapy with ketamine for the treatment of psychiatric disorders to summarise their effects and make recommendations for future research. MethodThe review protocol was prospectively registered with PROSPERO (registration number CRD42022318120). Potential studies were searched for in MEDLINE, Embase, PsycINFO, SCOPUS, the Cochrane library and Google Scholar. Eligible studies combined ketamine and psychotherapy for the treatment of psychiatric disorders and did not use case reports or qualitative designs. Key findings relating to psychotherapy type, diagnosis, ketamine protocol, sequencing of psychotherapy and study design are reported. Risk of bias was assessed using modified Joanna Briggs critical appraisal tools. ResultsNineteen studies evaluating 1006 patients were included in the systematic review. A variety of supportive individual and group, manualised and non-manualised psychotherapies were used. The majority of studies evaluated substance use disorders, post-traumatic stress disorder and treatment-resistant depression. Ketamine protocols and sequencing of ketamine/psychotherapy treatment varied substantially between studies. Outcomes were largely positive for the addition of psychotherapy to ketamine treatment. ConclusionThe combination of psychotherapy and ketamine offers promise for the treatment of psychiatric disorders, but study heterogeneity prevents definitive recommendations for their integration. Larger randomised controlled trials using manualised psychotherapies and standardised ketamine protocols are recommended to clarify the extent to which the addition of psychotherapy to ketamine improves outcomes over ketamine treatment alone.Click Here to Read the Full Article

Ketamine, ketamine infusion, PTSD, TBI

Eugene Lipov, Zubin Sethi, Guriqbal Nandra, Christopher Frueh, Efficacy of combined subanesthetic ketamine infusion and cervical sympathetic blockade as a symptomatic treatment of PTSD/TBI in a special forces patient with a 1-year follow-up: A case report, Heliyon, Volume 9, Issue 4, 2023, e14891, ISSN 2405-8440, https://doi.org/10.1016/j.heliyon.2023.e14891.(https://www.sciencedirect.com/science/article/pii/S2405844023020984) Abstract: Co-occurrence of posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) symptoms are particularly prevalent in the special operations forces' community, along with other related conditions (e.g., endocrine dysregulation, sleep disorders, chronic pain). Ketamine infusion (KI) has been shown to increase neuroplasticity as well as memory improvement and cervical sympathetic block (CSB) has been shown to improve cognitive function, reduce sympathetic overactivity, and improve other symptoms of PTSD. We want to report the efficacious use of a single intervention consisting of bilateral CSB technique with subanesthetic KI X5 in a Special Operations Forces patient, diagnosed with PTSD with comorbid TBI, evaluated during treatment and at 1-year follow-up. We postulated KI and CSB would have a synergistic effect. Our patient received KI starting at 0.5 mg/kg, which was escalated daily. KI was combined with right-sided ultrasound-guided CSB (C6 and C4 levels). This was followed the next day by left-sided CSB and KI. Patient's PTSD symptoms were evaluated using the Posttraumatic Stress Disorder Checklist (PCL-5), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), suicidal ideation and other related factors by Concise Health Risk Tracking Self Report (CHRTSR). All measures were assessed prior to treatment, during treatment, and 394 days after. KI combined with CSB showed immediate and prolonged benefits 394 days later regarding the symptoms of PTSD, anxiety, depression, suicidal ideation, and cognitive deterioration (patient report). KI combined with CSB can markedly reduce symptoms of PTSD, psychiatric comorbidities, and cognitive dysfunction.

depression, major depression, psilocybin, TRD

Abstract: "Background: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints. Methods: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. Results: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. Limitations: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. Conclusions: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients." Click Here to Read the Full Article Guy M. Goodwin, Scott T. Aaronson, Oscar Alvarez, Merve Atli, James C. Bennett, Megan Croal, Charles DeBattista, Boadie W. Dunlop, David Feifel, David J. Hellerstein, Muhammad Ishrat Husain, John R. Kelly, Molly R. Lennard-Jones, Rasmus W. Licht, Lindsey Marwood, Sunil Mistry, Tomáš Páleníček, Ozlem Redjep, Dimitris Repantis, Robert A. Schoevers, Batya Septimus, Hollie J. Simmons, Jair C. Soares, Metten Somers, Susan C. Stansfield, Jessica R. Stuart, Hannah H. Tadley, Nisha K. Thiara, Joyce Tsai, Mourad Wahba, Sam Williams, Rachel I. Winzer, Allan H. Young, Matthew B. Young, Sid Zisook, Ekaterina Malievskaia, Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life, Journal of Affective Disorders, Volume 327, 2023, Pages 120-127, ISSN 0165-0327, https://doi.org/10.1016/j.jad.2023.01.108. (https://www.sciencedirect.com/science/article/pii/S016503272300126Xv)

depression, major depression, psilocybin, TRD

Abstract: "Background: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints. Methods: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. Results: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. Limitations: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. Conclusions: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients." Click Here to Read the Full Article Guy M. Goodwin, Scott T. Aaronson, Oscar Alvarez, Merve Atli, James C. Bennett, Megan Croal, Charles DeBattista, Boadie W. Dunlop, David Feifel, David J. Hellerstein, Muhammad Ishrat Husain, John R. Kelly, Molly R. Lennard-Jones, Rasmus W. Licht, Lindsey Marwood, Sunil Mistry, Tomáš Páleníček, Ozlem Redjep, Dimitris Repantis, Robert A. Schoevers, Batya Septimus, Hollie J. Simmons, Jair C. Soares, Metten Somers, Susan C. Stansfield, Jessica R. Stuart, Hannah H. Tadley, Nisha K. Thiara, Joyce Tsai, Mourad Wahba, Sam Williams, Rachel I. Winzer, Allan H. Young, Matthew B. Young, Sid Zisook, Ekaterina Malievskaia, Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life, Journal of Affective Disorders, Volume 327, 2023, Pages 120-127, ISSN 0165-0327, https://doi.org/10.1016/j.jad.2023.01.108. (https://www.sciencedirect.com/science/article/pii/S016503272300126Xv)

addiction, alcohol misuse, psychedelic treatment, substance use disorder

Raman Sharma, Rachel Batchelor & Jacqueline Sin (2023) Psychedelic Treatments for Substance Use Disorder and Substance Misuse: A Mixed Methods Systematic Review, Journal of Psychoactive Drugs, DOI: 10.1080/02791072.2023.2190319 Abstract: Renewed interest in psychedelic substances in the 21st century has seen the exploration of psychedelic treatments for various psychiatric disorders including substance use disorder (SUD). This review aimed to assess the effectiveness of psychedelic treatments for people with SUD and those falling below diagnostic thresholds (i.e. substance misuse). We systematically searched 11 databases, trial registries, and psychedelic organization websites for empirical studies examining adults undergoing psychedelic treatment for SUD or substance misuse, published in the English language, between 2000 and 2021. Seven studies investigating treatment using psilocybin, ibogaine, and ayahuasca, alone or adjunct with psychotherapy reported across 10 papers were included. Measures of abstinence, substance use, psychological and psychosocial outcomes, craving, and withdrawal reported positive results, however, this data was scarce among studies examining a wide range of addictions including opioid, nicotine, alcohol, cocaine and unspecified substance. The qualitative synthesis from three studies described subjective experience of psychedelic-assisted treatments enhanced self-awareness, insight, and confidence. At present, there is no sufficient research evidence to suggest effectiveness of any of the psychedelics on any specific substance use disorder or substance misuse. Further research using rigorous effectiveness evaluation methods with larger sample sizes and longer-term follow-up is required.

Reid Robison, Madeline Brendle, Claire Moore, Hannah Cross, Lindsay Helm, Shannon Darling, Stephen Thayer, Paul Thielking & Scott Shannon (2023) Ketamine-Assisted Group Psychotherapy for Frontline Healthcare Workers with COVID-19-Related Burnout and PTSD: A Case Series of Effectiveness/Safety for 10 Participants, Journal of Psychoactive Drugs, DOI: 10.1080/02791072.2023.2186285 "This study reports on 10 frontline healthcare workers, employed during the COVID-19 pandemic and experiencing symptoms of burnout and PTSD, treated with group ketamine-assisted psychotherapy (KAP) in a private outpatient clinic setting. Participants attended 6 sessions once weekly. These included 1 preparation session, 3 ketamine sessions (2 sublingual, 1 intramuscular), 2 integration sessions. Measures of PTSD (PCL-5), depression (PHQ-9), and anxiety (GAD-7) were administered at baseline and post-treatment. During ketamine sessions, the Emotional Breakthrough Inventory (EBI) and the 30-item Mystical Experience Questionnaire (MEQ-30) were recorded. Participant feedback was gathered 1-month post-treatment. We observed improvements in participants' average PCL-5 (59% reduction), PHQ-9 (58% reduction), and GAD-7 (36% reduction) scores from pre- to post-treatment. At post-treatment, 100% of participants screened negative for PTSD, 90% had minimal/mild depression or clinically significant improvement, and 60% had minimal/mild anxiety or clinically significant improvement. MEQ and EBI scores had large variations among participants at each ketamine session. Ketamine was well tolerated, and no significant adverse events were reported. Participant feedback corroborated findings of improvements observed in mental health symptoms. We found immediate improvements treating 10 frontline healthcare workers experiencing burnout, PTSD, depression, and anxiety using weekly group KAP and integration." Click Here to Read the Full Article 

Summary Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A Î²-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications. Click Here to Read the Full Article

Summary Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A Î²-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications. Click Here to Read the Full Article

addiction, Alcohol Use Disorder, Alcoholism

Jaguga, F., Kirwa, P., Gakinya, B. et al. Intravenous ketamine for severe alcohol use disorder at Moi Teaching & Referral Hospital, Kenya: a case report. Subst Abuse Treat Prev Policy 18, 11 (2023). https://doi.org/10.1186/s13011-023-00519-0 Abstract BackgroundAlcohol use disorder is prevalent globally and in Kenya, and is associated with significant health and socio-economic consequences. Despite this, available pharmacological treatment options are limited. Recent evidence indicates that intravenous (IV) ketamine can be beneficial for the treatment of alcohol use disorder, but is yet to be approved for this indication. Further, little has been done to describe the use of IV ketamine for alcohol use disorder in Africa. The goal of this paper, is to: 1) describe the steps we took to obtain approval and prepare for off-label use of IV ketamine for patients with alcohol use disorder at the second largest hospital in Kenya, and 2) describe the presentation and outcomes of the first patient who received IV ketamine for severe alcohol use disorder at the hospital.Case presentationIn preparing for the off-label use of ketamine for alcohol use disorder, we brought together a multi-disciplinary team of clinicians including psychiatrists, pharmacists, ethicists, anesthetists, and members of the drug and therapeutics committee, to spearhead the process. The team developed a protocol for administering IV ketamine for alcohol use disorder that took into account ethical and safety issues. The national drug regulatory authority, the Pharmacy and Poison's Board, reviewed and approved the protocol.Our first patient was a 39-year-old African male with severe alcohol use disorder and comorbid tobacco use disorder and bipolar disorder. The patient had attended in-patient treatment for alcohol use disorder six times and each time had relapsed between one to four months after discharge. On two occasions, the patient had relapsed while on optimal doses of oral and implant naltrexone. The patient received IV ketamine infusion at a dose of 0.71 mg/kg. The patient relapsed within one week of receiving IV ketamine while on naltrexone, mood stabilizers, and nicotine replacement therapy.Discussion & conclusionsThis case report describes for the first time the use of IV ketamine for alcohol use disorder in Africa. Findings will be useful in informing future research and in guiding other clinicians interested in administering IV ketamine for patients with alcohol use disorder.

addiction, Alcohol Use Disorder, Alcoholism

Jaguga, F., Kirwa, P., Gakinya, B. et al. Intravenous ketamine for severe alcohol use disorder at Moi Teaching & Referral Hospital, Kenya: a case report. Subst Abuse Treat Prev Policy 18, 11 (2023). https://doi.org/10.1186/s13011-023-00519-0 Abstract BackgroundAlcohol use disorder is prevalent globally and in Kenya, and is associated with significant health and socio-economic consequences. Despite this, available pharmacological treatment options are limited. Recent evidence indicates that intravenous (IV) ketamine can be beneficial for the treatment of alcohol use disorder, but is yet to be approved for this indication. Further, little has been done to describe the use of IV ketamine for alcohol use disorder in Africa. The goal of this paper, is to: 1) describe the steps we took to obtain approval and prepare for off-label use of IV ketamine for patients with alcohol use disorder at the second largest hospital in Kenya, and 2) describe the presentation and outcomes of the first patient who received IV ketamine for severe alcohol use disorder at the hospital.Case presentationIn preparing for the off-label use of ketamine for alcohol use disorder, we brought together a multi-disciplinary team of clinicians including psychiatrists, pharmacists, ethicists, anesthetists, and members of the drug and therapeutics committee, to spearhead the process. The team developed a protocol for administering IV ketamine for alcohol use disorder that took into account ethical and safety issues. The national drug regulatory authority, the Pharmacy and Poison's Board, reviewed and approved the protocol.Our first patient was a 39-year-old African male with severe alcohol use disorder and comorbid tobacco use disorder and bipolar disorder. The patient had attended in-patient treatment for alcohol use disorder six times and each time had relapsed between one to four months after discharge. On two occasions, the patient had relapsed while on optimal doses of oral and implant naltrexone. The patient received IV ketamine infusion at a dose of 0.71 mg/kg. The patient relapsed within one week of receiving IV ketamine while on naltrexone, mood stabilizers, and nicotine replacement therapy.Discussion & conclusionsThis case report describes for the first time the use of IV ketamine for alcohol use disorder in Africa. Findings will be useful in informing future research and in guiding other clinicians interested in administering IV ketamine for patients with alcohol use disorder.

Abstract:  "Background: Previous research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo group (NCT03537014). This raises important questions regarding potential mechanisms of MDMA-assisted therapy. In the present study, we examined epigenetic changes in three key HPA axis genes before and after MDMA and placebo with therapy. As a pilot sub-study to the parent clinical trial, we assessed potential HPA epigenetic predictors for treatment response with genomic DNA derived from saliva (MDMA, n = 16; placebo, n = 7). Methylation levels at all 259 CpG sites annotated to three HPA genes (CRHR1, FKBP5, and NR3C1) were assessed in relation to treatment response as measured by the Clinician-Administered PTSD Scale (CAPS-5; Total Severity Score). Second, group (MDMA vs. placebo) differences in methylation change were assessed for sites that predicted treatment response. Results: Methylation change across groups significantly predicted symptom reduction on 37 of 259 CpG sites tested, with two sites surviving false discovery rate (FDR) correction. Further, the MDMA-treatment group showed more methylation change compared to placebo on one site of the NR3C1 gene. Conclusion: The findings of this study suggest that therapy-related PTSD symptom improvements may be related to DNA methylation changes in HPA genes and such changes may be greater in those receiving MDMA-assisted therapy. These findings can be used to generate hypothesis driven analyses for future studies with larger cohorts." Authors: Candace R. Lewis, Joseph Tafur, Sophie Spencer, Joseph M. Green, Charlotte Harrison, Benjamin Kelmendi, David M. Rabin, Rachel Yehuda, Berra Yazar-Klosinski & Baruch R. Cahn Click Here to Read the Full Article

Mathai, D.S., Nayak, S.M., Yaden, D.B. et al. Reconsidering "dissociation" as a predictor of antidepressant efficacy for esketamine. Psychopharmacology 240, 827-836 (2023). https://doi.org/10.1007/s00213-023-06324-8 Abstract: "Rationale The relationship between subjective drug experience and antidepressant outcomes for ketamine derivatives is poorly understood but of high clinical relevance. Esketamine is the patented (S)-enantiomer of ketamine and has regulatory approval for psychiatric applications. Objectives We examined the relationship between acute dissociation, as measured by the Clinician-Administered Dissociative States Scale (CADSS), and antidepressant efficacy, as measured by the Montgomery-Ã…sberg Depression Rating Scale (MADRS), for esketamine across the 4-week induction phase of treatment. Methods This post hoc analysis combined data (N=576) from the TRANSFORM-1 and TRANSFORM-2 clinical trials of esketamine for treatment-resistant depression. Linear mixed models were performed using total MADRS score as the outcome variable with the following independent variables: baseline MADRS score, treatment condition×time interaction, and CADSS×time interaction. To assess whether initial dissociation predicted rapid antidepressant benefit with esketamine, a separately planned regression was performed with day 2 MADRS as the outcome variable with the following dependent variables: baseline MADRS, treatment condition, and day 1 CADSS. Results The linear mixed model did not show any effect of a CADSS×time interaction (p=0.7). Looking solely at the effect of day 1 CADSS on day 2 MADRS revealed that each additional CADSS point was associated with a−.04 [95% CI−.08,−.002] (p=.04) decrease in MADRS score. Conclusions We found no evidence of a clinically significant positive or negative association between dissociation and antidepressant effect for esketamine. Our findings suggest that subsequent inquiry in this area will benefit from improved characterization of drug experiences relevant to therapeutic outcomes." Authors: David S. Mathai, Sandeep M. Nayak, David B. Yaden & Albert Garcia-Romeu Click Here to Read the Full Article

Abstract:  "Antidepressants require several weeks for the onset of action, a lag time that may exceed life expectancy in palliative care. Ketamine has demonstrated rapid antidepressant effects, but has been minimally studied in cancer and palliative care populations. Herein, the objective was to determine the feasibility, safety, tolerability and preliminary efficacy of intranasal racemic ketamine for major depressive disorder (MDD) in patients with advanced cancer. We conducted a single-arm, open-label phase II trial at the Princess Margaret Cancer Centre in Toronto, ON, Canada. Participants with advanced cancer with moderate to severe MDD received three flexible doses of intranasal (IN) ketamine (50-150 mg) over a one-week period. The primary efficacy outcome was an antidepressant response and remission rates as determined by the Montgomery-Ã…sberg Depression Rating Scale (MADRS) from baseline to the Day 8 primary endpoint. Twenty participants were enrolled in the trial, receiving at least one dose of IN ketamine, with fifteen participants receiving all three doses. The Day 8 antidepressant response (MADRS decreased by >50%) and remission (MADRS < 10 on Day 8) rates were high at 70% and 45%, respectively. Mean MADRS scores decreased significantly from baseline (mean MADRS of 31, standard deviation 7.6) to Day 8 (11 +/− 7.4) with an overall decrease of 20 points (p < 0.001). Antidepressant effects were partially sustained in the second week in the absence of additional ketamine doses, with a Day 14 mean MADRS score of 14 +/− 9.9. Common adverse effects included fatigue, dissociation, nausea, dysgeusia and headaches; almost all adverse effects were mild and transient, resolving within 2 h of each ketamine dose with one dropout related to adverse effects (negative dissociative episode). Given these promising findings, larger, controlled trials are merited." Authors: Joshua D. Rosenblat, Froukje E. deVries, Zoe Doyle, Roger S. McIntyre, Gary Rodin, Camilla Zimmermann, Ernie Mak, Breffni Hannon, Christian Schulz-Quach, Aida Al Kindy, Zeal Patel & Madeline Li Click Here to Read the Full Article

Abstract:  "Antidepressants require several weeks for the onset of action, a lag time that may exceed life expectancy in palliative care. Ketamine has demonstrated rapid antidepressant effects, but has been minimally studied in cancer and palliative care populations. Herein, the objective was to determine the feasibility, safety, tolerability and preliminary efficacy of intranasal racemic ketamine for major depressive disorder (MDD) in patients with advanced cancer. We conducted a single-arm, open-label phase II trial at the Princess Margaret Cancer Centre in Toronto, ON, Canada. Participants with advanced cancer with moderate to severe MDD received three flexible doses of intranasal (IN) ketamine (50-150 mg) over a one-week period. The primary efficacy outcome was an antidepressant response and remission rates as determined by the Montgomery-Ã…sberg Depression Rating Scale (MADRS) from baseline to the Day 8 primary endpoint. Twenty participants were enrolled in the trial, receiving at least one dose of IN ketamine, with fifteen participants receiving all three doses. The Day 8 antidepressant response (MADRS decreased by >50%) and remission (MADRS < 10 on Day 8) rates were high at 70% and 45%, respectively. Mean MADRS scores decreased significantly from baseline (mean MADRS of 31, standard deviation 7.6) to Day 8 (11 +/− 7.4) with an overall decrease of 20 points (p < 0.001). Antidepressant effects were partially sustained in the second week in the absence of additional ketamine doses, with a Day 14 mean MADRS score of 14 +/− 9.9. Common adverse effects included fatigue, dissociation, nausea, dysgeusia and headaches; almost all adverse effects were mild and transient, resolving within 2 h of each ketamine dose with one dropout related to adverse effects (negative dissociative episode). Given these promising findings, larger, controlled trials are merited." Authors: Joshua D. Rosenblat, Froukje E. deVries, Zoe Doyle, Roger S. McIntyre, Gary Rodin, Camilla Zimmermann, Ernie Mak, Breffni Hannon, Christian Schulz-Quach, Aida Al Kindy, Zeal Patel & Madeline Li Click Here to Read the Full Article

David M. O'Shaughnessy, Zoltán Sarnyai, Frances Quirk, Robin Rodd, Traditional Amazonian medicine in addiction treatment: Qualitative results, SSM - Qualitative Research in Health, Volume 2, 2022, 100086, ISSN 2667-3215,https://doi.org/10.1016/j.ssmqr.2022.100086.(https://www.sciencedirect.com/science/article/pii/S2667321522000488) Abstract: Traditional Amazonian medicine, and in particular the psychoactive substance ayahuasca, has generated significant research interest along with the recent revival of psychedelic medicine. Previously we published within-treatment quantitative results from a residential addiction treatment centre that predominately employs Peruvian traditional Amazonian medicine, and here we follow up that work with a qualitative study of within-treatment patient experiences. Open-ended interviews with 9 inpatients were conducted from 2014 to 2015, and later analysed using thematic analysis. Our findings support the possibility of therapeutic effects from Amazonian medicine, but also highlight the complexity of Amazonian medical practices, suggesting that the richness of such traditions should not be reduced to the use of ayahuasca only. Click Here to Read the Full Article

David M. O'Shaughnessy, Zoltán Sarnyai, Frances Quirk, Robin Rodd, Traditional Amazonian medicine in addiction treatment: Qualitative results, SSM - Qualitative Research in Health, Volume 2, 2022, 100086, ISSN 2667-3215,https://doi.org/10.1016/j.ssmqr.2022.100086.(https://www.sciencedirect.com/science/article/pii/S2667321522000488) Abstract: Traditional Amazonian medicine, and in particular the psychoactive substance ayahuasca, has generated significant research interest along with the recent revival of psychedelic medicine. Previously we published within-treatment quantitative results from a residential addiction treatment centre that predominately employs Peruvian traditional Amazonian medicine, and here we follow up that work with a qualitative study of within-treatment patient experiences. Open-ended interviews with 9 inpatients were conducted from 2014 to 2015, and later analysed using thematic analysis. Our findings support the possibility of therapeutic effects from Amazonian medicine, but also highlight the complexity of Amazonian medical practices, suggesting that the richness of such traditions should not be reduced to the use of ayahuasca only. Click Here to Read the Full Article

depression, major depressive disorder, MDD, psilocybin-assisted therapy

Robin von Rotz, Eva M. Schindowski, Johannes Jungwirth, Anna Schuldt, Nathalie M. Rieser, Katharina Zahoranszky, Erich Seifritz, Albina Nowak, Peter Nowak, Lutz Jäncke, Katrin H. Preller, Franz X. Vollenweider, Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo controlled, double-blind, randomised clinical trial, eClinicalMedicine, Volume 56, 2023, 101809, ISSN 2589-5370, https://doi.org/10.1016/j.eclinm.2022.101809. (https://www.sciencedirect.com/science/article/pii/S2589537022005387) Abstract: Background: Psilocybin has been suggested as a novel, rapid-acting treatment for depression. Two consecutive doses have been shown to markedly decrease symptom severity in an open-label setting or when compared to a waiting list group. To date, to our knowledge, no other trial compared a single, moderate dose of psilocybin to a placebo condition. Methods: In this double-blind, randomised clinical trial, 52 participants diagnosed with major depressive disorder and no unstable somatic conditions were allocated to receive either a single, moderate dose (0.215 mg/kg body weight) of psilocybin or placebo in conjunction with psychological support. MADRS and BDI scores were assessed to estimate depression severity, while changes from baseline to 14 days after the intervention were defined as primary endpoints. The trial took place between April 11th, 2019 and October 12th, 2021 at the psychiatric university hospital in Zürich, Switzerland and was registered with clinicaltrials.gov (NCT03715127). Findings: The psilocybin condition showed an absolute decrease in symptom severity of âˆ’13.0 points compared to baseline and were significantly larger than those in the placebo condition (95% CI âˆ’15.0 to âˆ’1.3; Cohens' d = 0.97; P = 0.0011; MADRS) and âˆ’13.2 points (95% CI; âˆ’13.4 to âˆ’1.3; Cohens' d = 0.67; P = 0.019; BDI) 14 days after the intervention. 14/26 (54%) participants met the MADRS remission criteria in the psilocybin condition. Interpretation: These results suggest that a single, moderate dose of psilocybin significantly reduces depressive symptoms compared to a placebo condition for at least two weeks. No serious adverse events were recorded. Larger, multi-centric trials with longer follow-up periods are needed to inform further optimisation of this novel treatment paradigm. Click Here to Read the Full Article

depression, major depressive disorder, MDD, psilocybin, psilocybin-assisted therapy

Robin von Rotz, Eva M. Schindowski, Johannes Jungwirth, Anna Schuldt, Nathalie M. Rieser, Katharina Zahoranszky, Erich Seifritz, Albina Nowak, Peter Nowak, Lutz Jäncke, Katrin H. Preller, Franz X. Vollenweider, Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo controlled, double-blind, randomised clinical trial, eClinicalMedicine, Volume 56, 2023, 101809, ISSN 2589-5370, https://doi.org/10.1016/j.eclinm.2022.101809. (https://www.sciencedirect.com/science/article/pii/S2589537022005387) Abstract: Background: Psilocybin has been suggested as a novel, rapid-acting treatment for depression. Two consecutive doses have been shown to markedly decrease symptom severity in an open-label setting or when compared to a waiting list group. To date, to our knowledge, no other trial compared a single, moderate dose of psilocybin to a placebo condition. Methods: In this double-blind, randomised clinical trial, 52 participants diagnosed with major depressive disorder and no unstable somatic conditions were allocated to receive either a single, moderate dose (0.215 mg/kg body weight) of psilocybin or placebo in conjunction with psychological support. MADRS and BDI scores were assessed to estimate depression severity, while changes from baseline to 14 days after the intervention were defined as primary endpoints. The trial took place between April 11th, 2019 and October 12th, 2021 at the psychiatric university hospital in Zürich, Switzerland and was registered with clinicaltrials.gov (NCT03715127). Findings: The psilocybin condition showed an absolute decrease in symptom severity of âˆ’13.0 points compared to baseline and were significantly larger than those in the placebo condition (95% CI âˆ’15.0 to âˆ’1.3; Cohens' d = 0.97; P = 0.0011; MADRS) and âˆ’13.2 points (95% CI; âˆ’13.4 to âˆ’1.3; Cohens' d = 0.67; P = 0.019; BDI) 14 days after the intervention. 14/26 (54%) participants met the MADRS remission criteria in the psilocybin condition. Interpretation: These results suggest that a single, moderate dose of psilocybin significantly reduces depressive symptoms compared to a placebo condition for at least two weeks. No serious adverse events were recorded. Larger, multi-centric trials with longer follow-up periods are needed to inform further optimisation of this novel treatment paradigm. Funding: The study was funded by the Swiss National Science Foundation, Crowdfunding, the Swiss Neuromatrix Foundation, and the Heffter Research Institute. Click Here to Read the Full Article

obsessive compulsive disorder, OCD, psilocybin

Benjamin Kelmendi, Stephen A. Kichuk, Giuliana DePalmer, Gayle Maloney, Terence H.W. Ching, Alexander Belser, Christopher Pittenger, Single-dose psilocybin for treatment-resistant obsessive compulsive disorder: A case report, Heliyon, Volume 8, Issue 12, 2022, e12135, ISSN 2405-8440, https://doi.org/10.1016/j.heliyon.2022.e12135. (https://www.sciencedirect.com/science/article/pii/S2405844022034235) Abstract: Classic psychedelics, such as psilocybin, act on the brain's serotonin system and produce striking psychological effects. Early work in the 1950s and 1960s and more recent controlled studies suggest benefit from psychedelic treatment in a number of conditions. A few case reports in recreational users and a single experimental study suggest benefit in patients with obsessive-compulsive disorder (OCD), but careful clinical data and long-term follow-up have been lacking. Here we describe a case of a patient with refractory OCD treated with psilocybin and followed prospectively for a year, with marked symptomatic improvement. We provide qualitative and quantitative detail of his experience during and after treatment. Improvement in OCD symptoms (YBOCS declined from 24 to 0-2) was accompanied by broader changes in his relationship to his emotions, social and work function, and quality of life. This individual was an early participant in an ongoing controlled study of psilocybin in the treatment of OCD (NCT03356483). These results are preliminary but promising, motivating ongoing investigations of the therapeutic potential of appropriately monitored and supported psychedelic treatment in the treatment of patients with obsessions and compulsions. Click Here to Read the Full Article

Kelly, Daniel F. MD*,‡; Heinzerling, Keith MD*,‡; Sharma, Akanksha MD*,‡; Gowrinathan, Shanthi MD*,‡; Sergi, Karina MS, MFT*; Mallari, Regin Jay BS*. Psychedelic-Assisted Therapy and Psychedelic Science: A Review and Perspective on Opportunities in Neurosurgery and Neuro-Oncology. Neurosurgery 92(4):p 680-694, April 2023. | DOI: 10.1227/neu.0000000000002275 Abstract: After a decades-long pause, psychedelics are again being intensely investigated for treating a wide range of neuropsychiatric ailments including depression, anxiety, addiction, post-traumatic stress disorder, anorexia, and chronic pain syndromes. The classic serotonergic psychedelics psilocybin and lysergic acid diethylamide and nonclassic psychedelics 3,4-methylenedioxymethamphetamine and ketamine are increasingly appreciated as neuroplastogens given their potential to fundamentally alter mood and behavior well beyond the time window of measurable exposure. Imaging studies with psychedelics are also helping advance our understanding of neural networks and connectomics. This resurgence in psychedelic science and psychedelic-assisted therapy has potential significance for the fields of neurosurgery and neuro-oncology and their diverse and challenging patients, many of whom continue to have mental health issues and poor quality of life despite receiving state-of-the-art care. In this study, we review recent and ongoing clinical trials, the http://webservices.ovid.com/mr..." style="box-sizing: inherit; color: rgb(51, 51, 51); font-family: "Fira Sans", Arial, "Helvetica Neue", Helvetica, sans-serif; font-size: 16px; font-variant-ligatures: normal; font-variant-caps: normal; font-weight: 400; letter-spacing: normal; orphans: 2; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: rgb(255, 255, 255); text-decoration-thickness: initial; text-decoration-style: initial; text-decoration-color: initial;">set and setting model of psychedelic-assisted therapy, potential risks and adverse events, proposed mechanisms of action, and provide a perspective on how the safe and evidence-based use of psychedelics could potentially benefit many patients, including those with brain tumors, pain syndromes, ruminative disorders, stroke, SAH, TBI, and movement disorders. By leveraging psychedelics' neuroplastic potential to rehabilitate the mind and brain, novel treatments may be possible for many of these patient populations, in some instances working synergistically with current treatments and in some using subpsychedelic doses that do not require mind-altering effects for efficacy. This review aims to encourage broader multidisciplinary collaboration across the neurosciences to explore and help realize the transdiagnostic healing potential of psychedelics.

depression, Ketamine, PTSD, suicide, Trauma

AUTHOR: Willms Joshua, McCauley Ben, Kerr Lindsay, Presto Peyton, Arun Ankith, Shah Nazeen, Irby Kierra, Strawn Megan, Kopel Jonathan TITLE: Case report: Medical student types journals during ketamine infusions for suicidal ideation, treatment-resistant depression, post-traumatic stress disorder, and generalized anxiety disorder JOURNAL: Frontiers in Psychiatry VOLUME: 13 YEAR: 2022 URL: https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1020214 DOI: 10.3389/fpsyt.2022.1020214 ISSN: 1664-0640 ABSTRACT: Suicide is the most common cause of death in male resident physicians and the second most common cause of death in resident physicians overall. Physicians also experience high rates of major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and burnout. These conditions frequently develop during medical school, and threaten not only physicians but the patients they care for. A 30-year-old medical student presented to our clinic with a history of treatment-resistant depression (TRD), generalized anxiety disorder (GAD), PTSD, and 5 years of daily suicidal ideation. Previous treatments included therapy, lifestyle modifications, and various combinations of six antidepressants. These interventions had little effect on the patient's mental health. The patient was treated at our clinic with an 8-month regimen of IV ketamine infusions and ketamine-assisted psychotherapy (KAP). The patient achieved remission from suicidality and PTSD within 1 month; and TRD and GAD within 7 months. The patient's Patient Health Questionnaire (PHQ-9) score decreased from 25 (severe depression) to 1 (not depressed). These findings suggest that ketamine and KAP may represent effective interventions for mental health applications in healthcare professionals. The patient made the unique decision to attempt to type narrative journals during four of his ketamine infusions (doses ranged from 1.8 to 2.1 mg/kg/h IV). The patient successfully typed detailed journals throughout each 1-h ketamine infusion. To our knowledge, these journals represent the first independently typed, first-person, real-time narratives of ketamine-induced non ordinary states of consciousness. The transcripts of these journals may provide useful insights for clinicians, particularly in the context of KAP.

depression, Ketamine, PTSD, suicide, Trauma

AUTHOR: Willms Joshua, McCauley Ben, Kerr Lindsay, Presto Peyton, Arun Ankith, Shah Nazeen, Irby Kierra, Strawn Megan, Kopel Jonathan TITLE: Case report: Medical student types journals during ketamine infusions for suicidal ideation, treatment-resistant depression, post-traumatic stress disorder, and generalized anxiety disorder JOURNAL: Frontiers in Psychiatry VOLUME: 13 YEAR: 2022 URL: https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1020214 DOI: 10.3389/fpsyt.2022.1020214 ISSN: 1664-0640 ABSTRACT: Suicide is the most common cause of death in male resident physicians and the second most common cause of death in resident physicians overall. Physicians also experience high rates of major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and burnout. These conditions frequently develop during medical school, and threaten not only physicians but the patients they care for. A 30-year-old medical student presented to our clinic with a history of treatment-resistant depression (TRD), generalized anxiety disorder (GAD), PTSD, and 5 years of daily suicidal ideation. Previous treatments included therapy, lifestyle modifications, and various combinations of six antidepressants. These interventions had little effect on the patient's mental health. The patient was treated at our clinic with an 8-month regimen of IV ketamine infusions and ketamine-assisted psychotherapy (KAP). The patient achieved remission from suicidality and PTSD within 1 month; and TRD and GAD within 7 months. The patient's Patient Health Questionnaire (PHQ-9) score decreased from 25 (severe depression) to 1 (not depressed). These findings suggest that ketamine and KAP may represent effective interventions for mental health applications in healthcare professionals. The patient made the unique decision to attempt to type narrative journals during four of his ketamine infusions (doses ranged from 1.8 to 2.1 mg/kg/h IV). The patient successfully typed detailed journals throughout each 1-h ketamine infusion. To our knowledge, these journals represent the first independently typed, first-person, real-time narratives of ketamine-induced non ordinary states of consciousness. The transcripts of these journals may provide useful insights for clinicians, particularly in the context of KAP.

Bogenschutz MP, Ross S, Bhatt S, et al. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2022;79(10):953-962. doi:10.1001/jamapsychiatry.2022.2096 Importance  Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown. Objective  To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy. Design, Setting, and Participants  In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD. Interventions  Study medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy. Main Outcomes and Measures  The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance. Results  A total of 95 participants (mean [SD] age, 46 [12] years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 3 (3.2%) were Asian, 4 (4.2%) were Black, 14 (14.7%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0-24.7; F1,86=6.43; P=.01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin. Conclusions and Relevance  Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD. Trial Registration  ClinicalTrials.gov Identifier: NCT02061293 Click Here to Read the Full Article

addiction, Cannabinoids, Ketamine, Noribogaine, opioids, withdrawal

Edinoff AN, Wu NW, Nix CA, et al. Historical Pathways for Opioid Addiction, Withdrawal with Traditional and Alternative Treatment Options with Ketamine, Cannabinoids, and Noribogaine: A Narrative Review. Health Psychology Research. 2022;10(4). doi:10.52965/001c.38672 Abstract: Even as prescription opioid dispensing rates have begun to decrease, the use of illicit opioids such as heroin and fentanyl has increased. Thus, the end of the opioid epidemic is not in sight, and treating patients that are addicted to opioids remains of utmost importance. Currently, the primary pharmacotherapies used to treat opioid addiction over the long term are the opioid antagonist naltrexone, the partial-agonist buprenorphine, and the full agonist methadone. Naloxone is an antagonist used to rapidly reverse opioid overdose. While these treatments are well-established and used regularly, the gravity of the opioid epidemic necessitates that all possible avenues of treatment be explored. Therefore, in this narrative review, we analyze current literature regarding use of the alternative medications ketamine, noribogaine, and cannabinoids in treating patients suffering from opioid use disorder. Beyond its use as an anesthetic, ketamine has been shown to have many applications in several medical specialties. Of particular interest to the subject at hand, ketamine is promising in treating individuals addicted to opioids, alcohol, and cocaine. Therapeutically administered cannabinoids have been proposed for the treatment of multiple illnesses. These include, but are not limited to epilepsy, Parkinson's disease, multiple sclerosis, chronic pain conditions, anxiety disorders, and addiction. The cannabinoid dronabinol has been seen to have varying effects. High doses appear to reduce withdrawal symptoms but this comes at the expense of increased adverse side effects such as sedation and tachycardia. Noribogaine is a weak MOR antagonist and relatively potent KOR agonist, which may explain the clinical anti-addictive effects. More research should be done to assess the viability of these medications for the treatment of OUD and withdrawal. Click Here to Read the Full Article

Anxiety, depression, Ketamine, telehealth

Thomas D. Hull, Matteo Malgaroli, Adam Gazzaley, Teddy J. Akiki, Alok Madan, Leonardo Vando, Kristin Arden, Jack Swain, Madeline Klotz, Casey Paleos, At-home, sublingual ketamine telehealth is a safe and effective treatment for moderate to severe anxiety and depression: Findings from a large, prospective, open-label effectiveness trial, Journal of Affective Disorders, Volume 314, 2022, Pages 59-67, ISSN 0165-0327, https://doi.org/10.1016/j.jad.2022.07.004 (https://www.sciencedirect.com/science/article/pii/S0165032722007625) Abstract: Background At-home Ketamine-assisted therapy (KAT) with psychosocial support and remote monitoring through telehealth platforms addresses access barriers, including the COVID-19 pandemic. Large-scale evaluation of this approach is needed for questions regarding safety and effectiveness for depression and anxiety. Methods In this prospective study, a large outpatient sample received KAT over four weeks through a telehealth provider. Symptoms were assessed using the Patient Health Questionnaire (PHQ-9) for depression, and the Generalized Anxiety Disorder scale (GAD-7) for anxiety. Demographics, adverse events, and patient-reported dissociation were also analyzed. Symptom trajectories were identified using Growth Mixture Modeling, along with outcome predictors. Results A sample of 1247 completed treatment with sufficient data, 62.8 % reported a 50 % or greater improvement on the PHQ-9, d = 1.61, and 62.9 % on the GAD-7, d = 1.56. Remission rates were 32.6 % for PHQ-9 and 31.3 % for GAD-7, with 0.9 % deteriorating on the PHQ-9, and 0.6 % on the GAD-7. Four patients left treatment early due to side effects or clinician disqualification, and two more due to adverse events. Three patient subpopulations emerged, characterized by Improvement (79.3 %), Chronic (11.4 %), and Delayed Improvement (9.3 %) for PHQ-9 and GAD-7. Endorsing side effects at Session 2 was associated with delayed symptom improvement, and Chronic patients were more likely than the other two groups to report dissociation at Session 4. Conclusion At-home KAT response and remission rates indicated rapid and significant antidepressant and anxiolytic effects. Rates were consistent with laboratory- and clinic-administered ketamine treatment. Patient screening and remote monitoring maintained low levels of adverse events. Future research should assess durability of effects. Keywords: Telemedicine; Major depression; Anxiety; Digital health; Ketamine-assisted therapy; Psychedelic-assisted therapy; Real-world Click Here to Read the Full Article

Barba, T., Buehler, S., Kettner, H., Radu, C., Cunha, B., Nutt, D., . . . Carhart-Harris, R. (2022). Effects of psilocybin versus escitalopram on rumination and thought suppression in depression. BJPsych Open, 8(5), E163. doi:10.1192/bjo.2022.565 doi:10.1192/bjo.2022.565

Barba, T., Buehler, S., Kettner, H., Radu, C., Cunha, B., Nutt, D., . . . Carhart-Harris, R. (2022). Effects of psilocybin versus escitalopram on rumination and thought suppression in depression. BJPsych Open, 8(5), E163. doi:10.1192/bjo.2022.565 doi:10.1192/bjo.2022.565

Manesh Girn, Leor Roseman, Boris Bernhardt, Jonathan Smallwood, Robin Carhart-Harris, R. Nathan Spreng, Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex, NeuroImage, Volume 256, 2022, 119220, ISSN 1053-8119,https://doi.org/10.1016/j.neuroimage.2022.119220.(https://www.sciencedirect.com/science/article/pii/S1053811922003445) Abstract: Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets (N = 15 and 9, respectively). Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping indicated that this was underpinned by a disruption of modular unimodal connectivity and increased unimodal-transmodal crosstalk. Results involving the second and third gradient, which, respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to an acute pharmacological manipulation, supporting a role for psychedelics as scientific tools to perturb cortical functional organization. Click Here to Read the Full Article

Manesh Girn, Leor Roseman, Boris Bernhardt, Jonathan Smallwood, Robin Carhart-Harris, R. Nathan Spreng, Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex, NeuroImage, Volume 256, 2022, 119220, ISSN 1053-8119,https://doi.org/10.1016/j.neuroimage.2022.119220.(https://www.sciencedirect.com/science/article/pii/S1053811922003445) Abstract: Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets (N = 15 and 9, respectively). Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping indicated that this was underpinned by a disruption of modular unimodal connectivity and increased unimodal-transmodal crosstalk. Results involving the second and third gradient, which, respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to an acute pharmacological manipulation, supporting a role for psychedelics as scientific tools to perturb cortical functional organization. Click Here to Read the Full Article

Bogenschutz MP, Ross S, Bhatt S, et al. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2022;79(10):953-962. doi:10.1001/jamapsychiatry.2022.2096 Importance  Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown. Objective  To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy. Design, Setting, and Participants  In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD. Interventions  Study medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy. Main Outcomes and Measures  The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance. Results  A total of 95 participants (mean [SD] age, 46 [12] years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 3 (3.2%) were Asian, 4 (4.2%) were Black, 14 (14.7%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0-24.7; F1,86=6.43; P=.01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin. Conclusions and Relevance  Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD. Trial Registration  ClinicalTrials.gov Identifier: NCT02061293 Click Here to Read the Full Article

Anxiety, psilocybin, social anxiety

Corinna L. Felsch, Kim P.C. Kuypers, Don't be afraid, try to meditate- potential effects on neural activity and connectivity of psilocybin-assisted mindfulness-based intervention for social anxiety disorder: A systematic review, Neuroscience & Biobehavioral Reviews, Volume 139, 2022, 104724, ISSN 0149 7634, https://doi.org/10.1016/j.neubiorev.2022.104724. (https://www.sciencedirect.com/science/article/pii/S0149763422002135) Abstract: Background: Current first-line treatment for social anxiety disorder (SAD), one of the most prevalent anxiety disorders, is limited in its efficacy. Hence, novel treatment approaches are urgently needed. The current review suggests a combination of meditation-based interventions and the administration of a psychedelic as a future alternative treatment approach. While both separate treatments show promise in the treatment of (other) clinical conditions, their combination has not yet been investigated in the treatment of psychopathologies. Aim: With a systematic literature review, we aim to identify the potential mechanisms by which combined psilocybin and mindfulness treatment could adjust anomalous neural activity underlying SAD and exert therapeutic effects. Results: Thirty experimental studies investigating the neural effects of meditation or psilocybin treatment in healthy and patient samples were included. Findings suggest that psilocybin-assisted meditation interventions might change cognitive processes like biased attention to threat linked to SAD by modulating connectivity of the salience network, balancing the activity and connectivity of cortical-midline structures, and increasing frontoparietal control over amygdala reactivity. Conclusions: Future studies should investigate whether psilocybin-assisted mindfulness-based intervention can provide therapeutic benefits to SAD patients who are do not remit following conventional therapy. Click Here to Read the Full Article

KAP, ketamine-assisted psychotherapy, Review

Abstract "Background: Few studies have evaluated the efficacy of ketamine-assisted psychotherapy (KAP) in the treatment of treatment-resistant depression (TRD) and substance use disorders (SUD).Methods: A systematic review of clinical trials reporting on the efficacy of KAP and discussing mechanisms of action, identified on PubMed and PsycInfo.Results: Five randomized-controlled trials reported on the efficacy of KAP treatment and discussed active mechanisms. Four of the studies treated adults with SUD and a single study treated adults with TRD. Overall, KAP had a significant positive effect on primary outcome measures compared to controls, however, the data is mixed. The study examining KAP for TRD found no benefit.Limitations: Lack of large, replicated clinical trials. No studies actively examining mechanisms of action.Conclusion: Evidence suggests that temporary neural changes caused by ketamine such as n-methyl-d-aspartate receptor (NMDAR) inhibition and increase of synaptic neuroplasticity affect treatment outcomes of KAP. Based on reports of preliminary findings, we speculate that adjunct psychotherapy, changes in perspective, and spirituality may also play a role." Click Here to View Full Article

Vincent Hartong & Arnold van Emmerik (2022) Psychedelic Microdosing, Mindfulness, and Anxiety: A Cross-Sectional Mediation Study, Journal of Psychoactive Drugs, DOI: 10.1080/02791072.2022.2080616

KAP, Ketamine Assisted Psychotherapy, ketamine-assisted psychotherapy

Drozdz SJ, Goel A, McGarr MW, Katz J, Ritvo P, Mattina GF, Bhat V, Diep C, Ladha KS. Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature. J Pain Res. 2022 Jun 15;15:1691-1706. doi: 10.2147/JPR.S360733. PMID: 35734507; PMCID: PMC9207256.

Drozdz SJ, Goel A, McGarr MW, Katz J, Ritvo P, Mattina GF, Bhat V, Diep C, Ladha KS. Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature. J Pain Res. 2022;15:1691-1706 https://doi.org/10.2147/JPR.S360733 Abstract: "Currently, ketamine is used in treating multiple pain, mental health, and substance abuse disorders due to rapid-acting analgesic and antidepressant effects. Its limited short-term durability has motivated research into the potential synergistic actions between ketamine and psychotherapy to sustain benefits. This systematic review on ketamine-assisted psychotherapy (KAP) summarizes existing evidence regarding present-day practices. Through rigorous review, seventeen articles that included 603 participants were identified. From available KAP publications, it is apparent that combined treatments can, in specific circumstances, initiate and prolong clinically significant reductions in pain, anxiety, and depressive symptoms, while encouraging rapport and treatment engagement, and promoting abstinence in patients addicted to other substances. Despite much variance in how KAP is applied (route of ketamine administration, ketamine dosage/frequency, psychotherapy modality, overall treatment length), these findings suggest psychotherapy, provided before, during, and following ketamine sessions, can maximize and prolong benefits. Additional large-scale randomized control trials are warranted to understand better the mutually influential relationships between psychotherapy and ketamine in optimizing responsiveness and sustaining long-term benefits in patients with chronic pain. Such investigations will assist in developing standardized practices and maintenance programs" Click Here to Read the Full Article

bipolar, depression, Ketamine

AUTHOR: Bennett Raquel, Yavorsky Christian, Bravo GaryTITLE: Ketamine for Bipolar Depression: Biochemical, Psychotherapeutic, and Psychedelic Approaches JOURNAL: Frontiers in Psychiatry VOLUME:13 YEAR: 2022 URL: https://www.frontiersin.org/articles/10.3389/fpsyt.2022.867484DOI: 10.3389/fpsyt.2022.867484 ISSN: 1664-0640 ABSTRACT: Bipolar disorder (type 1) is a serious and chronic psychiatric illness that can be difficult to treat. Many bipolar patients have refractory depressive episodes. Racemic ketamine, a glutamate modulator with prominent dissociate and psychedelic properties, has been demonstrated to have rapid acting antidepressant and anti-obsessional effects which may be useful for treating the symptoms of bipolar depression. Most of the existing research literature on unipolar and bipolar depression has looked at racemic ketamine in the sub-psychedelic dose range given by infusion as a stand-alone treatment (without concurrent psychotherapy). This article expands on the existing research by articulating three different paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The authors use composite clinical vignettes to illustrate different ways of working with ketamine to treat bipolar depression, and discuss a variety of clinical considerations for using ketamine with this population, including route, dose, frequency, chemical mitigators, and adverse events. Note that the conceptual paradigms could be applied to any ketamine treatment, with broad applicability beyond bipolar treatment.

bipolar, depression, Ketamine

AUTHOR: Bennett Raquel, Yavorsky Christian, Bravo GaryTITLE: Ketamine for Bipolar Depression: Biochemical, Psychotherapeutic, and Psychedelic Approaches JOURNAL: Frontiers in Psychiatry VOLUME:13 YEAR: 2022 URL: https://www.frontiersin.org/articles/10.3389/fpsyt.2022.867484DOI: 10.3389/fpsyt.2022.867484 ISSN: 1664-0640 ABSTRACT: Bipolar disorder (type 1) is a serious and chronic psychiatric illness that can be difficult to treat. Many bipolar patients have refractory depressive episodes. Racemic ketamine, a glutamate modulator with prominent dissociate and psychedelic properties, has been demonstrated to have rapid acting antidepressant and anti-obsessional effects which may be useful for treating the symptoms of bipolar depression. Most of the existing research literature on unipolar and bipolar depression has looked at racemic ketamine in the sub-psychedelic dose range given by infusion as a stand-alone treatment (without concurrent psychotherapy). This article expands on the existing research by articulating three different paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The authors use composite clinical vignettes to illustrate different ways of working with ketamine to treat bipolar depression, and discuss a variety of clinical considerations for using ketamine with this population, including route, dose, frequency, chemical mitigators, and adverse events. Note that the conceptual paradigms could be applied to any ketamine treatment, with broad applicability beyond bipolar treatment.

depression, Ketamine, Ketamine Treatment

Abstract: This manuscript reviews the clinical evidence regarding single-dose intravenous (IV) administration of the novel glutamatergic modulator racemic (R,S)-ketamine (hereafter referred to as ketamine) as well as its S-enantiomer, intranasal esketamine, for the treatment of major depressive disorder (MDD). Initial studies found that a single subanesthetic-dose IV ketamine infusion rapidly (within one day) improved depressive symptoms in individuals with MDD and bipolar depression, with antidepressant effects lasting three to seven days. In 2019, esketamine received FDA approval as an adjunctive treatment for treatment-resistant depression (TRD) in adults. Esketamine was approved under a risk evaluation and mitigation strategy (REMS) that requires administration under medical supervision. Both ketamine and esketamine are currently viable treatment options for TRD that offer the possibility of rapid symptom improvement. The manuscript also reviews ketamine's use in other psychiatric diagnoses-including suicidality, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse, and social anxiety disorder-and its potential adverse effects. Despite limited data, side effects for antidepressant-dose ketamine-including dissociative symptoms, hypertension, and confusion/agitation-appear to be tolerable and limited to around the time of treatment. Relatively little is known about ketamine's longer-term effects, including increased risks of abuse and/or dependence. Attempts to prolong ketamine's effects with combined therapy or a repeat-dose strategy are also reviewed, as are current guidelines for its clinical use. In addition to presenting a novel and valuable treatment option, studying ketamine also has the potential to transform our understanding of the mechanisms underlying mood disorders and the development of novel therapeutics. Yavi, M., Lee, H., Henter, I.D. et al. Ketamine treatment for depression: a review. Discov Ment Health 2, 9 (2022). https://doi.org/10.1007/s44192-022-00012-3 Click Here to Read the Full Article

depression, Ketamine, Ketamine Treatment

Abstract: This manuscript reviews the clinical evidence regarding single-dose intravenous (IV) administration of the novel glutamatergic modulator racemic (R,S)-ketamine (hereafter referred to as ketamine) as well as its S-enantiomer, intranasal esketamine, for the treatment of major depressive disorder (MDD). Initial studies found that a single subanesthetic-dose IV ketamine infusion rapidly (within one day) improved depressive symptoms in individuals with MDD and bipolar depression, with antidepressant effects lasting three to seven days. In 2019, esketamine received FDA approval as an adjunctive treatment for treatment-resistant depression (TRD) in adults. Esketamine was approved under a risk evaluation and mitigation strategy (REMS) that requires administration under medical supervision. Both ketamine and esketamine are currently viable treatment options for TRD that offer the possibility of rapid symptom improvement. The manuscript also reviews ketamine's use in other psychiatric diagnoses-including suicidality, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse, and social anxiety disorder-and its potential adverse effects. Despite limited data, side effects for antidepressant-dose ketamine-including dissociative symptoms, hypertension, and confusion/agitation-appear to be tolerable and limited to around the time of treatment. Relatively little is known about ketamine's longer-term effects, including increased risks of abuse and/or dependence. Attempts to prolong ketamine's effects with combined therapy or a repeat-dose strategy are also reviewed, as are current guidelines for its clinical use. In addition to presenting a novel and valuable treatment option, studying ketamine also has the potential to transform our understanding of the mechanisms underlying mood disorders and the development of novel therapeutics. Yavi, M., Lee, H., Henter, I.D. et al. Ketamine treatment for depression: a review. Discov Ment Health 2, 9 (2022). https://doi.org/10.1007/s44192-022-00012-3 Click Here to Read the Full Article

Daws, R.E., Timmermann, C., Giribaldi, B. et al. Increased global integration in the brain after psilocybin therapy for depression. Nat Med 28, 844-851 (2022). https://doi.org/10.1038/s41591-022-01744-zAbstract: Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10mg and 25mg, 7d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1d after the 25-mg dose. Beck's depression inventory was the primary outcome measure (MR/J00460X/1). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2×25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2×1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose (NCT03429075). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.Click Here to Read the Full Article

Daws, R.E., Timmermann, C., Giribaldi, B. et al. Increased global integration in the brain after psilocybin therapy for depression. Nat Med 28, 844-851 (2022). https://doi.org/10.1038/s41591-022-01744-zAbstract: Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10mg and 25mg, 7d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1d after the 25-mg dose. Beck's depression inventory was the primary outcome measure (MR/J00460X/1). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2×25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2×1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose (NCT03429075). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.Click Here to Read the Full Article

depression, Ketamine

L. Alison McInnes, Jimmy J. Qian, Rishab S. Gargeya, Charles DeBattista, Boris D. Heifets, A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings, Journal of Affective Disorders, Volume 301, 2022, Pages 486-495, ISSN 0165-0327, https://doi.org/10.1016/j.jad.2021.12.097 Abstract: Background: Outcomes of ketamine intravenous therapy (KIT) for depression in real-world care settings have been minimally evaluated. We set out to quantify treatment response to KIT in a large sample of patients from community-based practices. Methods: We retrospectively analyzed 9016 depression patients who received KIT between 2016 and 2020 at one of 178 community practices across the United States. Depression symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9). The induction phase of KIT was defined to be a series of 4-8 infusions administered over 7 to 28 days. Results: Among the 537 patients who underwent induction and had sufficient data, 53.6% of patients showed a response (≥ 50% reduction in PHQ-9 score) at 14-31 days post-induction and 28.9% remitted (PHQ-9 score drop to < 5). The effect size was d = 1.5. Among patients with baseline suicidal ideation (SI), 73.0% exhibited a reduction in SI. A subset (8.4%) of patients experienced an increase in depressive symptoms after induction while 6.0% of patients reported increased SI. The response rate was uniform across 4 levels of baseline depression severity. However, more severe illness was weakly correlated with a greater drop in scores while remission status was weakly inversely correlated with depression severity. Kaplan-Meier analyses showed that a patient who responds to KIT induction has approximately 80% probability of sustaining response at 4 weeks and approximately 60% probability at 8 weeks, even without maintenance infusions. Conclusion: KIT can elicit a robust antidepressant response in community clinics; however, a small percentage of patients worsened. Click Here to Read the Full Article

depression, intravenous ketamine, Ketamine

L. Alison McInnes, Jimmy J. Qian, Rishab S. Gargeya, Charles DeBattista, Boris D. Heifets, A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings, Journal of Affective Disorders, Volume 301, 2022, Pages 486-495, ISSN 0165-0327, https://doi.org/10.1016/j.jad.2021.12.097 Abstract: Background: Outcomes of ketamine intravenous therapy (KIT) for depression in real-world care settings have been minimally evaluated. We set out to quantify treatment response to KIT in a large sample of patients from community-based practices. Methods: We retrospectively analyzed 9016 depression patients who received KIT between 2016 and 2020 at one of 178 community practices across the United States. Depression symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9). The induction phase of KIT was defined to be a series of 4-8 infusions administered over 7 to 28 days. Results: Among the 537 patients who underwent induction and had sufficient data, 53.6% of patients showed a response (≥ 50% reduction in PHQ-9 score) at 14-31 days post-induction and 28.9% remitted (PHQ-9 score drop to < 5). The effect size was d = 1.5. Among patients with baseline suicidal ideation (SI), 73.0% exhibited a reduction in SI. A subset (8.4%) of patients experienced an increase in depressive symptoms after induction while 6.0% of patients reported increased SI. The response rate was uniform across 4 levels of baseline depression severity. However, more severe illness was weakly correlated with a greater drop in scores while remission status was weakly inversely correlated with depression severity. Kaplan-Meier analyses showed that a patient who responds to KIT induction has approximately 80% probability of sustaining response at 4 weeks and approximately 60% probability at 8 weeks, even without maintenance infusions. Conclusion: KIT can elicit a robust antidepressant response in community clinics; however, a small percentage of patients worsened. Click Here to Read the Full Article

depression, Ketamine

Muscat S-A, Hartelius G, Crouch CR, Morin KW. Optimized Clinical Strategies for Treatment-Resistant Depression: Integrating Ketamine Protocols with Trauma- and Attachment-Informed Psychotherapy. Psych. 2022; 4(1):119-141. https://doi.org/10.3390/psych4010012

Muscat S-A, Hartelius G, Crouch CR, Morin KW. Optimized Clinical Strategies for Treatment-Resistant Depression: Integrating Ketamine Protocols with Trauma- and Attachment-Informed Psychotherapy. Psych. 2022; 4(1):119-141. https://doi.org/10.3390/psych4010012

psilocybin

Ziff, S., Stern, B., Lewis, G., Majeed, M., & Gorantla, V. R. (2022). Analysis of Psilocybin-Assisted Therapy in Medicine: A Narrative Review. Cureus, 14(2), e21944. https://doi.org/10.7759/cureus.21944

Dai, D., Miller, C., Valdivia, V. et al. Neurocognitive effects of repeated ketamine infusion treatments in patients with treatment resistant depression: a retrospective chart review. BMC Psychiatry 22, 140 (2022). https://doi.org/10.1186/s12888-022-03789-3 Background Ketamine has emerged as a rapid-acting antidepressant in treatment-resistant depression (TRD) increasingly used in non-research, clinical settings. Few studies, however, have examined neurocognitive effects of repeated racemic ketamine infusion treatments in patients with TRD. In an effort to identify potential effects after serial infusions, we conducted a retrospective chart review to identify statistically significant changes in cognition in patient undergoing serial intravenous infusions; concomitantly, we examined baseline cognition as potential predictor of anti-depressant potential. Methods Twenty-two patients with TRD were examined after they finished the induction phase of 8-10 repeated intravenous ketamine infusions and completed the assessments of their depressive symptoms (measured by the 16-item Quick Inventory of Depressive Symptomatology-Self Report Scale: QIDS-SR16) and cognitive function (measured by the Montreal Cognitive Assessment: MoCA) before the first and the last ketamine treatments. Results Repeated ketamine infusions administered through an escalating dose protocol with 8-10 infusion sessions produced a 47.2% reduction response in depression; there was no evidence of impairment as reflected in MoCA testing. There was a moderate association between baseline cognition and antidepressant response with a Pearson correlation of 0.453. Conclusion In this naturalistic sample of patients with TRD in our clinical service, repeated ketamine infusions significantly decreased depression symptoms without impairing cognitive performance. The baseline cognition may positively predict antidepressant responses of repeated ketamine treatment. Click Here to Read the Full Article

Dai, D., Miller, C., Valdivia, V. et al. Neurocognitive effects of repeated ketamine infusion treatments in patients with treatment resistant depression: a retrospective chart review. BMC Psychiatry 22, 140 (2022). https://doi.org/10.1186/s12888-022-03789-3 Background Ketamine has emerged as a rapid-acting antidepressant in treatment-resistant depression (TRD) increasingly used in non-research, clinical settings. Few studies, however, have examined neurocognitive effects of repeated racemic ketamine infusion treatments in patients with TRD. In an effort to identify potential effects after serial infusions, we conducted a retrospective chart review to identify statistically significant changes in cognition in patient undergoing serial intravenous infusions; concomitantly, we examined baseline cognition as potential predictor of anti-depressant potential. Methods Twenty-two patients with TRD were examined after they finished the induction phase of 8-10 repeated intravenous ketamine infusions and completed the assessments of their depressive symptoms (measured by the 16-item Quick Inventory of Depressive Symptomatology-Self Report Scale: QIDS-SR16) and cognitive function (measured by the Montreal Cognitive Assessment: MoCA) before the first and the last ketamine treatments. Results Repeated ketamine infusions administered through an escalating dose protocol with 8-10 infusion sessions produced a 47.2% reduction response in depression; there was no evidence of impairment as reflected in MoCA testing. There was a moderate association between baseline cognition and antidepressant response with a Pearson correlation of 0.453. Conclusion In this naturalistic sample of patients with TRD in our clinical service, repeated ketamine infusions significantly decreased depression symptoms without impairing cognitive performance. The baseline cognition may positively predict antidepressant responses of repeated ketamine treatment. Click Here to Read the Full Article

Benjamin Kelmendi, Alfred P. Kaye, Christopher Pittenger, Alex C. Kwan, Psychedelics, Current Biology, Volume 32, Issue 2, 2022, Pages R63-R67, ISSN 0960-9822, https://doi.org/10.1016/j.cub.2021.12.009. (https://www.sciencedirect.com/science/article/pii/S0960982221016857) Abstract: "Psychedelics are compounds that alter consciousness by acting on serotonin receptors in the brain. The term 'psychedelic', from the Greek for mind manifesting, refers to the drugs' subjective effects and was first proposed by Humphry Osmond in 1956. Other terms have been used to emphasize different aspects of the psychological experiences produced by various related compounds, including hallucinogens (perceptual), entheogens (spiritual), and empathogens or entactogens (social/emotional). The diversity in terminology reflects the existence of hundreds of potential psychedelic compounds with a spectrum of behavioral and neurobiological effects. Recent data on the effectiveness of psychedelics for treating mental illnesses has led to a resurgence of interest in their neurobiological effects. The purpose of this Primer is to provide those interested in the field of psychedelics with a concise and accessible overview of the scientific data." Click Here to Read the Full Article

AUTHOR=Dames Shannon, Kryskow Pamela, Watler CrosbieTITLE=A Cohort-Based Case Report: The Impact of Ketamine-Assisted Therapy Embedded in a Community of Practice Framework for Healthcare Providers With PTSD and Depression JOURNAL=Frontiers in Psychiatry VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/articles/10.3389/fpsyt.2021.803279DOI=10.3389/fpsyt.2021.803279 ISSN=1664-0640 ABSTRACT=Amid an international pandemic and a worsening mental health crisis, ketamine-assisted therapy is emerging as a promising solution for those deemed "treatment resistant." Post-traumatic stress disorder (PTSD) and depression are on the rise, with accelerating direct (e.g., burden of suffering) and indirect (e.g., disability/role impairment and impact on family) costs. Psychedelic-assisted therapies show significant promise in the treatment of a number of clinically challenging conditions, including depression, anxiety, PTSD, addiction, and end-of-life distress. Ketamine is currently the only safe, effective and legal widely available psychedelic-like medicine. To address the echo pandemic of health care provider distress, a multi-disciplinary team was charged with developing a ketamine-assisted psychotherapy program, delivered in a community of practice (CoP) group model and evaluated in a quality improvement framework. Program evaluation occurred through mixed methods. Quantitative mental health assessments included the PHQ-9 for depression, the PCL-5 for PTSD, GAD-7 for generalized anxiety disorder (GAD), and B-IPF for work/life functionality. Participant narrative feedback was collected to evaluate outcomes and for quality improvement purposes. Mean mental health scores were collected across three cohorts, totaling 94 patients. The mean aggregate scores of participants meeting the mental health assessment cut-off criteria (screening positive) were analyzed to assess clinical significance. Mean aggregate results comparing baseline vs. outcome measures (measured within 1-2 weeks after completion of the 12-week program) were clinically significant, demonstrating significant improvements in depression, post-traumatic stress disorder, generalized anxiety disorder and work/life functionality. In summary, 91% saw improvements in generalized anxiety, 79% saw improvements in depression, 86% of those who screened positive for PTSD now screen negative, and 92% had significant life/work functionality improvements. Qualitative feedback was overwhelmingly positive, with several unsolicited self-reports of transformation. Participant and team feedback enables the program to continue improving with each iteration. Results speak to the effectiveness of ketamine for psychedelic-assisted therapy, supported by a CoP framework. Outcomes are relevant for mental health programming, education and healthcare policy. Click Here to Read the Full Article

AUTHOR=Dames Shannon, Kryskow Pamela, Watler CrosbieTITLE=A Cohort-Based Case Report: The Impact of Ketamine-Assisted Therapy Embedded in a Community of Practice Framework for Healthcare Providers With PTSD and Depression JOURNAL=Frontiers in Psychiatry VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/articles/10.3389/fpsyt.2021.803279DOI=10.3389/fpsyt.2021.803279 ISSN=1664-0640 ABSTRACT=Amid an international pandemic and a worsening mental health crisis, ketamine-assisted therapy is emerging as a promising solution for those deemed "treatment resistant." Post-traumatic stress disorder (PTSD) and depression are on the rise, with accelerating direct (e.g., burden of suffering) and indirect (e.g., disability/role impairment and impact on family) costs. Psychedelic-assisted therapies show significant promise in the treatment of a number of clinically challenging conditions, including depression, anxiety, PTSD, addiction, and end-of-life distress. Ketamine is currently the only safe, effective and legal widely available psychedelic-like medicine. To address the echo pandemic of health care provider distress, a multi-disciplinary team was charged with developing a ketamine-assisted psychotherapy program, delivered in a community of practice (CoP) group model and evaluated in a quality improvement framework. Program evaluation occurred through mixed methods. Quantitative mental health assessments included the PHQ-9 for depression, the PCL-5 for PTSD, GAD-7 for generalized anxiety disorder (GAD), and B-IPF for work/life functionality. Participant narrative feedback was collected to evaluate outcomes and for quality improvement purposes. Mean mental health scores were collected across three cohorts, totaling 94 patients. The mean aggregate scores of participants meeting the mental health assessment cut-off criteria (screening positive) were analyzed to assess clinical significance. Mean aggregate results comparing baseline vs. outcome measures (measured within 1-2 weeks after completion of the 12-week program) were clinically significant, demonstrating significant improvements in depression, post-traumatic stress disorder, generalized anxiety disorder and work/life functionality. In summary, 91% saw improvements in generalized anxiety, 79% saw improvements in depression, 86% of those who screened positive for PTSD now screen negative, and 92% had significant life/work functionality improvements. Qualitative feedback was overwhelmingly positive, with several unsolicited self-reports of transformation. Participant and team feedback enables the program to continue improving with each iteration. Results speak to the effectiveness of ketamine for psychedelic-assisted therapy, supported by a CoP framework. Outcomes are relevant for mental health programming, education and healthcare policy. Click Here to Read the Full Article

depression, Ketamine

Smith-Apeldoorn, S., Veraart, J., Ruhé, H., Aan het Rot, M., Kamphuis, J., De Boer, M., & Schoevers, R. (2022). Repeated, low-dose oral esketamine in patients with treatment-resistant depression: Pilot study. BJPsych Open, 8(1), E4. doi:10.1192/bjo.2021.1059 Background: Intravenous infusion of ketamine can produce rapid and large symptom reduction in patients with treatment-resistant depression (TRD) but presents major obstacles to clinical applicability, especially in community settings. Oral esketamine may be a promising addition to our TRD treatment armamentarium. Aims: To explore the safety, tolerability and potential clinical effectiveness of a 3-week treatment with repeated, low-dose oral esketamine. Method: Seven patients with chronic and severe TRD received 1.25 mg/kg generic oral esketamine daily, over 21 consecutive days. Scores on the Systematic Assessment for Treatment Emergent Events (SAFTEE), Community Assessment of Psychic Experiences (CAPE), Clinician Administered Dissociative States Scale (CADSS) and Hamilton Rating Scale for Depression (HRSD) instruments, as well as blood pressure and heart rate, were repeatedly assessed. Results: Treatment with oral esketamine was well-tolerated. No serious side-effects occurred, and none of the participants discontinued treatment prematurely. Psychotomimetic effects were the most frequently reported adverse events. Mean HDRS score decreased by 16.5%, from 23.6 to 19.7. Three participants showed reductions in HDRS scores above the minimum clinically important difference (eight-point change), of whom two showed partial response. No participants showed full response or remission. Conclusions: These results strengthen the idea that oral esketamine is a safe and well-tolerated treatment for patients with chronic and severe TRD, but therapeutic effects were modest. Results were used to design a randomised controlled trial that is currently in progress.

addiction, Ketamine, Ketamine Assisted Psychotherapy

Walsh, Z., Mollaahmetoglu, O., Rootman, J., Golsof, S., Keeler, J., Marsh, B., . . . Morgan, C. (2022). Ketamine for the treatment of mental health and substance use disorders: Comprehensive systematic review. BJPsych Open, 8(1), E19. doi:10.1192/bjo.2021.1061

addiction, Ketamine, substance use disorders

Walsh, Z., Mollaahmetoglu, O., Rootman, J., Golsof, S., Keeler, J., Marsh, B., . . . Morgan, C. (2022). Ketamine for the treatment of mental health and substance use disorders: Comprehensive systematic review. BJPsych Open, 8(1), E19. doi:10.1192/bjo.2021.1061 Abstract BackgroundIn the past two decades, subanaesthetic doses of ketamine have been demonstrated to have rapid and sustained antidepressant effects, and accumulating research has demonstrated ketamine's therapeutic effects for a range of psychiatric conditions.AimsIn light of these findings surrounding ketamine's psychotherapeutic potential, we systematically review the extant evidence on ketamine's effects in treating mental health disorders.MethodThe systematic review protocol was registered in PROSPERO (identifier CRD42019130636). Human studies investigating the therapeutic effects of ketamine in the treatment of mental health disorders were included. Because of the extensive research in depression, bipolar disorder and suicidal ideation, only systematic reviews and meta-analyses were included. We searched Medline and PsycINFO on 21 October 2020. Risk-of-bias analysis was assessed with the Cochrane Risk of Bias tools and A Measurement Tool to Assess Systematic Reviews (AMSTAR) Checklist.ResultsWe included 83 published reports in the final review: 33 systematic reviews, 29 randomised controlled trials, two randomised trials without placebo, three non-randomised trials with controls, six open-label trials and ten retrospective reviews. The results were presented via narrative synthesis.ConclusionsSystematic reviews and meta-analyses provide support for robust, rapid and transient antidepressant and anti-suicidal effects of ketamine. Evidence for other indications is less robust, but suggests similarly positive and short-lived effects. The conclusions should be interpreted with caution because of the high risk of bias of included studies. Optimal dosing, modes of administration and the most effective forms of adjunctive psychotherapeutic support should be examined further.

bipolar, bipolar disorder, psilocybin

David E. Gard, Mollie M. Pleet, Ellen R. Bradley, Andrew D. Penn, Matthew L. Gallenstein, Lauren S. Riley, Meghan DellaCrosse, Emily M. Garfinkle, Erin E. Michalak, Joshua D. Woolley, Evaluating the risk of psilocybin for the treatment of bipolar depression: A review of the research literature and published case studies, Journal of Affective Disorders Reports, Volume 6, 2021, 100240, ISSN 2666-9153, https://doi.org/10.1016/j.jadr.2021.100240. (https://www.sciencedirect.com/science/article/pii/S2666915321001669) Abstract: Growing evidence suggests that psilocybin, the active ingredient in hallucinogenic mushrooms, can rapidly and durably improve symptoms of depression, leading to recent breakthrough status designation by the FDA and legalization for mental health treatment in some jurisdictions. Depression in bipolar disorder is associated with significant morbidity and has few effective treatments. However, there is little available scientific data on the risk of psilocybin use in people with bipolar disorder. Individuals with bipolar disorder have been excluded from modern clinical trials, out of understandable concerns of activating mania or worsening the illness course. As psilocybin becomes more available, people with these disorders will likely seek psilocybin treatment for depression and have likely already been doing so in unregulated settings. Our goal here is to summarize the known risks of psilocybin use (and similar substances) in bipolar disorder and to systematically evaluate examples of published case history data, in order to critically evaluate the relative risk of psilocybin as a treatment for bipolar depression. We found 17 cases suggesting that there is potential risk for activating a manic episode, thereby warranting caution. Nonetheless, the relative lack of systematic data or common case examples indicating risk appears to show that a cautious trial, using modern trial methods focusing on appropriate 'set' and 'setting', targeted at those lowest at risk for mania in the bipolar spectrum (e.g., bipolar 2 disorder), is very much needed, especially given the degree to which depression impacts this population. Click Here to Read the Full Article

bipolar, bipolar disorder, psilocybin

David E. Gard, Mollie M. Pleet, Ellen R. Bradley, Andrew D. Penn, Matthew L. Gallenstein, Lauren S. Riley, Meghan DellaCrosse, Emily M. Garfinkle, Erin E. Michalak, Joshua D. Woolley, Evaluating the risk of psilocybin for the treatment of bipolar depression: A review of the research literature and published case studies, Journal of Affective Disorders Reports, Volume 6, 2021, 100240, ISSN 2666-9153, https://doi.org/10.1016/j.jadr.2021.100240. (https://www.sciencedirect.com/science/article/pii/S2666915321001669) Abstract: Growing evidence suggests that psilocybin, the active ingredient in hallucinogenic mushrooms, can rapidly and durably improve symptoms of depression, leading to recent breakthrough status designation by the FDA and legalization for mental health treatment in some jurisdictions. Depression in bipolar disorder is associated with significant morbidity and has few effective treatments. However, there is little available scientific data on the risk of psilocybin use in people with bipolar disorder. Individuals with bipolar disorder have been excluded from modern clinical trials, out of understandable concerns of activating mania or worsening the illness course. As psilocybin becomes more available, people with these disorders will likely seek psilocybin treatment for depression and have likely already been doing so in unregulated settings. Our goal here is to summarize the known risks of psilocybin use (and similar substances) in bipolar disorder and to systematically evaluate examples of published case history data, in order to critically evaluate the relative risk of psilocybin as a treatment for bipolar depression. We found 17 cases suggesting that there is potential risk for activating a manic episode, thereby warranting caution. Nonetheless, the relative lack of systematic data or common case examples indicating risk appears to show that a cautious trial, using modern trial methods focusing on appropriate 'set' and 'setting', targeted at those lowest at risk for mania in the bipolar spectrum (e.g., bipolar 2 disorder), is very much needed, especially given the degree to which depression impacts this population. Click Here to Read the Full Article

Alan K. Davis, Gabrielle Agin-Liebes, Megan España, Brian Pilecki & Jason Luoma (2022) Attitudes and Beliefs about the Therapeutic Use of Psychedelic Drugs among Psychologists in the United States, Journal of Psychoactive Drugs, 54:4, 309-318, DOI: 10.1080/02791072.2021.1971343

depression, Esketamine, Ketamine

Sapkota, A., Khurshid, H., Qureshi, I. A., Jahan, N., Went, T. R., Sultan, W., & Alfonso, M. (2021). Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review. Cureus, 13(8), e17352. https://doi.org/10.7759/cureus.17352 Abstract: "Intranasal form of esketamine, the S-enantiomer of racemic ketamine, was approved by the US FDA in 2019 for treatment-resistant depression (TRD) in adults. Since intranasal esketamine is a newly approved drug with a novel mechanism of action, much still remains unknown in regard to its use in TRD. The objective of this study is to systematically review the latest existing evidence on intranasal esketamine, and provide a better insight into its safety and efficacy in TRD in adults. PubMed, MEDLINE (through PubMed), and Google Scholar were systematically searched from 2016 to 2021, using automation tools. After removal of duplicates and screening on the basis of title/abstract, eligibility criteria were applied and quality appraisal was done independently by two reviewers. A total of 10 studies were selected for the final review which included five clinical trials (three short-term trials, one withdrawal design relapse prevention study, and one long-term study), three post hoc studies, one case/non-case study, and one review article. Out of three short-term clinical trials, only one demonstrated a statistically significant difference between treatment with esketamine plus oral antidepressant (OAD) vs placebo plus OAD. The result of the relapse prevention study showed significantly delayed relapse of depressive symptoms in esketamine plus OAD arm when compared to placebo plus OAD arm. Similarly, the result of the long-term clinical trial showed that the improvement in depressive symptoms was found to be sustained in those using esketamine. The most common adverse effects of esketamine included nausea, dizziness, dissociation, headache, vertigo, somnolence, and dysgeusia (altered sense of taste); most were mild-moderate in severity. One case/non-case study reported rare adverse effects including panic attacks, mania, ataxia, akathisia, self-harm ideation, increased loquacity (talkativeness), and autoscopy. Intranasal esketamine has shown efficacy in reducing depressive symptoms in clinical trials, but the clinical meaningfulness of the treatment effect in the real-world population still needs to be explored. Although the safety profile of esketamine appears to be favorable in most clinical trials, some serious side effects are being reported to the FDA Adverse Event Reporting System, and therefore requires further investigation. More robust clinical trials, especially long-term randomized controlled trials are needed which can help provide a better assessment on the efficacy and safety of intranasal esketamine in the treatment of TRD." Click Here to Read the Article

depression, Esketamine, Ketamine

Sapkota, A., Khurshid, H., Qureshi, I. A., Jahan, N., Went, T. R., Sultan, W., & Alfonso, M. (2021). Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review. Cureus, 13(8), e17352. https://doi.org/10.7759/cureus.17352 Abstract: "Intranasal form of esketamine, the S-enantiomer of racemic ketamine, was approved by the US FDA in 2019 for treatment-resistant depression (TRD) in adults. Since intranasal esketamine is a newly approved drug with a novel mechanism of action, much still remains unknown in regard to its use in TRD. The objective of this study is to systematically review the latest existing evidence on intranasal esketamine, and provide a better insight into its safety and efficacy in TRD in adults. PubMed, MEDLINE (through PubMed), and Google Scholar were systematically searched from 2016 to 2021, using automation tools. After removal of duplicates and screening on the basis of title/abstract, eligibility criteria were applied and quality appraisal was done independently by two reviewers. A total of 10 studies were selected for the final review which included five clinical trials (three short-term trials, one withdrawal design relapse prevention study, and one long-term study), three post hoc studies, one case/non-case study, and one review article. Out of three short-term clinical trials, only one demonstrated a statistically significant difference between treatment with esketamine plus oral antidepressant (OAD) vs placebo plus OAD. The result of the relapse prevention study showed significantly delayed relapse of depressive symptoms in esketamine plus OAD arm when compared to placebo plus OAD arm. Similarly, the result of the long-term clinical trial showed that the improvement in depressive symptoms was found to be sustained in those using esketamine. The most common adverse effects of esketamine included nausea, dizziness, dissociation, headache, vertigo, somnolence, and dysgeusia (altered sense of taste); most were mild-moderate in severity. One case/non-case study reported rare adverse effects including panic attacks, mania, ataxia, akathisia, self-harm ideation, increased loquacity (talkativeness), and autoscopy. Intranasal esketamine has shown efficacy in reducing depressive symptoms in clinical trials, but the clinical meaningfulness of the treatment effect in the real-world population still needs to be explored. Although the safety profile of esketamine appears to be favorable in most clinical trials, some serious side effects are being reported to the FDA Adverse Event Reporting System, and therefore requires further investigation. More robust clinical trials, especially long-term randomized controlled trials are needed which can help provide a better assessment on the efficacy and safety of intranasal esketamine in the treatment of TRD." Click Here to Read the Article

Wießner, I., Falchi, M., Palhano-Fontes, F., Feilding, A., Ribeiro, S., & Tófoli, L. (2023). LSD, madness and healing: Mystical experiences as possible link between psychosis model and therapy model. Psychological Medicine, 53(4), 1151-1165. doi:10.1017/S0033291721002531 BackgroundFor a century, psychedelics have been investigated as models of psychosis for demonstrating phenomenological similarities with psychotic experiences and as therapeutic models for treating depression, anxiety, and substance use disorders. This study sought to explore this paradoxical relationship connecting key parameters of the psychotic experience, psychotherapy, and psychedelic experience.MethodsIn a randomized, double-blind, placebo-controlled, crossover design, 24 healthy volunteers received 50 μg D-lysergic acid diethylamide (LSD) or inactive placebo. Psychotic experience was assessed by aberrant salience (Aberrant Salience Inventory, ASI), therapeutic potential by suggestibility (Creative Imagination Scale, CIS) and mindfulness (Five Facet Mindfulness Questionnaire, FFMQ; Mindful Attention Awareness Scale, MAAS; Experiences Questionnaire, EQ), and psychedelic experience by four questionnaires (Altered State of Consciousness Questionnaire, ASC; Mystical Experiences Questionnaire, MEQ; Challenging Experiences Questionnaire, CEQ; Ego-Dissolution Inventory, EDI). Relationships between LSD-induced effects were examined.ResultsLSD induced psychedelic experiences, including alteration of consciousness, mystical experiences, ego-dissolution, and mildly challenging experiences, increased aberrant salience and suggestibility, but not mindfulness. LSD-induced aberrant salience correlated highly with complex imagery, mystical experiences, and ego-dissolution. LSD-induced suggestibility correlated with no other effects. Individual mindfulness changes correlated with aspects of aberrant salience and psychedelic experience.ConclusionsThe LSD state resembles a psychotic experience and offers a tool for healing. The link between psychosis model and therapeutic model seems to lie in mystical experiences. The results point to the importance of meaning attribution for the LSD psychosis model and indicate that psychedelic-assisted therapy might benefit from therapeutic suggestions fostering mystical experiences.Click Here to Read the Full Article

Jolien K E Veraart and others, Pharmacodynamic Interactions Between Ketamine and Psychiatric Medications Used in the Treatment of Depression: A Systematic Review, International Journal of Neuropsychopharmacology, Volume 24, Issue 10, October 2021, Pages 808-831, https://doi.org/10.1093/ijnp/pyab039

Jolien K E Veraart and others, Pharmacodynamic Interactions Between Ketamine and Psychiatric Medications Used in the Treatment of Depression: A Systematic Review, International Journal of Neuropsychopharmacology, Volume 24, Issue 10, October 2021, Pages 808-831, https://doi.org/10.1093/ijnp/pyab039

MDMA, psilocybin, Trauma

Catherine I. V. Bird, Nadav L. Modlin & James J. H. Rucker (2021) Psilocybin and MDMA for the treatment of trauma-related psychopathology, International Review of Psychiatry, 33:3, 229-249, DOI: 10.1080/09540261.2021.1919062

MDMA, psilocybin, Trauma

Catherine I. V. Bird, Nadav L. Modlin & James J. H. Rucker (2021) Psilocybin and MDMA for the treatment of trauma-related psychopathology, International Review of Psychiatry, 33:3, 229-249, DOI: 10.1080/09540261.2021.1919062

psilocybin

Lowe H, Toyang N, Steele B, Valentine H, Grant J, Ali A, Ngwa W, Gordon L. The Therapeutic Potential of Psilocybin. Molecules. 2021; 26(10):2948. https://doi.org/10.3390/molecules26102948 Abstract: The psychedelic effects of some plants and fungi have been known and deliberately exploited by humans for thousands of years. Fungi, particularly mushrooms, are the principal source of naturally occurring psychedelics. The mushroom extract, psilocybin has historically been used as a psychedelic agent for religious and spiritual ceremonies, as well as a therapeutic option for neuropsychiatric conditions. Psychedelic use was largely associated with the "hippie" counterculture movement, which, in turn, resulted in a growing, and still lingering, negative stigmatization for psychedelics. As a result, in 1970, the U.S. government rescheduled psychedelics as Schedule 1 drugs, ultimately ending scientific research on psychedelics. This prohibition on psychedelic drug research significantly delayed advances in medical knowledge on the therapeutic uses of agents such as psilocybin. A 2004 pilot study from the University of California, Los Angeles, exploring the potential of psilocybin treatment in patients with advanced-stage cancer managed to reignite interest and significantly renewed efforts in psilocybin research, heralding a new age in exploration for psychedelic therapy. Since then, significant advances have been made in characterizing the chemical properties of psilocybin as well as its therapeutic uses. This review will explore the potential of psilocybin in the treatment of neuropsychiatry-related conditions, examining recent advances as well as current research. This is not a systematic review. Click Here to Read the Full Article

MDMA, PTSD, Trauma

Mitchell, J.M., Bogenschutz, M., Lilienstein, A. et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med 27, 1025-1033 (2021). https://doi.org/10.1038/s41591-021-01336-3 Abstract: Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n=90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P<0.0001, d=0.91) and to significantly decrease the SDS total score (P=0.0116, d=0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Click Here to Read the Full Article

Mitchell, J.M., Bogenschutz, M., Lilienstein, A. et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med 27, 1025-1033 (2021). https://doi.org/10.1038/s41591-021-01336-3 Abstract: Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n=90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P<0.0001, d=0.91) and to significantly decrease the SDS total score (P=0.0116, d=0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Click Here to Read the Full Article

Jerome Sarris, Daniel Perkins, Lachlan Cribb, Violeta Schubert, Emerita Opaleye, José Carlos Bouso, Milan Scheidegger, Helena Aicher, Hana Simonova, Miroslav Horák, Nicole Leite Galvão-Coelho, David Castle, Luís Fernando Tófoli, Ayahuasca use and reported effects on depression and anxiety symptoms: An international cross sectional study of 11,912 consumers, Journal of Affective Disorders Reports, Volume 4, 2021, 100098, ISSN 2666-9153, https://doi.org/10.1016/j.jadr.2021.100098.(https://www.sciencedirect.com/science/article/pii/S2666915321000251) Abstract: BackgroundAyahuasca is a psychoactive Amazonian brew which has emerging data indicating that it has antidepressant and anxiolytic properties. MethodsThis paper uses data from the Global Ayahuasca Project (GAP), which was undertaken across 2017-2020 and involved 11912 people, to examine the perceived effects of Ayahuasca consumption on affective symptoms. The study focused on the subsample reporting depression or anxiety diagnoses at time of Ayahuasca consumption. ResultsOf participants reporting depression (n = 1571) or anxiety (n = 1125) at the time of consuming Ayahuasca, 78% reported that their depression was either 'very much' improved (46%), or 'completely resolved' (32%); while 70% of those with anxiety reported that their symptoms were 'very much' improved (54%), or 'completely resolved' (16%). A range of factors were associated with greater reported affective symptoms improvement, including subjective mystical experience, number of Ayahuasca sessions, and number of personal psychological insights experienced. 2.7% and 4.5% of drinkers with depression or anxiety, respectively, reported worsening of symptoms. LimitationsThis study is recognized as a cross-sectional analysis which cannot assess treatment efficacy. Selection bias may exist due to survey-respondents with favorable experience being potentially biased towards participation. ConclusionsDrinkers of Ayahuasca in naturalistic settings perceived remarkable benefits for their affective symptoms in this survey assessment. There is no obvious evidence of negative mental health effects being associated with long-term consumption. Additional randomized controlled trial evidence is required to establish the efficacy of Ayahuasca in affective disorders, and to understand the worsened symptoms reported by a small percentage of drinkers. Click Here to Read the Full Article

Abstract:  "BACKGROUND Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. METHODS In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6. RESULTS A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups. CONCLUSIONS On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London's Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075..)" Click Here to Read the Full Article

Jerome Sarris, Daniel Perkins, Lachlan Cribb, Violeta Schubert, Emerita Opaleye, José Carlos Bouso, Milan Scheidegger, Helena Aicher, Hana Simonova, Miroslav Horák, Nicole Leite Galvão-Coelho, David Castle, Luís Fernando Tófoli, Ayahuasca use and reported effects on depression and anxiety symptoms: An international cross sectional study of 11,912 consumers, Journal of Affective Disorders Reports, Volume 4, 2021, 100098, ISSN 2666-9153, https://doi.org/10.1016/j.jadr.2021.100098.(https://www.sciencedirect.com/science/article/pii/S2666915321000251) Abstract: BackgroundAyahuasca is a psychoactive Amazonian brew which has emerging data indicating that it has antidepressant and anxiolytic properties. MethodsThis paper uses data from the Global Ayahuasca Project (GAP), which was undertaken across 2017-2020 and involved 11912 people, to examine the perceived effects of Ayahuasca consumption on affective symptoms. The study focused on the subsample reporting depression or anxiety diagnoses at time of Ayahuasca consumption. ResultsOf participants reporting depression (n = 1571) or anxiety (n = 1125) at the time of consuming Ayahuasca, 78% reported that their depression was either 'very much' improved (46%), or 'completely resolved' (32%); while 70% of those with anxiety reported that their symptoms were 'very much' improved (54%), or 'completely resolved' (16%). A range of factors were associated with greater reported affective symptoms improvement, including subjective mystical experience, number of Ayahuasca sessions, and number of personal psychological insights experienced. 2.7% and 4.5% of drinkers with depression or anxiety, respectively, reported worsening of symptoms. LimitationsThis study is recognized as a cross-sectional analysis which cannot assess treatment efficacy. Selection bias may exist due to survey-respondents with favorable experience being potentially biased towards participation. ConclusionsDrinkers of Ayahuasca in naturalistic settings perceived remarkable benefits for their affective symptoms in this survey assessment. There is no obvious evidence of negative mental health effects being associated with long-term consumption. Additional randomized controlled trial evidence is required to establish the efficacy of Ayahuasca in affective disorders, and to understand the worsened symptoms reported by a small percentage of drinkers. Click Here to Read the Full Article

Abstract:  "BACKGROUND Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. METHODS In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6. RESULTS A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups. CONCLUSIONS On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London's Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075..)" Click Here to Read the Full Article

Rafael Guimarães dos Santos, José Carlos Bouso, Juliana Mendes Rocha, Giordano Novak Rossi & Jaime E Hallak (2021) The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges, Risk Management and Healthcare Policy, 14:, 901-910, DOI: 10.2147/RMHP.S300656

Halstead, M., Reed, S., Krause, R., & Williams, M. T. (2021). Ketamine-Assisted Psychotherapy for PTSD Related to Racial Discrimination. Clinical Case Studies, 20(4), 310-330. https://doi.org/10.1177/1534650121990894 Abstract: "Current research suggests that ketamine-assisted psychotherapy has benefit for the treatment of mental disorders. We report on the results of ketamine-assisted intensive outpatient psychotherapeutic treatment of a client with treatment-resistant, posttraumatic stress disorder (PTSD) as a result of experiences of racism and childhood sexual abuse. The client's presenting symptoms included hypervigilance, social avoidance, feelings of hopelessness, and intense recollections. These symptoms impacted all areas of daily functioning. Psychoeducation was provided on how untreated intergenerational trauma, compounded by additional traumatic experiences, potentiated the client's experience of PTSD and subsequent maladaptive coping mechanisms. Ketamine was administered four times over a 13-day span as an off-label, adjunct to psychotherapy. Therapeutic interventions and orientations utilized were mindfulness-based cognitive therapy (MBCT) and functional analytic psychotherapy (FAP). New skills were obtained in helping the client respond effectively to negative self-talk, catastrophic thinking, and feelings of helplessness. Treatment led to a significant reduction in symptoms after completion of the program, with gains maintained 4months post-treatment. This case study demonstrates the effective use of ketamine as an adjunct to psychotherapy in treatment-resistant PTSD." Click Here to Read the Full Article

Joanes Grandjean, David Buehlmann, Michaela Buerge, Hannes Sigrist, Erich Seifritz, Franz X. Vollenweider, Christopher R. Pryce, Markus Rudin, Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice, NeuroImage, Volume 225, 2021, 117456, ISSN 1053-8119, https://doi.org/10.1016/j.neuroimage.2020.117456.(https://www.sciencedirect.com/science/article/pii/S1053811920309411) Abstract: Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that displays altered FC in depressive disorders. In this study, we investigated the effects of psilocybin on FC across the entire brain with a view to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin- relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and cortical areas, including elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interactions between 5-HT- and DA-regulated neural networks contribute to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings. Click Here to Read the Full Article

Adriana Feder, Sara Costi, Sarah B. Rutter, Abigail B. Collins, Usha Govindarajulu, Manish K. Jha, Sarah R. Horn, Marin Kautz, Morgan Corniquel, Katherine A. Collins, Laura Bevilacqua, Andrew M. Glasgow, Jess Brallier, Robert H. Pietrzak, James W. Murrough and Dennis S. Charney Publisher: American Psychiatric Association ISSN: 0002-953XeISSN1535-7228 Online:January 5, 2021 Print: February 01, 2021 Accepted:September 21, 2020 Revised:July 28, 2020 2020 Received:May 06, 2020 Pages:193 - 202 Abstract "Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. Methods:Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Ã…sberg Depression Rating Scale (MADRS), and side effect measures. Results:The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events. Conclusions:This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD." Click Here to Read the Full Article

depression, Ketamine

Shiroma, P.R., Thuras, P., Wels, J. et al. A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression. Transl Psychiatry 10, 206 (2020). https://doi.org/10.1038/s41398-020-00897-0

Rafael Guimarães dos Santos, José Carlos Bouso, Juliana Mendes Rocha, Giordano Novak Rossi & Jaime E Hallak (2021) The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges, Risk Management and Healthcare Policy, 14:, 901-910, DOI: 10.2147/RMHP.S300656

Candice M. Monson, Anne C. Wagner, Ann T. Mithoefer, Rachel E. Liebman, Allison A. Feduccia, Lisa Jerome, Berra Yazar-Klosinski, Amy Emerson, Rick Doblin & Michael C. Mithoefer (2020) MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial, European Journal of Psychotraumatology, 11:1, DOI: 10.1080/20008198.2020.1840123

Anxiety, MDMA, MDMA-Assisted Psychotherapy

Wolfson, P.E., Andries, J., Feduccia, A.A. et al. MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study. Sci Rep 10, 20442 (2020). https://doi.org/10.1038/s41598-020-75706-1

Jelen LA, Young AH, Stone JM. Ketamine: A tale of two enantiomers. Journal of Psychopharmacology. 2021;35(2):109-123. doi:10.1177/0269881120959644 Abstract: "The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems." Click Here to Read the Full Article

Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(5):481-489. doi:10.1001/jamapsychiatry.2020.3285 Abstract: Importance  Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. Objective  To investigate the effect of psilocybin therapy in patients with MDD. Design, Setting, and Participants  This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population). Interventions  Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay. Main Outcomes and Measures  The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR). Results  Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d=2.5; 95% CI, 1.4-3.5; P<.001) and week 8 (Cohen d=2.6; 95% CI, 1.5-3.7; P<.001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d=2.6; 95% CI, 1.8-3.5; P<.001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d=2.3; 95% CI, 1.5-3.0; P<.001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score). Conclusions and Relevance  Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression. Click Here to Read the Full Article

Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(5):481-489. doi:10.1001/jamapsychiatry.2020.3285 Abstract: Importance  Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. Objective  To investigate the effect of psilocybin therapy in patients with MDD. Design, Setting, and Participants  This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population). Interventions  Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay. Main Outcomes and Measures  The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR). Results  Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d=2.5; 95% CI, 1.4-3.5; P<.001) and week 8 (Cohen d=2.6; 95% CI, 1.5-3.7; P<.001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d=2.6; 95% CI, 1.8-3.5; P<.001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d=2.3; 95% CI, 1.5-3.0; P<.001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score). Conclusions and Relevance  Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression. Click Here to Read the Full Article

Feduccia, A.A., Jerome, L., Mithoefer, M.C. et al. Discontinuation of medications classified as reuptake inhibitors affects treatment response of MDMA-assisted psychotherapy. Psychopharmacology 238, 581-588 (2021). https://doi.org/10.1007/s00213-020-05710-w Rationale MDMA-assisted psychotherapy is under investigation as a novel treatment for posttraumatic stress disorder (PTSD). The primary mechanism of action of MDMA involves the same reuptake transporters targeted by antidepressant medications commonly prescribed for PTSD. Objectives Data were pooled from four phase 2 trials of MDMA-assisted psychotherapy. To explore the effect of tapering antidepressant medications, participants who had been randomized to receive active doses of MDMA (75-125 mg) were divided into two groups (taper group (n=16) or non-taper group (n=34)). Methods Between-group comparisons were made for PTSD and depression symptom severity at the baseline and the primary endpoint, and for peak vital signs across two MDMA sessions. Results Demographics, baseline PTSD, and depression severity were similar between the taper and non-taper groups. At the primary endpoint, the non-taper group (mean=45.7, SD=27.17) had a significantly (p=0.009) lower CAPS-IV total scores compared to the taper group (mean=70.3, SD=33.60). More participants in the non-taper group (63.6%) no longer met PTSD criteria at the primary endpoint than those in the taper group (25.0%). The non-taper group (mean=12.7, SD=10.17) had lower depression symptom severity scores (p=0.010) compared to the taper group (mean=22.6, SD=16.69). There were significant differences between groups in peak systolic blood pressure (p=0.043) and diastolic blood pressure (p=0.032). Conclusions Recent exposure to antidepressant drugs that target reuptake transporters may reduce treatment response to MDMA-assisted psychotherapy. Click Here to Read the Full Article

Brian T Anderson, Alicia Danforth, Prof Robert Daroff, Christopher Stauffer, Eve Ekman, Gabrielle Agin-Liebes, Alexander Trope, Matthew Tyler Boden, Prof James Dilley, Jennifer Mitchell, Joshua Woolley, Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study, EClinicalMedicine, Volume 27, 2020, 100538, ISSN 2589-5370, https://doi.org/10.1016/j.eclinm.2020.100538.(https://www.sciencedirect.com/science/article/pii/S2589537020302820) Abstract: BackgroundPsilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. This study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with a high degree of demoralization and traumatic loss. MethodsSelf-identified gay men OLTAS with moderate-to-severe demoralization (Demoralization Scale-II ≥8) were recruited from the community of a major US city for a single-site open-label study of psilocybin-assisted group therapy comprising 8-10 group therapy visits and one psilocybin administration visit (0·3-0·36mg/kg po). Primary outcomes were rate and severity of adverse events, and participant recruitment and retention. The primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures ANOVA. Trial registration: Clinicaltrials.gov (NCT02950467) FindingsFrom 17 July 2017 to 16 January 2019, 18 participants (mean age 59·2 years (SD 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. We detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. We detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [SD 6·01], ηp2=0·47, 90% CI 0·21-0·60). InterpretationWe demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in OLTAS. Groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs. FundingCarey Turnbull, Heffter Research Institute, NIMH R25 MH060482, NIH UL1 TR001872, River Styx Foundation, Saisei Foundation, Sarlo Foundation, Stupski Foundation, Usona Institute, US Department of Veterans Affairs (Advanced Neurosciences Fellowship and IK2CX001495). Click Here to Read the Full Article

Marseille E, Kahn JG, Yazar-Klosinski B, Doblin R (2020) The cost-effectiveness of MDMA-assisted psychotherapy for the treatment of chronic, treatment-resistant PTSD. PLoS ONE 15(10): e0239997. https://doi.org/10.1371/journal.pone.0239997 "Background Chronic posttraumatic stress disorder (PTSD) is a disabling condition that generates considerable morbidity, mortality, and both medical and indirect social costs. Treatment options are limited. A novel therapy using 3,4-methylenedioxymethamphetamine (MDMA) has shown efficacy in six phase 2 trials. Its cost-effectiveness is unknown. Methods and findings To assess the cost-effectiveness of MDMA-assisted psychotherapy (MAP) from the health care payer's perspective, we constructed a decision-analytic Markov model to portray the costs and health benefits of treating patients with chronic, severe, or extreme, treatment-resistant PTSD with MAP. In six double-blind phase 2 trials, MAP consisted of a mean of 2.5 90-minute trauma-focused psychotherapy sessions before two 8-hour sessions with MDMA (mean dose of 125 mg), followed by a mean of 3.5 integration sessions for each active session. The control group received an inactive placebo or 25-40 mg. of MDMA, and otherwise followed the same regimen. Our model calculates net medical costs, mortality, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Efficacy was based on the pooled results of six randomized controlled phase 2 trials with 105 subjects; and a four-year follow-up of 19 subjects. Other inputs were based on published literature and on assumptions when data were unavailable. We modeled results over a 30-year analytic horizon and conducted extensive sensitivity analyses. Our model calculates expected medical costs, mortality, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio. Future costs and QALYs were discounted at 3% per year. For 1,000 individuals, MAP generates discounted net savings of $103.2 million over 30 years while accruing 5,553 discounted QALYs, compared to continued standard of care. MAP breaks even on cost at 3.1 years while delivering 918 QALYs. Making the conservative assumption that benefits cease after one year, MAP would accrue net costs of $7.6 million while generating 288 QALYS, or $26,427 per QALY gained. Conclusion MAP provided to patients with severe or extreme, chronic PTSD appears to be cost-saving while delivering substantial clinical benefit. Third-party payers are likely to save money within three years by covering this form of therapy." Click Here to Read the Full Article

Rachael L. Sumner, Rebecca McMillan, Meg J. Spriggs, Doug Campbell, Gemma Malpas, Elizabeth Maxwell, Carolyn Deng, John Hay, Rhys Ponton, Frederick Sundram, Suresh D. Muthukumaraswamy, Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors, European Neuropsychopharmacology, Volume 38, 2020, Pages 73-85, ISSN 0924-977X, https://doi.org/10.1016/j.euroneuro.2020.07.009. (https://www.sciencedirect.com/science/article/pii/S0924977X20302340) Abstract: "Major depressive disorder negatively impacts the sensitivity and adaptability of the brain's predictive coding framework. The current electroencephalography study into the antidepressant properties of ketamine investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression using the auditory roving mismatch negativity (rMMN). The rMMN paradigm was run 3-4 h after a single 0.44 mg/kg intravenous dose of ketamine or active placebo (remifentanil infused to a target plasma concentration of 1.7 ng/mL) in order to measure the neural effects of ketamine in the period when an improvement in depressive symptoms emerges. Depression symptomatology was measured using the Montgomery-Asberg Depression Rating Scale (MADRS); 70% of patients demonstrated at least a 50% reduction their MADRS global score. Ketamine significantly increased the MMN and P3a event related potentials, directly contrasting literature demonstrating ketamine's acute attenuation of the MMN. This effect was only reliable when all repetitions of the post-deviant tone were used. Dynamic causal modelling showed greater modulation of forward connectivity in response to a deviant tone between right primary auditory cortex and right inferior temporal cortex, which significantly correlated with antidepressant response to ketamine at 24 h. This is consistent with the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores deficits in sensitivity to prediction error that are hypothesised to underlie depression. However, the lack of repetition suppression evident in the MMN evoked data compared to studies of healthy adults suggests that, at least within the short term, ketamine does not improve deficits in adaptive internal model calibration." Click Here to Read the Full Article

Rachael L. Sumner, Rebecca McMillan, Meg J. Spriggs, Doug Campbell, Gemma Malpas, Elizabeth Maxwell, Carolyn Deng, John Hay, Rhys Ponton, Frederick Sundram, Suresh D. Muthukumaraswamy, Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors, European Neuropsychopharmacology, Volume 38, 2020, Pages 73-85, ISSN 0924-977X, https://doi.org/10.1016/j.euroneuro.2020.07.009. (https://www.sciencedirect.com/science/article/pii/S0924977X20302340) Abstract: "Major depressive disorder negatively impacts the sensitivity and adaptability of the brain's predictive coding framework. The current electroencephalography study into the antidepressant properties of ketamine investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression using the auditory roving mismatch negativity (rMMN). The rMMN paradigm was run 3-4 h after a single 0.44 mg/kg intravenous dose of ketamine or active placebo (remifentanil infused to a target plasma concentration of 1.7 ng/mL) in order to measure the neural effects of ketamine in the period when an improvement in depressive symptoms emerges. Depression symptomatology was measured using the Montgomery-Asberg Depression Rating Scale (MADRS); 70% of patients demonstrated at least a 50% reduction their MADRS global score. Ketamine significantly increased the MMN and P3a event related potentials, directly contrasting literature demonstrating ketamine's acute attenuation of the MMN. This effect was only reliable when all repetitions of the post-deviant tone were used. Dynamic causal modelling showed greater modulation of forward connectivity in response to a deviant tone between right primary auditory cortex and right inferior temporal cortex, which significantly correlated with antidepressant response to ketamine at 24 h. This is consistent with the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores deficits in sensitivity to prediction error that are hypothesised to underlie depression. However, the lack of repetition suppression evident in the MMN evoked data compared to studies of healthy adults suggests that, at least within the short term, ketamine does not improve deficits in adaptive internal model calibration." Click Here to Read the Full Article

MDMA, MDMA-Assisted Psychotherapy, PTSD, Trauma

Jerome, L., Feduccia, A.A., Wang, J.B. et al. Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology 237, 2485-2497 (2020). https://doi.org/10.1007/s00213-020-05548-2 Rationale Posttraumatic stress disorder (PTSD) is a chronic condition that has wide-ranging negative effects on an individual's health and interpersonal relationships. Treatments with long-term benefits are needed to promote the safety and well-being of those suffering from PTSD. Objectives To examine long-term change in PTSD symptoms and additional benefits/harms after 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD. Methods Participants received two to three active doses of MDMA (75-125 mg) during blinded or open-label psychotherapy sessions with additional non-drug therapy sessions. PTSD symptoms were assessed using the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) at baseline, 1 to 2 months after the last active MDMA session (treatment exit), and at least 12 months post final MDMA session (LTFU). A mixed-effect repeated-measures (MMRM) analysis assessed changes in CAPS-IV total severity scores. The number of participants who met PTSD diagnostic criteria was summarized at each time point. Participants completed a long-term follow-up questionnaire. Results There was a significant reduction in CAPS-IV total severity scores from baseline to treatment exit (LS mean (SE)=−44.8 (2.82), p<.0001), with a Cohen's d effect size of 1.58 (95% CI=1.24, 1.91). CAPS-IV scores continued to decrease from treatment exit to LTFU (LS mean (SE)=−5.2 (2.29), p<.05), with a Cohen's d effect size of 0.23 (95% CI=0.04, 0.43). The number of participants who no longer met PTSD criteria increased from treatment exit (56.0%) to LTFU (67.0%). The majority of participants reported benefits, including improved relationships and well-being, and a minority reported harms from study participation. Conclusions PTSD symptoms were reduced 1 to 2 months after MDMA-assisted psychotherapy, and symptom improvement continued at least 12 months post-treatment. Phase 3 trials are investigating this novel treatment approach in a larger sample of participants with chronic PTSD. Click Here to Read the Full Article

bipolar, bipolar depression, depression, Ketamine, unipolar depression

Kryst, J., Kawalec, P., Mitoraj, A.M. et al. Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials. Pharmacol. Rep 72, 543-562 (2020). https://doi.org/10.1007/s43440-020-00097-z Abstract: BackgroundDue to unmet clinical needs for efficient drugs with a rapid onset of antidepressant effects, we aimed to evaluate the efficacy of single-dose ketamine in different subgroups of patients with major depression and establish whether repeated ketamine administration could be a viable strategy to maintain treatment gains.MethodsElectronic databases (Medline via PubMed, Embase, Cochrane Library, Trip Database) were systematically searched until February 22, 2019, for published peer-reviewed randomized controlled trials (RCTs) concerning a single and repeated administration of ketamine in patients with major depression. All relevant RCTs were selected and critically appraised, and a meta-analysis of eligible studies was performed.ResultsA total of 20 studies were included in the meta-analysis. The largest effect of ketamine vs. controls in reducing depressive symptoms was observed at 24 h (SMD=− 0.89; 95% CI − 1.24; − 0.53; p<0.00001); however, a significant difference was shown for up to 7 days after a single dose. Significant differences compared with controls were observed for up to 7 days in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, while there were no significant differences at 7 days when ketamine was used as monotherapy. In patients with major depression, initial antidepressant effects of ketamine were maintained during repeated dosing. At 2-3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD=− 0.70; 95% CI − 1.15; − 0.25 or SMD=− 0.81; 95% CI − 1.41; − 0.20 (depending on the dosing regimen used); p≤0.009 vs placebo.ConclusionsOur meta-analysis revealed rapid and robust antidepressant effects of single-dose ketamine in patients with treatment-resistant depression (TRD). By pooling data from RCTs, we showed for the first time that repeated ketamine administration is effective in sustaining initial antidepressant effects observed after single dosing.Click Here to Read the Full Article

Laura Basso, Luisa Bönke, Sabine Aust, Matti Gärtner, Isabella Heuser-Collier, Christian Otte, Katja Wingenfeld, Malek Bajbouj, Simone Grimm, Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients, Journal of Psychiatric Research, Volume 123, 2020, Pages 1-8, ISSN 0022-3956, https://doi.org/10.1016/j.jpsychires.2020.01.002. (https://www.sciencedirect.com/science/article/pii/S0022395619310660) Abstract: "Background While electroconvulsive therapy (ECT) is considered the gold standard for acute treatment of patients with otherwise treatment-resistant depression, ketamine has recently emerged as a fast-acting treatment alternative for these patients. Efficacy and onset of action are currently among the main factors that influence clinical decision making, however, the effect of these treatments on cognitive functions should also be a crucial point, given that cognitive impairment in depression is strongly related to disease burden and functional recovery. ECT is known to induce transient cognitive impairment, while little is known about ketamine's impact on cognition. This study therefore aims to compare ECT and serial ketamine administration not only with regard to their antidepressant efficacy but also to acute neurocognitive effects. Methods: Fifty patients suffering from depression were treated with either serial ketamine infusions or ECT. Depression severity and cognitive functions were assessed before, during, and after treatment. Results: ECT and ketamine administration were equally effective, however, the antidepressant effects of ketamine occurred faster. Ketamine improved neurocognitive functioning, especially attention and executive functions, whereas ECT was related to a small overall decrease in cognitive performance. Conclusions: Due to its pro-cognitive effects and faster antidepressant effect, serial ketamine administration might be a more favorable short-term treatment option than ECT." Click Here to Read the Full Article

Laura Basso, Luisa Bönke, Sabine Aust, Matti Gärtner, Isabella Heuser-Collier, Christian Otte, Katja Wingenfeld, Malek Bajbouj, Simone Grimm, Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients, Journal of Psychiatric Research, Volume 123, 2020, Pages 1-8, ISSN 0022-3956, https://doi.org/10.1016/j.jpsychires.2020.01.002. (https://www.sciencedirect.com/science/article/pii/S0022395619310660) Abstract: "Background While electroconvulsive therapy (ECT) is considered the gold standard for acute treatment of patients with otherwise treatment-resistant depression, ketamine has recently emerged as a fast-acting treatment alternative for these patients. Efficacy and onset of action are currently among the main factors that influence clinical decision making, however, the effect of these treatments on cognitive functions should also be a crucial point, given that cognitive impairment in depression is strongly related to disease burden and functional recovery. ECT is known to induce transient cognitive impairment, while little is known about ketamine's impact on cognition. This study therefore aims to compare ECT and serial ketamine administration not only with regard to their antidepressant efficacy but also to acute neurocognitive effects. Methods: Fifty patients suffering from depression were treated with either serial ketamine infusions or ECT. Depression severity and cognitive functions were assessed before, during, and after treatment. Results: ECT and ketamine administration were equally effective, however, the antidepressant effects of ketamine occurred faster. Ketamine improved neurocognitive functioning, especially attention and executive functions, whereas ECT was related to a small overall decrease in cognitive performance. Conclusions: Due to its pro-cognitive effects and faster antidepressant effect, serial ketamine administration might be a more favorable short-term treatment option than ECT." Click Here to Read the Full Article

psilocybin

Barrett, F.S., Doss, M.K., Sepeda, N.D. et al. Emotions and brain function are altered up to one month after a single high dose of psilocybin. Sci Rep 10, 2214 (2020). https://doi.org/10.1038/s41598-020-59282-y

Collin M. Reiff, M.D., Elon E. Richman, M.D., Charles B. Nemeroff, M.D., Ph.D., Linda L. Carpenter, M.D., Alik S. Widge, M.D., Ph.D., Carolyn I. Rodriguez, M.D., Ph.D., Ned H. Kalin, M.D., William M. McDonald, M.D., and the Work Group on Biomarkers and Novel Treatments, a Division of the American Psychiatric Association Council of Research. Published in the American Journal of Psychiatry, Volume 177 Issue 5, May 01, 2020, Pages 391-410. https://doi.org/10.1176/appi.ajp.2019.19010035 Objective: The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders. Methods: Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on "psilocybin," "lysergic acid diethylamide," "LSD," "ayahuasca," "3,4-methylenedioxymethamphetamine," and "MDMA," in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms "clinical trial," "therapy," or "imaging" in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care. Results: The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as "breakthrough therapies" for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders. Conclusions: Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.

LSD

AUTHOR: Fuentes Juan José, Fonseca Francina, Elices Matilde, Farré Magí, Torrens Marta TITLE: Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials JOURNAL: Frontiers in Psychiatry VOLUME:10 YEAR: 2020 URL:https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00943 DOI: 10.3389/fpsyt.2019.00943 ISSN: 1664-0640 ABSTRACT: Lysergic acid diethylamide (LSD) was studied from the 1950s to the 1970s to evaluate behavioral and personality changes, as well as remission of psychiatric symptoms in various disorders. LSD was used in the treatment of anxiety, depression, psychosomatic diseases and addiction. However, most of the studies were not performed under contemporary standards, and it has taken several decades for a resurgence of interest in LSD research and its therapeutic potential for psychiatry. The aim of this review is to identify controlled and randomized clinical trials that assess the potential use of LSD in psychiatry. PRISMA guidelines for systematic review were followed. A literature search of PubMed and Psychedelic bibliography from Multidisciplinary Association for Psychedelic Studies (MAPS) databases was performed as well as a manual search of references from evaluated studies. Only randomized-controlled clinical trials were included. Study quality was systematically calculated by using the Cochrane Collaboration Tool for assessing risk of bias. A final selection of 11 articles was made after considering inclusion and exclusion criteria. LSD was administered to 567 patients in a dose ranging from 20 to 800 mcg. Despite the design heterogeneity of clinical trials, positive results were observed, thus revealing the therapeutic potential of LSD to reduce psychiatric symptomatology, mainly in alcoholism. The vast majority of authors describe significant and positive short-term changes in patients, despite the fact that in some studies an important homogenization was observed between the LSD treatment group and control group at long-term follow-up. Multiple variables regarding LSD treatment therapeutic approach and quality of experience were revealed and related to therapeutic outcomes. LSD is revealed as a potential therapeutic agent in psychiatry; the evidence to date is strongest for the use of LSD in the treatment of alcoholism. Despite the difficulty of designing proper double blind clinical trials with this substance, new studies that conform to modern standards are necessary in order to strengthen our knowledge on its use and open new doors in the future. Click Here to Read the Full Article

Falk, E., Schlieper, D., van Caster, P., Lutterbeck, M. J., Schwartz, J., Cordes, J., Grau, I., Kienbaum, P., & Neukirchen, M. (2020). A rapid positive influence of S-ketamine on the anxiety of patients in palliative care: a retrospective pilot study. BMC palliative care, 19(1), 1. https://doi.org/10.1186/s12904-019-0499-1 Abstract Background: Patients in palliative care need rapid-acting pharmacological options for psychological distress. N- methyl-D-aspartate antagonist ketamine is known to have a fast onset of anti-depressant and anxiolytic action. Its S- enantiomer S-ketamine (or esketamine) is an analgesic used as a routine treatment for refractory pain as an intravenous infusion (0.25 mg/kg over 45 min). This study investigates whether S-ketamine pain therapy has a positive impact on psychological distress caused by anxiety and depression in palliative care. Methods: Patient routine data from a palliative care unit of a tertiary care hospital were used in a retrospective analysis after positive ethics approval. Eight patients, who received analgesic S-ketamine treatment, were compared to a control group matched by gender and age. The main analysis was conducted using three-way mixed MANOVA followed by two-way mixed ANOVA. Target variables were the values for anxiety and depression in the state-trait anxiety-depression inventory STADI. The predictor variables were the time of measurement before (T1) and after (T2) S-ketamine application and group membership. Results: Comparison of the S-ketamine group (n = 8; 4 male, 4 female; average age 52 years) with the control group (n = 8; 3 male, 5 female; average age 55 years) revealed a significant multivariate effect on anxiety and depression F(1, 14) = 4.78; p = 0.046; r = 0.50. The univariate comparisons showed a significant reduction of the anxiety scores from T1 to T2 in the S-ketamine group compared to the control group F(1, 14) = 10.14; p = 0.007; r = 0.65. With regard to depression, there was no significant reduction from T1 to T2 in the group comparison F(1, 14) = 1.60; p = 0.23; r = 0.32. No long-lasting effects on pain were found. Conclusions: Our findings show that psychological distress of patients in palliative care may improve after a single administration of S-ketamine, which mainly alleviates anxiety in those patients. Limitations of this study arise from non-randomization, retrospective analysis and low sample size. Therefore, further prospective and ideally randomized studies are necessary.

addiction, alcohol abuse, alcohol misuse, Ketamine, memory

Das, R.K., Gale, G., Walsh, K. et al. Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nat Commun 10, 5187 (2019). https://doi.org/10.1038/s41467-019-13162-w Abstract: Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired overconsumption disorders, such as harmful alcohol and drug use. The process of memory reconsolidation - where stored memories become briefly labile upon retrieval - may offer a means to disrupt MRMs and prevent relapse. However, reliable means for pharmacologically weakening MRMs in humans remain elusive. Here we demonstrate that the N-methyl D-aspartate (NMDA) antagonist ketamine is able to disrupt MRMs in hazardous drinkers when administered immediately after their retrieval. MRM retrieval+ketamine (RET+KET) effectively reduced the reinforcing effects of alcohol and long-term drinking levels, compared to ketamine or retrieval alone. Blood concentrations of ketamine and its metabolites during the critical 'reconsolidation window' predicted beneficial changes only following MRM reactivation. Pharmacological reconsolidation interference may provide a means to rapidly rewrite maladaptive memory and should be further pursued in alcohol and drug use disorders.

addiction, alcohol abuse, alcohol misuse, Ketamine, memory

Das, R.K., Gale, G., Walsh, K. et al. Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nat Commun 10, 5187 (2019). https://doi.org/10.1038/s41467-019-13162-w Abstract: Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired overconsumption disorders, such as harmful alcohol and drug use. The process of memory reconsolidation - where stored memories become briefly labile upon retrieval - may offer a means to disrupt MRMs and prevent relapse. However, reliable means for pharmacologically weakening MRMs in humans remain elusive. Here we demonstrate that the N-methyl D-aspartate (NMDA) antagonist ketamine is able to disrupt MRMs in hazardous drinkers when administered immediately after their retrieval. MRM retrieval+ketamine (RET+KET) effectively reduced the reinforcing effects of alcohol and long-term drinking levels, compared to ketamine or retrieval alone. Blood concentrations of ketamine and its metabolites during the critical 'reconsolidation window' predicted beneficial changes only following MRM reactivation. Pharmacological reconsolidation interference may provide a means to rapidly rewrite maladaptive memory and should be further pursued in alcohol and drug use disorders.

depression, ketamine therapy

Citation: Mandal, Suprio; Sinha, Vinod Kumar; Goyal, Nishant. Efficacy of ketamine therapy in the treatment of depression. Indian Journal of Psychiatry 61(5):p 480-485, Sep-Oct 2019. | DOI: 10.4103/psychiatry.IndianJPsychiatry_484_18 Abstract Background:Severe depressive disorder is among most debilitating condition. Conventional pharmacotherapy usually takes several weeks (usually 4-12 weeks) to improve symptoms. Ketamine is an N-methyl-D aspartate receptor antagonist having rapid action on depressive symptoms.Objectives:The effect of subanesthetic dose of ketamine was assessed on depressive and anxiety symptoms. Illness severity and improvement were assessed after treatment with ketamine.Materials and Methods:Twenty-five drug-free/naïve patients of the male sex, with severe depression having no previous history of psychotic disorder, head injury, organic disorder, cardiological problem, or substance abuse were admitted for the study. Assessments were made at baseline and injection ketamine hydrochloride was given at a subanesthetic dose of 0.5 mg/kg intravenous bolus after preparation. Assessments were repeated 1 h after the first dose. Six doses were given over 2 weeks and assessments were repeated. Final assessments were made after 1 month of the last dose.Results:There was a significant improvement in depression, anxiety, and the severity of illness after 2 weeks and 1 month of the last dose of ketamine. Significant improvement at 1 st h of the first dose was seen in depression and anxiety and not for illness severity. There were transient adverse effects observed in some patients which subsided within 1 h.Conclusion:Ketamine has a robust and rapid effect on depression, which was seen immediately after the administration of ketamine and sustained at the end of 1 month.Click Here to Read the Full Article

MDMA, MDMA-Assisted Psychotherapy, PTSD, Trauma

Mithoefer, M.C., Feduccia, A.A., Jerome, L. et al. MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology 236, 2735-2745 (2019). https://doi.org/10.1007/s00213-019-05249-5 Background Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD. Methods Six randomized, double-blind, controlled clinical trials at five study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75-125 mg, n=72) or placebo/control doses (0-40 mg, n=31) were administered to individuals with PTSD during manualized psychotherapy sessions in two or three 8-h sessions spaced a month apart. Three non-drug 90-min therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session. Results After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups −22.0 (5.17), P<0.001]. The between-group Cohen's d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups −6.0 (3.03), P=0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following. Conclusions MDMA-assisted psychotherapy was efficacious and well tolerated in a large sample of adults with PTSD. These studies supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment. Click Here to Read the Full Article

Nardou, R., Lewis, E.M., Rothhaas, R. et al. Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature 569, 116-120 (2019). https://doi.org/10.1038/s41586-019-1075-9 Abstract: "A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures1. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience2. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/−)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this critical period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neurodevelopmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury3." Click Here to Read the Full Article

Authors: John H. Krystal, Chadi G. Abdallah, Gerard Sanacora, Dennis S. Charney, Ronald S. Duman Article Info: NEUROVIEW, VOLUME 101, ISSUE 5, P774-778, MARCH 06, 2019 https://doi.org/10.1016/j.neuron.2019.02.005 "Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy. The rapid, profound, and sustainable antidepressant effects of ketamine seem poised to transform the treatment of depression, while mechanisms through which it may work are overturning the received wisdom regarding the underlying neurobiology...." Click Here to Read the Full Article

Authors: John H. Krystal, Chadi G. Abdallah, Gerard Sanacora, Dennis S. Charney, Ronald S. Duman Article Info: NEUROVIEW, VOLUME 101, ISSUE 5, P774-778, MARCH 06, 2019 https://doi.org/10.1016/j.neuron.2019.02.005 "Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy. The rapid, profound, and sustainable antidepressant effects of ketamine seem poised to transform the treatment of depression, while mechanisms through which it may work are overturning the received wisdom regarding the underlying neurobiology...." Click Here to Read the Full Article

KAP, Ketamine Assisted Psychotherapy, research

Abstract: "Currently, ketamine is the only legal psychedelic medicine available to mental health providers for the treatment of emotional suffering. Over the past several years, ketamine has come into psychiatric use as an intervention for treatment resistant depression (TRD), administered intravenously without a psychotherapeutic component. In these settings, ketamine's psychedelic effects are viewed as undesirable "side effects." In contrast, we believe ketamine can benefit patients with a wide variety of diagnoses when administered with psychotherapy and using its psychedelic properties without need for intravenous (IV) access. Its proven safety over decades of use makes it ideal for office and supervised at-home use. The unique experience that ketamine facilitates with its biological, experiential, and psychological impacts has been tailored to optimize office-based treatment evolving into a method that we call Ketamine Assisted Psychotherapy (KAP). This article is the first to explore KAP within an analytical framework examining three distinct practices that use similar methods. Here, we present demographic and outcome data from 235 patients. Our findings suggest that KAP is an effective method for decreasing depression and anxiety in a private practice setting, especially for older patients and those with severe symptom burden."Click Here to Read the Full Article

I. Ivan Ezquerra-Romano, W. Lawn, E. Krupitsky, C.J.A. Morgan, Ketamine for the treatment of addiction: Evidence and potential mechanisms, Neuropharmacology, Volume 142, 2018, Pages 72-82, ISSN 0028-3908, https://doi.org/10.1016/j.neuropharm.2018.01.017. (https://www.sciencedirect.com/science/article/pii/S0028390818300170) Abstract: Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine's ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine's efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

I. Ivan Ezquerra-Romano, W. Lawn, E. Krupitsky, C.J.A. Morgan, Ketamine for the treatment of addiction: Evidence and potential mechanisms, Neuropharmacology, Volume 142, 2018, Pages 72-82, ISSN 0028-3908, https://doi.org/10.1016/j.neuropharm.2018.01.017. (https://www.sciencedirect.com/science/article/pii/S0028390818300170) Abstract: Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine's ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine's efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Sean J. Belouin, Jack E. Henningfield, Psychedelics: Where we are now, why we got here, what we must do, Neuropharmacology, Volume 142, 2018, Pages 7-19, ISSN 0028 3908, https://doi.org/10.1016/j.neuropharm.2018.02.018. (https://www.sciencedirect.com/science/article/pii/S0028390818300753) Abstract: "The purpose of this commentary is to provide an introduction to this special issue of Neuropharmacology with a historical perspective of psychedelic drug research, their use in psychiatric disorders, research-restricting regulatory controls, and their recent emergence as potential breakthrough therapies for several brain-related disorders. It begins with the discovery of lysergic acid diethylamide (LSD) and its promising development as a treatment for several types of mental illnesses during the 1940s. This was followed by its abuse and stigmatization in the 1960s that ultimately led to the placement of LSD and other psychedelic drugs into the most restrictively regulated drug schedule of the United States Controlled Substances Act (Schedule I) in 1970 and its international counterparts. These regulatory controls severely constrained development of psychedelic substances and their potential for clinical research in psychiatric disorders. Despite the limitations, there was continued research into brain mechanisms of action for psychedelic drugs with potential clinical applications which began during the 1990s and early 2000s. Finding pathways to accelerate clinical research in psychedelic drug development is supported by the growing body of research findings that are documented throughout this special issue of Neuropharmacology. Accumulated research to date suggests psychedelic drug assisted psychotherapy may emerge as a potential breakthrough treatment for several types of mental illnesses including depression, anxiety, post-traumatic stress disorder, and addiction that are refractory to current evidenced based therapies. This research equally shows promise in advancing the understanding of the brain, brain related functioning, and the consequential effects of untreated brain related diseases that have been implicated in causing and/or exacerbating numerous physical disease state conditions. The authors conclude that more must be done to effectively address mental illnesses and brain related diseases which have become so pervasive, destructive, and whose treatments are becoming increasingly resistant to current evidenced based therapies. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'." Click Here to Read the Full Article

depression, Ketamine

Fava, M., Freeman, M.P., Flynn, M. et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry 25, 1592-1603 (2020). https://doi.org/10.1038/s41380-018-0256-5

Anxiety, autism, MDMA, MDMA-Assisted Psychotherapy, social anxiety

Danforth, A.L., Grob, C.S., Struble, C. et al. Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study. Psychopharmacology 235, 3137-3148 (2018). https://doi.org/10.1007/s00213-018-5010-9 Rationale Standard therapeutic approaches to reduce social anxiety in autistic adults have limited effectiveness. Since 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy shows promise as a treatment for other anxiety disorders, a blinded, placebo-controlled pilot study was conducted. Objectives To explore feasibility and safety of MDMA-assisted psychotherapy for reduction of social fear and avoidance that are common in the autistic population. Methods Autistic adults with marked to very severe social anxiety were randomized to receive MDMA (75 to 125 mg, n=8) or inactive placebo (0 mg, n=4) during two 8-h psychotherapy sessions (experimental sessions) in a controlled clinical setting. Double-blinded experimental sessions were spaced approximately 1 month apart with 3 non-drug psychotherapy sessions following each. The primary outcome was change in Leibowitz Social Anxiety Scale (LSAS) Total scores from Baseline to one month after the second experimental session. Outcomes were measured again six months after the last experimental session. Results Improvement in LSAS scores from baseline to the primary endpoint was significantly greater for MDMA group compared to the placebo group (P=0.037), and placebo-subtracted Cohen's d effect size was very large (d=1.4, CI −0.074, 2.874). Change in LSAS scores from baseline to 6-month follow-up showed similar positive results (P=0.036), with a Cohen's d effect size of 1.1 (CI −0.307, 2.527). Social anxiety remained the same or continued to improve slightly for most participants in the MDMA group after completing the active treatment phase. Conclusions This pilot trial demonstrated rapid and durable improvement in social anxiety symptoms in autistic adults following MDMA-assisted psychotherapy. Initial safety and efficacy outcomes support expansion of research into larger samples to further investigate this novel treatment for social anxiety. Click Here to Read the Full Article

Abstract Background: The glutamatergic modulator ketamine has rapid antidepressant effects in individuals with major depressive disorder and bipolar depression. Thus, modulating glutamatergic transmission may be critical to effectively treating depression, though the mechanisms by which this occurs are not fully understood. Methods: This double-blind, crossover, placebo-controlled study analyzed data from 18 drug-free major depressive disorder subjects and 18 heathy controls who received a single i.v. infusion of ketamine hydrochloride (0.5 mg/kg) as well as an i.v. saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6 to 9 hours after both ketamine and placebo infusions. During scanning, participants passively received tactile stimulation to the right index finger. Antidepressant response was assessed across timepoints using the Montgomery-Asberg Depression Rating Scale. Dynamic causal modeling was used to measure changes in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-mediated connectivity estimates in major depressive disorder subjects and controls using a simple model of somatosensory evoked responses. Results: Both major depressive disorder and healthy subjects showed ketamine-mediated NMDA-blockade sensitization, with major depressive disorder subjects showing enhanced NMDA connectivity estimates in backward connections and controls showing enhanced NMDA connectivity estimates in forward connections in our model. Within our major depressive disorder subject group, ketamine efficacy, as measured by improved mood ratings, correlated with reduced NMDA and AMPA connectivity estimates in discrete extrinsic connections within the somatosensory cortical network. Conclusions: These findings suggest that AMPA- and NMDA-mediated glutamatergic signaling play a key role in antidepressant response to ketamine and, further, that dynamic causal modeling is a powerful tool for modeling AMPA- and NMDA-mediated connectivity in vivo. Clinicaltrials.gov: NCT#00088699. Click Here to Read the Full Article

Abstract Background: The glutamatergic modulator ketamine has rapid antidepressant effects in individuals with major depressive disorder and bipolar depression. Thus, modulating glutamatergic transmission may be critical to effectively treating depression, though the mechanisms by which this occurs are not fully understood. Methods: This double-blind, crossover, placebo-controlled study analyzed data from 18 drug-free major depressive disorder subjects and 18 heathy controls who received a single i.v. infusion of ketamine hydrochloride (0.5 mg/kg) as well as an i.v. saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6 to 9 hours after both ketamine and placebo infusions. During scanning, participants passively received tactile stimulation to the right index finger. Antidepressant response was assessed across timepoints using the Montgomery-Asberg Depression Rating Scale. Dynamic causal modeling was used to measure changes in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-mediated connectivity estimates in major depressive disorder subjects and controls using a simple model of somatosensory evoked responses. Results: Both major depressive disorder and healthy subjects showed ketamine-mediated NMDA-blockade sensitization, with major depressive disorder subjects showing enhanced NMDA connectivity estimates in backward connections and controls showing enhanced NMDA connectivity estimates in forward connections in our model. Within our major depressive disorder subject group, ketamine efficacy, as measured by improved mood ratings, correlated with reduced NMDA and AMPA connectivity estimates in discrete extrinsic connections within the somatosensory cortical network. Conclusions: These findings suggest that AMPA- and NMDA-mediated glutamatergic signaling play a key role in antidepressant response to ketamine and, further, that dynamic causal modeling is a powerful tool for modeling AMPA- and NMDA-mediated connectivity in vivo. Clinicaltrials.gov: NCT#00088699. Click Here to Read the Full Article

Psychedelic Assisted Psychotherapy, Psychedelic-Assisted Psychotherapy

AUTHOR: Schenberg Eduardo Ekman TITLE: Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development JOURNAL: Frontiers in Pharmacology VOLUME: 9 YEAR: 2018 URL: https://www.frontiersin.org/articles/10.3389/fphar.2018.00733/full DOI=10.3389/fphar.2018.00733 ISSN=1663-9812 ABSTRACT: Mental disorders are rising while development of novel psychiatric medications is declining. This stall in innovation has also been linked with intense debates on the current diagnostics and explanations for mental disorders, together constituting a paradigmatic crisis. A radical innovation is psychedelic-assisted psychotherapy (PAP): professionally supervised use of ketamine, MDMA, psilocybin, LSD and ibogaine as part of elaborated psychotherapy programs. Clinical results so far have shown safety and efficacy, even for "treatment resistant" conditions, and thus deserve increasing attention from medical, psychological and psychiatric professionals. But more than novel treatments, the PAP model also has important consequences for the diagnostics and explanation axis of the psychiatric crisis, challenging the discrete nosological entities and advancing novel explanations for mental disorders and their treatment, in a model considerate of social and cultural factors, including adversities, trauma, and the therapeutic potential of some non-ordinary states of consciousness.

Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., Pinter, C., Hough, D., Sanacora, G., Manji, H., & Drevets, W. C. (2018). Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. The American journal of psychiatry, 175(7), 620-630. https://doi.org/10.1176/appi.ajp.2018.17060720 Objective: The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk. Method: In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Ã…sberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25. Results: A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=-5.3, SE=2.10; effect size=0.61) and at ∼24 hours (least-square mean difference=-7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=-4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache. Conclusions: These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide. Click Here to Read the Full Article

Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., Pinter, C., Hough, D., Sanacora, G., Manji, H., & Drevets, W. C. (2018). Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. The American journal of psychiatry, 175(7), 620-630. https://doi.org/10.1176/appi.ajp.2018.17060720 Objective: The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk. Method: In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Ã…sberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25. Results: A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=-5.3, SE=2.10; effect size=0.61) and at ∼24 hours (least-square mean difference=-7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=-4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache. Conclusions: These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide. Click Here to Read the Full Article

depression, Ketamine

Zanos, P., Gould, T. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 23, 801-811 (2018). https://doi.org/10.1038/mp.2017.255 Abstract: Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met with enthusiasm, ketamine's widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine's antidepressant actions but lack its undesirable effects. Here we review hypotheses for the mechanism of action of ketamine as an antidepressant, including synaptic or GluN2B-selective extra-synaptic N-methyl-D-aspartate receptor (NMDAR) inhibition, inhibition of NMDARs localized on GABAergic interneurons, inhibition of NMDAR-dependent burst firing of lateral habenula neurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. We also discuss links between ketamine's antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine's (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine's action are not mutually exclusive and may act in a complementary manner to exert acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine's antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression. Click Here to Read the Full Article

Zanos, P., Gould, T. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 23, 801-811 (2018). https://doi.org/10.1038/mp.2017.255 Abstract: Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met with enthusiasm, ketamine's widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine's antidepressant actions but lack its undesirable effects. Here we review hypotheses for the mechanism of action of ketamine as an antidepressant, including synaptic or GluN2B-selective extra-synaptic N-methyl-D-aspartate receptor (NMDAR) inhibition, inhibition of NMDARs localized on GABAergic interneurons, inhibition of NMDAR-dependent burst firing of lateral habenula neurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. We also discuss links between ketamine's antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine's (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine's action are not mutually exclusive and may act in a complementary manner to exert acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine's antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression. Click Here to Read the Full Article

Nugent, A.C., Ballard, E.D., Gould, T.D. et al. Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry 24, 1040-1052 (2019). https://doi.org/10.1038/s41380-018-0028-2 Abstract: Ketamine's mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to 1 day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post-ketamine gamma power and antidepressant response; specifically, higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine's mechanism of action from studies of healthy controls alone. Click Here to Read the Full Article

Nugent, A.C., Ballard, E.D., Gould, T.D. et al. Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry 24, 1040-1052 (2019). https://doi.org/10.1038/s41380-018-0028-2 Abstract: Ketamine's mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to 1 day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post-ketamine gamma power and antidepressant response; specifically, higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine's mechanism of action from studies of healthy controls alone. Click Here to Read the Full Article

Kaelen, M., Giribaldi, B., Raine, J. et al. The hidden therapist: evidence for a central role of music in psychedelic therapy. Psychopharmacology 235, 505-519 (2018). https://doi.org/10.1007/s00213-017-4820-5 Rationale Recent studies have supported the safety and efficacy of psychedelic therapy for mood disorders and addiction. Music is considered an important component in the treatment model, but little empirical research has been done to examine the magnitude and nature of its therapeutic role. Objectives The present study assessed the influence of music on the acute experience and clinical outcomes of psychedelic therapy. Methods Semi-structured interviews inquired about the different ways in which music influenced the experience of 19 patients undergoing psychedelic therapy with psilocybin for treatment-resistant depression. Interpretative phenomenological analysis was applied to the interview data to identify salient themes. In addition, ratings were given for each patient for the extent to which they expressed "liking," "resonance" (the music being experienced as "harmonious" with the emotional state of the listener), and "openness" (acceptance of the music-evoked experience). Results Analyses of the interviews revealed that the music had both "welcome" and "unwelcome" influences on patients' subjective experiences. Welcome influences included the evocation of personally meaningful and therapeutically useful emotion and mental imagery, a sense of guidance, openness, and the promotion of calm and a sense of safety. Conversely, unwelcome influences included the evocation of unpleasant emotion and imagery, a sense of being misguided and resistance. Correlation analyses showed that patients' experience of the music was associated with the occurrence of "mystical experiences" and "insightfulness." Crucially, the nature of the music experience was significantly predictive of reductions in depression 1 week after psilocybin, whereas general drug intensity was not. Conclusions This study indicates that music plays a central therapeutic function in psychedelic therapy. Click Here to Read the Full Article

Kaelen, M., Giribaldi, B., Raine, J. et al. The hidden therapist: evidence for a central role of music in psychedelic therapy. Psychopharmacology 235, 505-519 (2018). https://doi.org/10.1007/s00213-017-4820-5 Rationale Recent studies have supported the safety and efficacy of psychedelic therapy for mood disorders and addiction. Music is considered an important component in the treatment model, but little empirical research has been done to examine the magnitude and nature of its therapeutic role. Objectives The present study assessed the influence of music on the acute experience and clinical outcomes of psychedelic therapy. Methods Semi-structured interviews inquired about the different ways in which music influenced the experience of 19 patients undergoing psychedelic therapy with psilocybin for treatment-resistant depression. Interpretative phenomenological analysis was applied to the interview data to identify salient themes. In addition, ratings were given for each patient for the extent to which they expressed "liking," "resonance" (the music being experienced as "harmonious" with the emotional state of the listener), and "openness" (acceptance of the music-evoked experience). Results Analyses of the interviews revealed that the music had both "welcome" and "unwelcome" influences on patients' subjective experiences. Welcome influences included the evocation of personally meaningful and therapeutically useful emotion and mental imagery, a sense of guidance, openness, and the promotion of calm and a sense of safety. Conversely, unwelcome influences included the evocation of unpleasant emotion and imagery, a sense of being misguided and resistance. Correlation analyses showed that patients' experience of the music was associated with the occurrence of "mystical experiences" and "insightfulness." Crucially, the nature of the music experience was significantly predictive of reductions in depression 1 week after psilocybin, whereas general drug intensity was not. Conclusions This study indicates that music plays a central therapeutic function in psychedelic therapy. Click Here to Read the Full Article

Objective: Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder. Method: In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1). Results: The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen's d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine's effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up. Conclusions: Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect. Click Here to Read the Full Article

Objective: Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder. Method: In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1). Results: The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen's d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine's effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up. Conclusions: Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect. Click Here to Read the Full Article

Background A range of studies has demonstrated the efficacy of the psychoactive Amazonian brew ayahuasca in addressing substance addiction. These have revealed that physiological and psychological mechanisms are deeply enmeshed. This article focuses on how interactive ritual contexts support the healing effort. The study of psychedelic-assisted treatments for addiction has much to gain from ethnographic analyses of healing experiences within the particular ecologies of use and care, where these interventions are rendered efficacious. Methods This is an ethnographically grounded, qualitative analysis of addiction-recovery experiences within ayahuasca rituals. It draws on long-term fieldwork and participant observation in ayahuasca communities, and in-depth, semi-structured interviews of participants with histories of substance misuse. Results Ayahuasca's efficacy in the treatment of addiction blends somatic, symbolic and collective dimensions. The layering of these effects, and the direction given to them through ritual, circumscribes the experience and provides tools to render it meaningful. Prevailing modes of evaluation are ill suited to account for the particular material and semiotic efficacy of complex interventions such as ayahuasca healing for addiction. The article argues that practices of care characteristic of the ritual spaces in which ayahuasca is collectively consumed, play a key therapeutic role. Conclusion The ritual use of ayahuasca stands in strong contrast to hegemonic understandings of addiction, paving new ground between the overstated difference between community and pharmacological interventions. The article concludes that fluid, adaptable forms of caregiving play a key role in the success of addiction recovery and that feeling part of a community has an important therapeutic potential. Click Here to Read the Full Article

Background A range of studies has demonstrated the efficacy of the psychoactive Amazonian brew ayahuasca in addressing substance addiction. These have revealed that physiological and psychological mechanisms are deeply enmeshed. This article focuses on how interactive ritual contexts support the healing effort. The study of psychedelic-assisted treatments for addiction has much to gain from ethnographic analyses of healing experiences within the particular ecologies of use and care, where these interventions are rendered efficacious. Methods This is an ethnographically grounded, qualitative analysis of addiction-recovery experiences within ayahuasca rituals. It draws on long-term fieldwork and participant observation in ayahuasca communities, and in-depth, semi-structured interviews of participants with histories of substance misuse. Results Ayahuasca's efficacy in the treatment of addiction blends somatic, symbolic and collective dimensions. The layering of these effects, and the direction given to them through ritual, circumscribes the experience and provides tools to render it meaningful. Prevailing modes of evaluation are ill suited to account for the particular material and semiotic efficacy of complex interventions such as ayahuasca healing for addiction. The article argues that practices of care characteristic of the ritual spaces in which ayahuasca is collectively consumed, play a key therapeutic role. Conclusion The ritual use of ayahuasca stands in strong contrast to hegemonic understandings of addiction, paving new ground between the overstated difference between community and pharmacological interventions. The article concludes that fluid, adaptable forms of caregiving play a key role in the success of addiction recovery and that feeling part of a community has an important therapeutic potential. Click Here to Read the Full Article

Kadriu, B., Gold, P.W., Luckenbaugh, D.A. et al. Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder. Mol Psychiatry 23, 1626-1631 (2018). https://doi.org/10.1038/mp.2017.109 Abstract: "Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment-resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230min, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness." Click Here to Read the Full Article

Kadriu, B., Gold, P.W., Luckenbaugh, D.A. et al. Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder. Mol Psychiatry 23, 1626-1631 (2018). https://doi.org/10.1038/mp.2017.109 Abstract: "Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment-resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230min, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness." Click Here to Read the Full Article

Thomas Kingsley Brown & Kenneth Alper (2018) Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes, The American Journal of Drug and Alcohol Abuse, 44:1, 24-36, DOI: 10.1080/00952990.2017.1320802

Thomas Kingsley Brown & Kenneth Alper (2018) Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes, The American Journal of Drug and Alcohol Abuse, 44:1, 24-36, DOI: 10.1080/00952990.2017.1320802

LSD

Liechti, M. Modern Clinical Research on LSD. Neuropsychopharmacol 42, 2114-2127 (2017). https://doi.org/10.1038/npp.2017.86

Geoffrey E. Noller, Chris M. Frampton & Berra Yazar-Klosinski (2018) Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study, The American Journal of Drug and Alcohol Abuse, 44:1, 37-46, DOI: 10.1080/00952990.2017.1310218

Geoffrey E. Noller, Chris M. Frampton & Berra Yazar-Klosinski (2018) Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study, The American Journal of Drug and Alcohol Abuse, 44:1, 37-46, DOI: 10.1080/00952990.2017.1310218

Sanacora G, Frye MA, McDonald W, et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry. 2017;74(4):399-405. doi:10.1001/jamapsychiatry.2017.0080 Importance  Several studies now provide evidence of ketamine hydrochloride's ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders. Observations  This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option. Conclusions and Relevance  The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety. Click Here to Read the Full Article

Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology. 2016;30(12):1181-1197. doi:10.1177/0269881116675513 Abstract: "Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes." Click Here to Read the Full Article

Nichols, D., Johnson, M. and Nichols, C. (2017), Psychedelics as Medicines: An Emerging New Paradigm. Clin. Pharmacol. Ther., 101: 209-219. https://doi.org/10.1002/cpt.557 Abstract: "Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network "resetting" after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched." Click Here to Read the Full Article

Abstract: Background Hallucinogenic drugs were used to treat alcoholic patients in the past, and recent developments in the study of hallucinogens led to a renewal of interest regarding the application of these drugs in the treatment of addiction. In this scenario, accumulating evidence suggests that the hallucinogenic brew ayahuasca (Aya) may have therapeutic effects on substance abuse problems. Methods We investigated the effects of Aya on spontaneous locomotor activity and ethanol(Eth)-induced hyperlocomotion and subsequent locomotor sensitization by a two-injection protocol. Additionally, we tested the effect of Aya on an 8-day counter-sensitization protocol to modify sensitized responses induced by a repeated treatment with Eth (1.8 g/kg) for 8 alternate days. Results Aya showed high sensitivity in preventing the development of Eth-induced behavioral sensitization, attenuating it at all doses (30, 100, 200, 300 or 500 mg/kg) without modifying spontaneous locomotor activity. At the highest doses (300 and 500 mg/kg), Aya also showed selectivity to both acute and sensitized Eth responses. Finally, a counter-sensitization strategy with 100 or 300 mg/kg of Aya for 8 consecutive days after the establishment of Eth-induced behavioral sensitization was effective in blocking its subsequent expression on an Eth challenge. Conclusions We demonstrated that Aya not only inhibits early behaviors associated with the initiation and development of Eth addiction, but also showed effectiveness in reversing long-term drug effects expression, inhibiting the reinstatement of Eth-induced behavioral sensitization when administered in the Eth-associated environment. Click Here to Read the Full Article

Abstract: Background Hallucinogenic drugs were used to treat alcoholic patients in the past, and recent developments in the study of hallucinogens led to a renewal of interest regarding the application of these drugs in the treatment of addiction. In this scenario, accumulating evidence suggests that the hallucinogenic brew ayahuasca (Aya) may have therapeutic effects on substance abuse problems. Methods We investigated the effects of Aya on spontaneous locomotor activity and ethanol(Eth)-induced hyperlocomotion and subsequent locomotor sensitization by a two-injection protocol. Additionally, we tested the effect of Aya on an 8-day counter-sensitization protocol to modify sensitized responses induced by a repeated treatment with Eth (1.8 g/kg) for 8 alternate days. Results Aya showed high sensitivity in preventing the development of Eth-induced behavioral sensitization, attenuating it at all doses (30, 100, 200, 300 or 500 mg/kg) without modifying spontaneous locomotor activity. At the highest doses (300 and 500 mg/kg), Aya also showed selectivity to both acute and sensitized Eth responses. Finally, a counter-sensitization strategy with 100 or 300 mg/kg of Aya for 8 consecutive days after the establishment of Eth-induced behavioral sensitization was effective in blocking its subsequent expression on an Eth challenge. Conclusions We demonstrated that Aya not only inhibits early behaviors associated with the initiation and development of Eth addiction, but also showed effectiveness in reversing long-term drug effects expression, inhibiting the reinstatement of Eth-induced behavioral sensitization when administered in the Eth-associated environment. Click Here to Read the Full Article

Anxiety, LSD, LSD Assisted Psychotherapy

Gasser, Peter MD*; Holstein, Dominique PhD†; Michel, Yvonne PhD‡; Doblin, Rick PhD§; Yazar-Klosinski, Berra PhD§; Passie, Torsten MD, MA∥; Brenneisen, Rudolf PhD. Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases. The Journal of Nervous and Mental Disease 202(7):p 513-520, July 2014. | DOI: 10.1097/NMD.0000000000000113 Abstract: A double-blind, randomized, active placebo-controlled pilot study was conducted to examine safety and efficacy of lysergic acid diethylamide (LSD)-assisted psychotherapy in 12 patients with anxiety associated with life-threatening diseases. Treatment included drug-free psychotherapy sessions supplemented by two LSD-assisted psychotherapy sessions 2 to 3 weeks apart. The participants received either 200 μg of LSD (n = 8) or 20 μg of LSD with an open-label crossover to 200 μg of LSD after the initial blinded treatment was unmasked (n = 4). At the 2-month follow-up, positive trends were found via the State-Trait Anxiety Inventory (STAI) in reductions in trait anxiety (p = 0.033) with an effect size of 1.1, and state anxiety was significantly reduced (p = 0.021) with an effect size of 1.2, with no acute or chronic adverse effects persisting beyond 1 day after treatment or treatment-related serious adverse events. STAI reductions were sustained for 12 months. These results indicate that when administered safely in a methodologically rigorous medically supervised psychotherapeutic setting, LSD can reduce anxiety, suggesting that larger controlled studies are warranted. Click Here to Read the Full Article

Jamie Sleigh, Martyn Harvey, Logan Voss, Bill Denny, Ketamine - More mechanisms of action than just NMDA blockade, Trends in Anaesthesia and Critical Care, Volume 4, Issues 2-3, 2014, Pages 76-81, ISSN 2210-8440,https://doi.org/10.1016/j.tacc.2014.03.002. (https://www.sciencedirect.com/science/article/pii/S2210844014200062) Summary:Ketamine has been in clinical use for over half a century, yet its precise mechanisms of action remain mysterious for the large part. Its hypnotic effects appear to be largely mediated by blockade of NMDA and HCN1 receptors, but cholinergic, aminergic, and opioid systems appear to play both a positive and negative modulatory role in both sedation and analgesia. Ketamine's effects in chronic pain, and as an antidepressant, far outlast the actual drug levels, and are probably mediated by a secondary increase in structural synaptic connectivity that is mediated by a neuronal response to the ketamine-induced hyper-glutamatergic state. Click Here to Read the Full Article

Ben Sessa (2014) Why Psychiatry Needs Psychedelics and Psychedelics Need Psychiatry, Journal of Psychoactive Drugs, 46:1, 57-62, DOI: 10.1080/02791072.2014.877322 Abstract: "Without researching psychedelic drugs for medical therapy, psychiatry is turning its back on a group of compounds that could have great potential. Without the validation of the medical profession, the psychedelic drugs, and those who take them off-license, remain archaic sentiments of the past, with the users maligned as recreational drug abusers and subject to continued negative opinion. These two disparate groups-psychiatrists and recreational psychedelic drug users-are united by their shared recognition of the healing potential of these compounds. A resolution of this conflict is essential for the future of psychiatric medicine and psychedelic culture alike. Progression will come from professionals working in the field adapting to fit a conservative paradigm. In this way, they can provide the public with important treatments and also raise the profile of expanded consciousness in mainstream society." Click Here to Read the Full Article

Ayahuasca-Assisted Therapy for Addiction: Results from a Preliminary Observational Study in Canada Author(s): Gerald Thomas, Philippe Lucas, N. Rielle Capler, Kenneth W. Tupper and Gina Martin Volume 6, Issue 1, 2013 Page: [30 - 42] Pages: 13 DOI: 10.2174/15733998113099990003 Abstract: "Introduction: This paper reports results from a preliminary observational study of ayahuasca-assisted treatment for problematic substance use and stress delivered in a rural First Nations community in British Columbia, Canada. Methods: The "Working with Addiction and Stress" retreats combined four days of group counselling with two expert-led ayahuasca ceremonies. This study collected pre-treatment and six months follow-up data from 12 participants on several psychological and behavioral factors related to problematic substance use, and qualitative data assessing the personal experiences of the participants six months after the retreat. Findings: Statistically significant (p < 0.05) improvements were demonstrated for scales assessing hopefulness, empowerment, mindfulness, and quality of life meaning and outlook subscales. Self-reported alcohol, tobacco and cocaine use declined, although cannabis and opiate use did not; reported reductions in problematic cocaine use were statistically significant. All study participants reported positive and lasting changes from participating in the retreats. Conclusions: This form of ayahuasca-assisted therapy appears to be associated with statistically significant improvements in several factors related to problematic substance use among a rural aboriginal population. These findings suggest participants may have experienced positive psychological and behavioral changes in response to this therapeutic approach, and that more rigorous research of ayahuasca-assisted therapy for problematic substance use is warranted." Click Here to Read the Full Article

Ayahuasca-Assisted Therapy for Addiction: Results from a Preliminary Observational Study in Canada Author(s): Gerald Thomas, Philippe Lucas, N. Rielle Capler, Kenneth W. Tupper and Gina Martin Volume 6, Issue 1, 2013 Page: [30 - 42] Pages: 13 DOI: 10.2174/15733998113099990003 Abstract: "Introduction: This paper reports results from a preliminary observational study of ayahuasca-assisted treatment for problematic substance use and stress delivered in a rural First Nations community in British Columbia, Canada. Methods: The "Working with Addiction and Stress" retreats combined four days of group counselling with two expert-led ayahuasca ceremonies. This study collected pre-treatment and six months follow-up data from 12 participants on several psychological and behavioral factors related to problematic substance use, and qualitative data assessing the personal experiences of the participants six months after the retreat. Findings: Statistically significant (p < 0.05) improvements were demonstrated for scales assessing hopefulness, empowerment, mindfulness, and quality of life meaning and outlook subscales. Self-reported alcohol, tobacco and cocaine use declined, although cannabis and opiate use did not; reported reductions in problematic cocaine use were statistically significant. All study participants reported positive and lasting changes from participating in the retreats. Conclusions: This form of ayahuasca-assisted therapy appears to be associated with statistically significant improvements in several factors related to problematic substance use among a rural aboriginal population. These findings suggest participants may have experienced positive psychological and behavioral changes in response to this therapeutic approach, and that more rigorous research of ayahuasca-assisted therapy for problematic substance use is warranted." Click Here to Read the Full Article

BACKGROUND: Anecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT1A and 5-HT2A/2C agonist, in patients with OCD. METHOD: Nine subjects with DSM-IV-defined OCD and no other current major psychiatric disorder participated in up to 4 single-dose exposures to psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100 mg/kg), medium (200 mg/kg), and high (300 mg/kg) doses were assigned in that order, and a very low dose (25 mg/kg) was inserted randomly and in double-blind fashion at any time after the first dose. Testing days were separated by at least 1 week. Each session was conducted over an 8-hour period in a controlled environment in an outpatient clinic; subjects were then transferred to a psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom severity were administered at 0, 4, 8, and 24 hours postingestion. The Hallucinogen Rating Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after ingestion. The study was conducted from November 2001 to November 2004. RESULTS: Nine subjects were administered a total of 29 psilocybin doses. One subject experienced transient hypertension without relation to anxiety or somatic symptoms, but no other significant adverse effects were observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-measures analysis of variance for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p = .515). Improvement generally lasted past the 24-hour timepoint. CONCLUSIONS: In a controlled clinical environment, psilocybin was safely used in subjects with OCD and was associated with acute reductions in core OCD symptoms in several subjects. Click Here to Read the Full Article