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:  "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: "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: 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: 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: "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

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)