Stay up to date on the latest research in psychedelic medicine

Every month, around 100 new studies on psychedelics are published, adding to what we know about these substances. To help clinicians and practitioners stay up-to-date with the most important findings, the Psychedelic Provider Network has teamed up with Blossom to review the latest studies.

April 2025 Research Summary

To keep clinicians and practitioners informed about the most relevant developments, the Psychedelic Provider Network and Blossom have reviewed the latest psychedelic research from April 2025. From over 159 new studies this month, we’ve highlighted three particularly important findings with direct implications for clinical practice.

First, we look at a significant real-world study evaluating oral esketamine for severe treatment-resistant depression. The study provides evidence for the effectiveness and tolerability of oral administration, suggesting it may be a practical and patient-friendly alternative to current intranasal or intravenous methods.

Next, we examine the first large-scale randomized clinical trial exploring intranasal esketamine as a treatment for smoking cessation among patients diagnosed with both lung cancer and major depressive disorder. This innovative study demonstrates meaningful improvements not only in smoking abstinence but also in associated mental health outcomes.

Finally, we critically assess a recent observational study questioning the added benefit of psychotherapy when combined with ketamine treatment for depression and PTSD. Given the study’s observational design, we discuss important caveats and emphasize considerations clinicians should bear in mind before adjusting treatment protocols.

These selected studies highlight practical considerations for treatment approaches, innovative therapeutic applications, and critical evaluations of existing protocols, all of which can guide clinicians working with psychedelic medicines. Let's review each study in detail.

Oral Esketamine for Severe Treatment-Resistant Depression

For clinicians treating patients with treatment-resistant depression (TRD), intravenous (IV), intramuscular (IM), and intranasal (e.g., Spravato) ketamine have been the most commonly used ways of administration. A shorter duration, high bioavailability, and less variance are some of the reasons for using these routes versus oral ketamine. 

Still, oral esketamine presents a potentially easier, less invasive, and more accessible option, though evidence supporting this route has been limited. Addressing this gap, a large real-world study in the Netherlands evaluated oral esketamine in 185 adults who had experienced limited or no benefit from multiple antidepressants and even electroconvulsive therapy (ECT).

Participants underwent a six-week open-label treatment program, receiving oral esketamine twice weekly at individually adjusted doses ranging from 35 to 210 mg / 70 kg. Each dose was supervised clinically, with careful monitoring of side effects, blood pressure, and cognitive function. Treatment sessions lasted approximately two to three hours.

Clinically significant improvements were observed, with depressive symptoms (measured by HDRS17 scores) dropping by about 26%. Approximately 47% of participants reported meaningful symptom relief, with about 27% achieving at least a 50% reduction in symptoms and nearly 16% reaching remission. Notably, improvements in daily functioning and reduced suicidal ideation were also observed, even in a highly refractory patient group. The dropout rate was low at 8%, suggesting good tolerability and acceptability among patients.

First Large-Scale Trial of Esketamine for Smoking Cessation

Smoking cessation is one of the areas where psychedelics can have an outsized impact. This is even more true for patients diagnosed with lung cancer, significantly improving survival and quality of life. However, quitting smoking can be challenging for individuals who also struggle with major depressive disorder (MDD), as depression often complicates and undermines quit attempts. 

While earlier research into psychedelic treatments for smoking cessation, such as psilocybin-assisted therapy, has shown promising results, including a notable January 2017 follow-up study that found 67% of participants abstinent at 12 months, data on ketamine-based treatments remain scarce. Addressing this gap, a large, rigorous randomized trial from China has evaluated intranasal esketamine specifically in patients facing the dual burden of lung cancer and MDD.

This multicenter, randomized, placebo-controlled trial included 236 patients diagnosed with lung cancer and treatment-resistant MDD who were heavy smokers (averaging about 19 cigarettes daily for approximately 31 years). Participants received either intranasal esketamine (35 mg weekly) or a placebo for eight sessions. Treatment began three weeks before lung surgery to optimize respiratory and mood-related outcomes. Standard behavioral counseling and mobile quit-support messaging accompanied the medical intervention.

At the six-month follow-up after treatment ended, esketamine significantly increased smoking abstinence rates compared to placebo. About 44% of participants receiving esketamine self-reported continuous abstinence, which was biologically verified in nearly 29%, versus only 8% in the placebo group. These results indicate that esketamine treatment effectively quadrupled the odds of maintaining long-term abstinence.

Beyond smoking cessation, esketamine markedly reduced depressive and anxiety symptoms, crucial as mood instability often triggers relapse. Depression severity scores improved substantially—from moderate-severe levels down to mild—with esketamine, whereas the placebo group experienced minimal improvement. Participants treated with esketamine also reported fewer respiratory symptoms, reduced nicotine dependence, and less frequent urges to smoke. Improved cognitive function was an additional notable benefit, likely related to better mood, reduced nicotine use, and improved respiratory health.

Adverse effects were generally mild and temporary, such as dizziness, sedation, and nausea. Dissociative symptoms were brief, manageable, and decreased over successive treatments. Importantly, no serious cardiovascular or psychiatric events were reported, underscoring esketamine’s safety profile in this medically complex population.

The Absence of Therapy in Ketamine Treatment

Ketamine treatment has become widely recognized as a rapidly effective therapy for depression and PTSD. Its clinical use has often involved integration with psychotherapy, under the assumption that psychotherapy may enhance and prolong ketamine’s beneficial effects by leveraging its rapid neuroplasticity-enhancing properties. However, few studies have looked at the value of the therapy versus only giving ketamine without therapy. A recent observational study evaluated whether psychotherapy adds measurable benefit when combined with ketamine, compared to ketamine treatment alone.

The study assessed overlapping groups of adults receiving either intravenous ketamine alone (35 mg per session) or ketamine combined with various psychotherapies (primarily ketamine-assisted psychotherapy and cognitive behavioral therapy) over 4–14 sessions within 30- and 180-day periods. Depression symptoms were evaluated with the Patient Health Questionnaire (PHQ-9), and PTSD symptoms were assessed using the PTSD Checklist (PCL-5). This observational design, while capturing real-world clinical practice, did not rigorously control for psychotherapy outside the study environment or fully standardize the type and quality of therapeutic interventions provided.

Both treatment approaches yielded significant and rapid improvements in depression and PTSD symptoms, with most improvements occurring within the first two weeks of treatment. However, contrary to the researchers' expectations, adding psychotherapy did not provide a statistically significant advantage over ketamine alone across the primary analyses. Exploratory subgroup analyses suggested that younger females might experience slightly greater improvements when psychotherapy was included, whereas older males seemed to benefit more from ketamine alone. These subgroup differences, while interesting, did not reach statistical significance and warrant further targeted investigation.

From a clinical perspective, this study’s findings should be interpreted cautiously due to its observational nature. Participants in the "ketamine-only" group might have accessed psychotherapy independently outside the study, potentially diluting observed differences between groups. Additionally, the varied psychotherapy approaches used could have influenced the consistency and quality of treatment delivery. Nonetheless, these findings raise important practical questions about optimizing the allocation of therapist resources. Given the finite availability of skilled therapists, identifying whether psychotherapy meaningfully enhances ketamine's effects, or if ketamine alone may be sufficient for some patients, is crucial for effective healthcare delivery.

The study also aligns somewhat with practices surrounding Spravato (intranasal esketamine), where formal psychotherapy is not inherently integrated into the treatment protocol. Patients often receive psychotherapy separately from the medical administration sessions, an approach that might reflect practical clinical realities rather than therapeutic ideals. This distinction reinforces the importance of understanding when and how psychotherapy might most effectively complement pharmacological treatments.

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April 2025 in Psychedelic Research

For the research on psychedelics in April, we’ve covered three ketamine studies. The first study on oral esketamine showed promising results for treatment-resistant depression, offering a more accessible administration route despite lower bioavailability compared to intravenous or intranasal methods. This advancement could expand treatment availability while maintaining clinical efficacy.

The first major clinical trial of esketamine for smoking cessation demonstrated improved abstinence rates and reduced depression in lung cancer patients. These results parallel earlier findings on psilocybin for smoking cessation, suggesting psychedelics may effectively address complex, comorbid conditions in clinical settings.

Finally, an observational study found that combining ketamine with psychotherapy showed no significant additional benefits during acute treatment for depression and PTSD. While these findings suggest ketamine's potential standalone efficacy, the study's observational nature and possible confounding factors warrant careful interpretation.