JAMA PsychiatryOctober 28, 2026Yuefeng Huang, Ahmet O Ceceli, Greg Kronberg et al.
Despite decades of clinical implementation of medications for opioid use disorder (OUD), overdose mortality rates remain high, underscoring a critical need for interventions that target the brain mechanisms underlying addiction. To assess the neural mechanisms of Mindfulness-Oriented Recovery Enhancement (MORE) and their associations with clinical outcomes, including craving and abstinence...
This nonrandomized clinical trial assesses associations between psilocybin therapy and changes in systemic markers of inflammation and mitochondrial stress in people with Parkinson disease and mood dysfunction.
This Viewpoint discusses the UMBRAA (unidentifiable multidrug blinding with reduced, authorized awareness) strategy to address the masking problem in psychedelic trials.
Importance Antidepressant efficacy of intravenous (IV) ketamine has been demonstrated in major depressive disorder; however, the efficacy and safety of ketamine for bipolar depression remain largely unknown, with limited data available in this specific population. Objective To evaluate the efficacy, safety, and tolerability of adjunctive IV ketamine compared with midazolam for...
To the Editor In JAMA Psychiatry, Cubała et al. report that inhaled mebufotenin (GH001) reduced depression severity by 15.5 points more than placebo on the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1 week, with 57.5% of patients achieving remission vs 0% in the placebo group. The effect size (d = −2.0) overwhelmingly surpasses those of selective serotonin reuptake inhibitors,...
This Viewpoint reviews the case of sodium oxybate, a product of gamma-hydroxybutyrate (GHB), to illustrate how psychedelics and other Schedule I substances can proceed through a similar regulatory pathway.
JAMA PsychiatryJuly 1, 2026Sung Ryul Shim, Hye Su Jeong, Tanner J. Bommersbach et al.1 citation
While intravenous ketamine is not approved by the US Food and Drug Administration, it is increasingly used with off-label indications as a novel treatment for suicidal and depressive symptoms. To systematically review and metasynthesize the efficacy and safety data for intravenous ketamine in treating major depressive episodes (MDEs). PubMed, PsycInfo, Cochrane Library, and Embase were...
Ketamine has well-known dissociative, analgesic, and antidepressant properties, but it is unknown whether the neurophysiologic effects that are associated with these properties can be modulated separately from one another. Considering that specific cortical oscillations have been associated with specific therapeutic effects, modulating selective aspects of ketamine neurophysiology could inform...
The phase 2 data presented here support the development of TSND-201 for posttraumatic stress disorder (PTSD), a disorder for which there is a significant unmet need for rapid-acting and effective treatments. TSND-201 (methylone) is a highly selective, rapid-acting neuroplastogen that releases serotonin, norepinephrine, and dopamine without direct activity at 5-hydroxytryptamine (5-HT) 2A...
Importance: Psychedelic drugs possess acute psychoactive effects that can compromise blinding integrity in randomized clinical trials (RCTs). Functional unblinding, when participants or raters correctly identify treatment allocation based on subjective effects, may bias outcomes through expectancy effects, challenging the validity of efficacy estimates and regulatory acceptance. Objective: To...
Importance: Few pharmacotherapies are approved for treatment-resistant depression, and many patients do not achieve remission following treatment with those therapies. Objective: To examine the efficacy and safety of single-day treatment with a synthetic formulation of inhaled mebufotenin (GH001) vs placebo in patients with treatment-resistant depression. Design, Setting, and Participants: This...
Importance: Psychedelic-assisted therapy (PAT) trials have high levels of functional unblinding, which biases results when comparing PAT with blinded interventions. Because PAT is effectively always open label, treatment results should be compared with those of open-label traditional antidepressants (TADs), so potential benefits associated with patients knowing their treatment is equal between...
Importance: Psilocybin shows promise in treating depression, although limitations of previous research warrant further research. Objective: To investigate the efficacy and safety of oral psilocybin, 25 mg, with adjunct psychotherapy in treatment-resistant depression (TRD). Design, Setting, and Participants: This was a 2-center, triple-blinded (investigator, participant, rater), phase 2b, active...
Can a guided psychedelic experience with psilocybin successfully treat refractory depression? In other words, setting aside any simple direct biological drug effect, can psychedelic-assisted psychotherapy1 alleviate suffering via what William James would call a mystical experience?2
This Viewpoint addresses the dual domains of psychedelic experience—neurobiological changes and subjective experience—and argues for rigorous investigation of both domains.
Importance Psilocybin use has surged in the US following decriminalization efforts and promising clinical trial results. Mirroring early cannabis legalization, public access and enthusiasm are outpacing regulatory oversight and scientific understanding, posing potential risks to public health. Objective To review emerging evidence on the public health implications of unregulated psilocybin...
Key Points Question For inpatients with moderate to severe depression, is repeated intravenous ketamine superior to a psychoactive placebo (midazolam) in reducing depressive symptoms? Findings In this randomized clinical trial, there was no statistically significant difference in the primary outcome, end-of-treatment Montgomery-Åsberg Depression Rating Scale score, between the ketamine and...
This Viewpoint describes the benefits of providing psychedelic treatment to persons with psychiatric conditions as life-preserving care before physician-assisted death.
Esketamine nasal spray, administered in conjunction with an oral antidepressant, is approved for treatment-resistant depression (TRD). However, the efficacy of esketamine nasal spray administered as monotherapy for patients with TRD has not yet been evaluated. To assess the efficacy and safety of esketamine monotherapy compared to placebo in reducing depressive symptoms in patients with TRD....
Microdosing psychedelics, including lysergic acid diethylamide (LSD), has gained attention for its potential benefits in several psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). However, LSD's efficacy in reducing ADHD symptoms remains unknown. To determine the safety and efficacy of repeated low doses of LSD in reducing ADHD symptoms compared with placebo. This...
Expectancy effects are significant confounding factors in psychiatric randomized clinical trials (RCTs), potentially affecting the interpretation of study results. This narrative review is the first, to our knowledge, to explore the relationship between expectancy effects, compromised blinding integrity, and the effects of active treatment/placebo in psychiatric RCTs. Additionally, we present...
This Viewpoint explores potential justifications underlying the US Food and Drug Administration (FDA)’s rejection of methylenedioxymethamphetamine (MDMA) as a treatment for posttraumatic stress disorder, including lack of blinding and issues around the integrity of relevant clinical trials.
Treatment-resistant depression (TRD) remains a critical challenge in psychiatry, with limited effective options. Esketamine, a rapid-acting antidepressant, is usually combined with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), but comparative evidence of these combinations' effectiveness in real-world settings is sparse. To determine...
There is unprecedented clinician, industry, and patient interest in the therapeutic development of psychedelic drugs. This is due to a combination of promising clinical trial results, positive media coverage, and the lack of novel pharmacologic treatments for psychiatric disorders in recent decades. However, the field faces a key methodological challenge: masking participants to treatment...