Research published in American Journal of Psychiatry

Continuing Questions About Esketamine 5 Years After Approval: Response to Ahmed et al.

American Journal of Psychiatry September 1, 2026

Continuing Questions About Esketamine 5 Years After Approval: Response to Ahmed et al.

DOI: 10.1176/appi.ajp.20260182

Cognitive, Electrophysiological, and Behavioral Presentation of First-Episode Psychosis With or Without Cannabis Exposure.

American Journal of Psychiatry June 3, 2026 Deepak C D'Souza, Jose A Cortes-Briones, Justin Raj et al.

OBJECTIVE Cannabis use is a known risk factor for psychosis, but it remains unclear whether cannabis-associated psychosis (CAP) differs meaningfully from non-cannabis-associated psychosis (NCAP) in clinical presentation, biology, or illness course. The objective of this study was to characterize the presentation and course of first-episode psychosis with and without cannabis exposure. METHODS...

DOI: 10.1176/appi.ajp.20250726

Low-Dose Buprenorphine Following Ketamine Treatment for Suicidal Ideation in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial.

American Journal of Psychiatry June 1, 2026 Jason M Tucciarone, Igor D. Bandeira, Christine Blasey et al. 5 citations

Ketamine rapidly reduces suicidal ideation in major depressive disorder (MDD), but its effects are transient. Preclinical and clinical studies suggest that ketamine's antidepressant and antisuicidal effects may be partly mediated by mu-opioid receptor (MOR) modulation. The authors investigated the efficacy and safety of low-dose sublingual buprenorphine, a partial MOR agonist, as a follow-on...

DOI: 10.1176/appi.ajp.20250840 Full text Major depressive disorder Bipolar disorder Buprenorphine Ketamine/esketamine +1

Regional Blood Flow Signatures of Opioidergic Modulation of Ketamine in Major Depressive Disorder: A Randomized Crossover Study.

American Journal of Psychiatry June 1, 2026 Luke A. Jelen, Owen O'Daly, Fernando O Zelaya et al. 2 citations

Accumulating evidence suggests that the opioid system may modulate ketamine's rapid antidepressant effects. The objective of this study was to test whether opioid system modulation via naltrexone alters ketamine's acute effects on regional cerebral blood flow (rCBF) in major depressive disorder (MDD), and whether these changes relate to symptom measures and map onto receptor density profiles....

DOI: 10.1176/appi.ajp.20250903 Full text Depressive disorders Ketamine/esketamine Neuroimaging Psychopharmacology

An Update on Somatic Treatments for Suicide Risk.

American Journal of Psychiatry June 1, 2026 Mina M Rizk, J John Mann 1 citation

Suicide is a major cause of death worldwide and a key public health challenge. Pharmacologic and neuromodulatory interventions are central to suicide prevention. This review summarizes evidence for these interventions with potential antisuicidal effects across major psychiatric disorders and, where possible, distinguishes their direct effects on suicide diathesis from those mediated by...

DOI: 10.1176/appi.ajp.20260287 Full text Ketamine Clozapine Electroconvulsive therapy Lithium +2

Envisioning Cannabinoid CB1 Receptor Biased Signaling as a Therapeutic Target for Schizophrenia.

American Journal of Psychiatry April 17, 2026 Shih-Hsuan Ku, Sierra J Stringfield, Mary M Torregrossa et al.

The relationship between the endocannabinoid system and the emergence and treatment of schizophrenia-related symptoms continues to be a topic of significant interest within psychiatry. Cannabis is the most widely used recreational drug worldwide, and individuals with schizophrenia use it at a much higher rate than the general population. The shared genetic risk for schizophrenia and cannabis...

DOI: 10.1176/appi.ajp.20250886 Full text Cannabis

Acute Effects of Cannabis on Alcohol Craving and Consumption: A Randomized Controlled Crossover Trial.

American Journal of Psychiatry February 1, 2026 Jane Metrik, Elizabeth R Aston, Rachel L Gunn et al.

Cannabis use is strongly linked with heavy drinking and worse alcohol treatment outcomes; however, it may also contribute to decreased alcohol consumption. To date, no human studies have established a causal effect of cannabis on alcohol motivation. The aim of this double-blind crossover randomized clinical trial was to examine dose-dependent acute effects of delta-9-tetrahydrocannabinol (THC)...

DOI: 10.1176/appi.ajp.20250115 Full text Cannabis Alcohol Craving Cue reactivity +1

Real-World Safety of Esketamine Nasal Spray: A Comprehensive Analysis Almost 5 Years After First Approval.

American Journal of Psychiatry September 10, 2025 Gerard Sanacora, Muhammad Ahmed, Brianne Brown et al. 24 citations

OBJECTIVE The objective of this study was to comprehensively examine the real-world safety of esketamine using 58 months of postapproval data in the United States. METHODS U.S. safety data from patient monitoring forms submitted to the esketamine Risk Evaluation and Mitigation Strategy (REMS) program and reports submitted to the Janssen U.S. Global Medical Safety (US-GMS) database were...

DOI: 10.1176/appi.ajp.20240655

Ketamine for Depression, but at What Cost? A Review of Ketamine’s Neurotoxic Effects From Preclinical and Human Studies

American Journal of Psychiatry September 10, 2025 Songze Li, Kristina T. Kumpf, Julian Urrutia et al. 13 citations

This review examines ketamine's neurotoxic potential across preclinical and clinical studies. The authors synthesized data from preclinical models, then integrated findings from human clinical trials of esketamine and observational studies in recreational users. Animal studies have found that repeated or high-dose subanesthetic ketamine administration results in consistent excitotoxic neuronal...

DOI: 10.1176/appi.ajp.20250276 Ketamine Cognition Observational study Clinical trial +9

An Update on the Behavioral and Neurobiological Effects of Cannabis Use in Adolescents: A Translational Perspective.

American Journal of Psychiatry July 1, 2025 Y. Hurd

The convergence of early initiation, increasing product potency, and widespread availability has reshaped the contemporary cannabis landscape, heightening concerns about its impact on adolescent mental health. Translational research combining longitudinal human neuroimaging and animal models provides compelling evidence that cannabis use-particularly with high-tetrahydrocannabinol (THC)...

DOI: 10.1176/appi.ajp.20250444 Full text

Reduced Brain Responsiveness to Emotional Stimuli With Escitalopram But Not Psilocybin Therapy for Depression

American Journal of Psychiatry May 7, 2025 Matthew B. Wall, Lysia Demetriou, Bruna Giribaldi et al. 16 citations

Despite large improvements in depressive symptoms in the psilocybin group, psilocybin therapy had only a minor effect on brain responsiveness to emotional stimuli. These results are consistent with prior findings that the antidepressant action of SSRIs is often accompanied by a reduction in emotional responsiveness, but this effect may not occur in psychedelic therapy.

DOI: 10.1176/appi.ajp.20230751 Full text Psilocybin Cognitive neuroscience Depressive disorders Psychopharmacology +7

An Update on Psychotherapy for the Treatment of PTSD.

American Journal of Psychiatry May 1, 2025 Barbara Olasov Rothbaum, Laura E Watkins 13 citations

Posttraumatic stress disorder (PTSD) symptoms are part of the normal response to trauma. Most trauma survivors will recover over time without intervention, but a significant minority will develop chronic PTSD, which is unlikely to remit without intervention. Currently, only two medications, sertraline and paroxetine, are approved by the U.S. Food and Drug Administration to treat PTSD, and the...

DOI: 10.1176/appi.ajp.20250110 Full text PTSD Treatment Trauma therapy Mental health interventions Evidence-based psychotherapy +1

20 Years of Aberrant Salience in Psychosis: What Have We Learned?

American Journal of Psychiatry March 26, 2025 Philip R. Corlett, Kurt M. Fraser 9 citations

" captured the attention of clinicians and cognitive and behavioral neuroscientists. It has become the de facto way of talking about delusion formation in labs and clinics. Here, evidence for this theory is critically evaluated in consideration of evolving data since its publication. A particular focus is placed on its specific predictions regarding the neural and behavioral loci of dopamine...

DOI: 10.1176/appi.ajp.20240556 Full text

Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis.

American Journal of Psychiatry March 1, 2025 Konstantinos N Fountoulakis, Athanasios Saitis, Alan F. Schatzberg 78 citations

Intranasal esketamine has been approved as an adjunctive therapy for treatment-resistant major depressive disorder with acute suicidal ideation and behavior. The authors conducted a systematic review and meta-analysis of the available data on its efficacy against depression and suicidality as well as its side effects. MEDLINE was searched with the keyword "esketamine" on March 24, 2024, using...

DOI: 10.1176/appi.ajp.20240515 Full text Treatment-resistant depression Depressive disorders Ketamine/esketamine Meta-analysis +3

Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?

American Journal of Psychiatry March 1, 2025 Marjorie R. Levinstein, Reece C Budinich, Jordi Bonaventura et al. 49 citations

Ketamine is a racemic compound and medication comprised of (S)-ketamine and (R)-ketamine enantiomers and its metabolites. It has been used for decades as a dissociative anesthetic, analgesic, and recreational drug. More recently, ketamine, its enantiomers, and its metabolites have been used or are being investigated for the treatment of refractory depression, as well as for comorbid disorders...

DOI: 10.1176/appi.ajp.20240378 Full text Ketamine/esketamine #ketamine esketamine Ketalar Special k +4

MDMA and MDMA-Assisted Therapy.

American Journal of Psychiatry 2025 Aaron Wolfgang, Gregory A. Fonzo, Joshua C. Gray et al. 47 citations

MDMA (i.e., 3,4-methylenedixoymethamphetamine), commonly known as "Ecstasy" or "Molly," has been used since the 1970s both in recreational and therapeutic settings. The Food and Drug Administration (FDA) designated MDMA-Assisted Therapy (MDMA-AT) as a Breakthrough Therapy for posttraumatic stress disorder (PTSD) in 2017, and the FDA is requiring an additional phase 3 trial after rejecting the...

DOI: 10.1176/appi.ajp.20230681 Full text Major depressive disorder PTSD Molly Methylenedioxymethamphetamine +6

Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial

American Journal of Psychiatry 2025 Scott T Aaronson, Andrew van der Vaart, Tammy Miller et al. 31 citations

This open-label study suggests efficacy and safety of psilocybin in severe TRD and supports further study of psychedelics in this population, including consideration of PTSD interaction effects.

DOI: 10.1176/appi.ajp.20231063 Psilocybin Magic mushrooms Major depressive disorder Psychedelics hallucinogens +7

Compass Psychological Support Model for COMP360 Psilocybin Treatment of Serious Mental Health Conditions

American Journal of Psychiatry 2025 Namik Kirlic, Molly Lennard-Jones, Merve Atli et al. 27 citations

The psychedelic experience can be challenging. There is a need for a structured framework for providing psychological support to individuals with mental health conditions receiving investigational psilocybin treatment. The primary benefit of such a framework is to support a safe and meaningful psilocybin experience. It also enables future research on the facets of psychological support and/or...

DOI: 10.1176/appi.ajp.20230884 Psilocybin Mental health Psychotherapist Compass +2

Benefits and Challenges of Ultra-Fast, Short-Acting Psychedelics in the Treatment of Depression

American Journal of Psychiatry 2025 Johannes G. Ramaekers, Johannes T. Reckweg, Natasha L. Mason 25 citations

Unlike classical antidepressants, psychedelics such as psilocybin have been shown to induce a rapid antidepressant response. In the wake of this development, interest has emerged in ultra-fast, short-acting psychedelics such as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and N,N-dimethyltryptamine (DMT) with the expectation that these can produce rapid antidepressant effects following an...

DOI: 10.1176/appi.ajp.20230890 5-MEO-DMT Depression Psychedelic drugs Quick-onset treatment +3

Psychedelics for the Treatment of Psychiatric Disorders: Interpreting and Translating Available Evidence and Guidance for Future Research.

American Journal of Psychiatry 2025 Roger S McIntyre, Angela T H Kwan, Rodrigo B. Mansur et al. 23 citations

During the past decade, there has been extraordinary public, media, and medical research interest in psychedelics as promising therapeutics for difficult-to-treat psychiatric disorders. Short-term controlled trial data suggest that certain psychedelics are effective and safe in the treatment of major depressive disorder, treatment-resistant depression, and posttraumatic stress disorder....

DOI: 10.1176/appi.ajp.20230902 Full text Alcohol use disorder Depressive disorders Methodology Psychedelics

Multidimensional Personality Changes Following Psilocybin-Assisted Therapy in Patients With Alcohol Use Disorder: Results From a Double-Blind, Placebo-Controlled Clinical Trial

American Journal of Psychiatry 2025 Noam Goldway, Snehal Bhatt, Stephen Ross et al. 23 citations

PAT elicited durable shifts in personality, suggesting normalization of abnormal personality trait expression in AUD. Further study is needed to clarify whether PAT exerts its beneficial effects by reducing impulsiveness or whether impulsive individuals inherently respond better to PAT.

DOI: 10.1176/appi.ajp.20230887 Psilocybin Alcohol use disorder Addiction Alcohol dependence +6

Psilocybin: From Psychiatric Pariah to Perceived Panacea

American Journal of Psychiatry 2025 Adrienne Grzenda, Gregory A. Fonzo, Aaron Wolfgang et al. 14 citations

The evidence is currently insufficient to recommend psilocybin with PST as a psychiatric treatment. Additional rigorously designed clinical trials are needed to definitively establish efficacy in larger and more diverse samples, address dosing considerations, improve blinding, and provide information on mechanisms of action and moderators of clinical response. Head-to-head comparisons with...

DOI: 10.1176/appi.ajp.20230682 Full text Psilocybin Panacea medicine Pariah group Psychotherapist +1

Toward Translatable Biomarkers of Psychedelic-Induced Neuroplasticity.

American Journal of Psychiatry 2025 David E. Olson 8 citations

Numerous preclinical studies have demonstrated that psychedelics promote the growth of cortical neurons in the prefrontal cortex. However, measuring psychedelic-induced structural plasticity in humans has remained a challenge. New advances in positron emission tomography imaging could facilitate the measurement of synaptic proteins in humans following psychedelic administration. Identifying a...

DOI: 10.1176/appi.ajp.20231054 Full text Ketamine Sv2a Psychoplastogen Psychedelics/hallucinogens/entheogens +3

Primum Non Nocere: The Onus to Characterize the Potential Harms of Psychedelic Treatment.

American Journal of Psychiatry 2025 Sharmin Ghaznavi, Jeremy N Ruskin, Stephen J Haggerty et al.

The last few years have seen exponential growth in interest, investment, advocacy, and research into psychedelics as therapeutics. This reflects an optimism about the potential promise of psychedelics as therapeutics. As with all therapeutic interventions, research is needed not only into their benefits but also potential risks. Indeed, when substances with therapeutic potential are scrutinized...

DOI: 10.1176/appi.ajp.20230914 Full text Adverse effects Ethics Psychedelics Risks

Novel Pharmacologic and Other Somatic Treatment Approaches for Posttraumatic Stress Disorder in Adults: State of the Evidence.

American Journal of Psychiatry December 1, 2024 Lauren M. Sippel, Jessica L. Hamblen, Benjamin Kelmendi et al. 11 citations

Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. The most commonly recommended first-line treatments for PTSD among adults are individual trauma-focused psychotherapies. Other evidence-based treatments include specific antidepressant medications and non-trauma-focused psychotherapies. Despite the...

DOI: 10.1176/appi.ajp.20230950 Full text Behavioral psychotherapy Cognitive psychotherapy Drug psychotherapy combination Evidence-based treatment +6

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