Research published in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

Cue-elicited prefrontal gamma-aminobutyric acid (GABA) dynamics in cannabis use disorder.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology September 15, 2026 Alexandra Gaillard, Daniel J Fehring, Philip J Sumner et al.

Chronic cannabis use drives neuroadaptations in reward and stress-related circuits that condition the brain to the drug and its associated cues. These changes underlie craving and heighten its sensitivity to cue- and stress-induced triggers, sustaining drug intake and promoting relapse. Task-based functional magnetic resonance imaging of drug cue reactivity paradigms has shown the dorsolateral...

DOI: 10.1038/s41386-026-02563-3 Full text

The role of BDNF promoter VI in mediating protective effects of prophylactic (R,S)-ketamine.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology August 29, 2026 Briana K Chen, Brenna L Williams, Anna Darling et al.

Brain-derived neurotrophic factor (BDNF) exon VI promoter is implicated in mediating activity-induced synthesis of hippocampal BDNF. BDNF is implicated in (R,S)-ketamine's antidepressant effects, but its role in (R,S)-ketamine-mediated prophylaxis is unknown. Using BDNF-e6 mice, in which promoter VI-driven BDNF production is disrupted, we tested its necessity for (R,S)-ketamine's prophylactic...

DOI: 10.1038/s41386-026-02536-6 Full text

Multimodal examination of the acute effects of cannabis on subjective and physiological stress-related outcomes: a randomized placebo-controlled laboratory study.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology August 22, 2026 Carrie Cuttler, Matteya A Proctor, Nicholas C. Glodosky et al.

People who use cannabis commonly report stress-relieving effects, yet no studies have simultaneously assessed the acute effects of cannabis on multiple stress systems under placebo-controlled conditions. We conducted a randomized, double-blind, placebo-controlled trial in which 120 people (56 men, 52 women, 12 non-binary/transgender) who regularly use cannabis were assigned to vape placebo, a...

DOI: 10.1038/s41386-026-02533-9 Full text

Evidence for pro-cognitive benefits of cannabinoids in people with bipolar disorder.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology July 21, 2026 Alannah Miranda, Breanna M Holloway, Elizabeth Peek et al.

Cannabis use is highly prevalent among people with bipolar disorder, potentially due to a desire to self-medicate against symptoms, such as racing thoughts and poor concentration. Such symptoms are associated with attention and inhibitory control deficits, functions that are regulated in-part by temporal perception. Temporal perception is impaired in BD and is slowed by acute cannabis exposure....

DOI: 10.1038/s41386-026-02489-w Full text

Acute dose-dependent effects of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) compared with 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin in a double-blind, placebo-controlled study in healthy participants.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology July 1, 2026 Denis Arikci, Joran Borgulya, Isabelle Straumann et al. 1 citation

Based on its in vitro profile and preliminary evidence, 4-bromo-2,5-dimethoxyphenethylamine (2C-B) may have psychoactive properties that are similar to 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin, which are investigated for the treatment of posttraumatic stress disorder and depressive disorders. We compared acute effects of 2C-B (10, 20, and 30 mg), 125 mg MDMA, and 25 mg psilocybin...

DOI: 10.1038/s41386-026-02428-9 Full text

Modulation of early non-rapid eye movement slow wave activity by ketamine in treatment-resistant depression.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology June 16, 2026 Nadia S. Hejazi, Mina Kheirkhah, Brady A. Riedner et al.

Slow-wave activity (SWA), a key indicator of sleep homeostasis, is often diminished in individuals with treatment-resistant depression (TRD). Ketamine, a rapid-acting antidepressant, increases SWA during the first period of non-rapid eye movement (NREM1) sleep. However, research into how ketamine affects sleep and its connection to treatment outcomes in TRD has been limited by small sample...

DOI: 10.1038/s41386-026-02465-4 Full text

The role of subcortical brain tissue iron as an indicator of dopamine neurophysiology in adolescent cannabis use.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology June 2, 2026 Sarah A Thomas, Meghan A Gonsalves, Gillian LeBlanc et al.

Approximately 10-20% of U.S. adolescents report past-year cannabis use (CU). Although regular CU beginning in adolescence is expected to blunt dopamine-related neurophysiology, this hypothesis has not been tested in adolescents due to methodological limitations. However, neurophysiology contributing to dopamine can be noninvasively indexed via subcortical tissue iron measured with magnetic...

DOI: 10.1038/s41386-026-02444-9 Full text

Investigational drugs in PTSD.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology June 1, 2026 Ted Obi, Kerry J. Ressler

Post-traumatic stress disorder (PTSD) remains one of psychiatry's most challenging disorders, common, disabling, and biologically complex. Despite decades of research, only sertraline and paroxetine are FDA-approved, both with modest efficacy. Even first-line trauma-focused psychotherapies leave up to half of patients with persistent symptoms. However, advances in neurobiology are reframing...

DOI: 10.1038/s41386-026-02371-9 Full text

Transcriptional profiles of antidepressant resistance across the corticolimbic pathway of chronically stressed mice.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology June 1, 2026 Trevonn M Gyles, Eric M Parise, Molly S Estill et al.

Treatment-resistant depression (TRD), defined by unsuccessful response to multiple antidepressants, affects approximately one-third of individuals with major depressive disorder, yet its underlying molecular mechanisms remain poorly understood. Here, we developed a preclinical model of TRD in which mice exposed to chronic social defeat stress were sequentially treated with fluoxetine (FLX) and...

DOI: 10.1038/s41386-026-02366-6 Full text

Psilocybin modulates social behaviour in male and female mice in a time-dependent manner.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 25, 2026 Sheida Shadani, Kaspar McCoy, Lina Ong et al.

With the resurgence of psychedelic research and growing evidence of their therapeutic potential, there is an urgent need to understand how these compounds act across biological sexes. Despite widespread interest in their use for conditions marked by social impairments, including depression, anxiety, and anorexia nervosa, the influence of sex as a biological variable on the prosocial effects of...

DOI: 10.1038/s41386-026-02450-x Full text

MDMA alters fear extinction, and reduces alcohol consumption in inbred alcohol preferring iP rats but not outbred Wistar rats.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology March 27, 2026 Kade L Huckstep, Billi Newton, Grace Bailey et al.

Comorbidity between post-traumatic stress disorder (PTSD) and alcohol use is common and mutually-reinforcing, yet there are no pharmacological strategies that specifically target trauma-linked escalation of alcohol intake. We evaluated whether 3,4-methylenedioxymethamphetamine (MDMA), given in a therapy-adjunctive fashion (30 min before fear extinction), could facilitate extinction of...

DOI: 10.1038/s41386-026-02394-2 Full text

Stereoselective, sex-dependent 5-HT2A receptor modulation of cortical plasticity by MDMA in mice.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology February 2, 2026 Maya C Gaines-Smith, Justin M Silverman, Michael Fiorillo et al. 3 citations

The psychoactive entactogen 3,4-methylenedioxymethamphetamine (MDMA), widely known as a recreational drug, is gaining renewed attention as a potential psychotherapeutic adjunct for treatment-resistant psychiatric disorders, yet its neurobiological mechanisms - particularly those related to its stereoisomers and sex-specific effects - remain poorly understood. Here, we report stereoselective and...

DOI: 10.1038/s41386-025-02313-x Full text

The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology February 1, 2026 Dongsun Park, Gwangho Lee, Bokyum Kim et al. 1 citation

Ketamine has emerged as a rapid-acting antidepressant that challenges classical monoaminergic frameworks and highlights the importance of synaptic and circuit-level plasticity in mood regulation. This review examines the hippocampus as a key site through which ketamine exerts both rapid and sustained antidepressant effects. We synthesize evidence showing that ketamine enhances hippocampal...

DOI: 10.1038/s41386-025-02288-9 Full text

Consciousness, subjectivity, and aging in western thought.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology January 15, 2026 George S Alexopoulos

A persisting debate exists on whether physical processes can fully account for the personal experience of reality or whether subjectivity transcends physical processes. However, scientists and philosophers agree that the subjective experience is influenced by information received from the body and the environment, modulated by emotions, concepts, skills, and memories acquired throughout life....

DOI: 10.1038/s41386-026-02321-5 Full text

Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA in a randomized, double-blind, placebo-controlled, crossover trial in healthy participants.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2026 Isabelle Straumann, Patrick Vizeli, Isidora Avedisian et al. 5 citations

3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally, as a research tool, and in MDMA-assisted therapy in patients with posttraumatic stress disorder. 3,4-Methylenedioxyamphetamine (MDA) is a psychoactive metabolite of MDMA. Acute effects of MDMA and MDA have never been directly compared in humans. Lysine-conjugated amphetamines slowly release active amphetamine once absorbed,...

DOI: 10.1038/s41386-025-02248-3 Full text

Effect of caffeine and cannabidiol (CBD) co-administration on Δ9-tetrahydrocannabinol (Δ9-THC) subjective effects, performance impairment, and pharmacokinetics.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology November 1, 2025 Justin C Strickland, Hayleigh E Tilton, Noah M Patton et al.

Cannabis products premixed with caffeine are increasingly present in the United States marketplace. Despite emergence of this product class, no human laboratory data have directly evaluated the isolated impact of caffeine on Δ9-tetrahydrocannabinol (Δ9-THC) effects as well as additional impacts of other common co-administered cannabinoids. This double-blind, randomized, placebo-controlled,...

DOI: 10.1038/s41386-025-02232-x Full text

Does cannabidiol reduce the adverse effects of cannabis in schizophrenia? A randomised, double-blind, cross-over trial.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology November 2025 Edward Chesney, Dominic Oliver, Ananya Sarma et al.

In patients with schizophrenia, cannabis use exacerbates symptoms and can lead to a relapse of psychosis. Some experimental studies in healthy volunteers suggest that pre-treatment with cannabidiol (CBD) may reduce these effects, but others do not. Here, we investigated whether pre-treatment with CBD ameliorates the acute adverse effects of cannabis in patients with schizophrenia. Participants...

DOI: 10.1038/s41386-025-02175-3 Full text

Timing matters: modeling the effects of gestational cannabis exposure on social behavior and microglia in the developing amygdala.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology October 2025 Aidan L Pham, Ashley E Marquardt, Kristen R Montgomery et al.

Cannabis is the most frequently used illicit drug during pregnancy, with use steadily increasing in the United States as legalization and decriminalization expand to more states. Many pregnant individuals use cannabis to reduce adverse symptoms of pregnancy, considering it to be less harmful than other pharmaceuticals or alcohol. The primary psychoactive component of cannabis,...

DOI: 10.1038/s41386-025-02173-5 Full text

Central Executive Network drives delta-9-tetrahydrocannabinol (THC)-induced nonlinear changes in large-scale functional connectivity in adolescent nonhuman primates.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology October 1, 2025 Andrew Jin Soo Byun, Harshawardhan U Deshpande, Jessi Stover et al.

Adolescent cannabinoid exposure has been implicated in enduring modifications to adult brain circuitry; however, well-controlled, systematic analyses investigating dose-dependent effects of chronic delta-9-tetrahydrocannabinol (THC) exposure on brain connectivity are lacking. It is hypothesized that large-scale intrinsic networks, such as default mode (DMN), central executive (CEN), and...

DOI: 10.1038/s41386-025-02068-5 Full text

Safety and tolerability of multiple sublingual microdoses of 5-MeO-DMT in adults with moderate symptoms of depression and/or anxiety: a randomized, double-blind, placebo-controlled study.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology July 15, 2025 Maria Beatriz Bistue Millón, Laura Noguera, Diana Bruno et al. 4 citations

This Phase I clinical trial is the first to rigorously evaluate the safety, tolerability, and pharmacokinetics of a novel sublingual formulation of 5-MeO-DMT, administered at sub-psychedelic doses to adults with moderate to high levels of anxiety and/or depression, without formal psychiatric diagnosis or ongoing treatment. Using a double-blind, placebo-controlled design, participants received a...

DOI: 10.1038/s41386-025-02167-3 Full text 5-MEO-DMT Mental health therapy Clinical trials Drug safety

Safety and cognitive pharmacodynamics following dose escalations with 3-methylmethcathinone (3-MMC): a first in human, designer drug study.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology June 1, 2025 Johannes G. Ramaekers, Johannes T. Reckweg, Natasha L. Mason et al. 8 citations

3-Methylmethcathinone (3-MMC) is a designer drug that belongs to the group of synthetic cathinones. The compound has been scheduled in many jurisdictions because of public health concerns associated with excessive use. To date, there are no clinical studies that have evaluated the risk profile of 3-MMC in the recreational range of low to moderate doses. The current, first-in-human study (N =...

DOI: 10.1038/s41386-024-02042-7 Full text

Effects of NMDA receptor antagonists on working memory and gamma oscillations, and the mediating role of the GluN2D subunit.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 15, 2025 Chitra Vinnakota, Matthew R Hudson, Kazutaka Ikeda et al. 6 citations

Working memory relies on synchronised network oscillations involving complex interplay between pyramidal cells and GABAergic interneurons. NMDA receptor (NMDAR) antagonists influence both network oscillations and working memory, but the relationship between these two consequences has not been elucidated. This study aimed to determine the effect of NMDAR antagonists on network oscillations...

DOI: 10.1038/s41386-025-02129-9 Full text Cognitive function Brain waves Memory research Neural receptors

Relative effectiveness of antidepressant treatments in treatment-resistant depression: a systematic review and network meta-analysis of randomized controlled trials.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 1, 2025 Johan Saelens, Anna Gramser, Victoria Watzal et al. 47 citations

This systematic review and network meta-analysis (NMA) sought to compare different antidepressant treatments for treatment-resistant depression (TRD) in order to facilitate evidence-based choices. A literature search of PubMed, Cochrane Library, and Embase from inception until April 13th, 2023 identified randomized, controlled trials (RCTs) of adults with depression who had not responded to at...

DOI: 10.1038/s41386-024-02044-5 Full text Treatment-resistant depression Depression treatment Electroconvulsive therapy Mental health interventions +1

Rapid and sustained antidepressant effects of vaporized N,N-dimethyltryptamine: a phase 2a clinical trial in treatment-resistant depression.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 1, 2025 Marcelo Falchi-Carvalho, Fernanda Palhano-Fontes, Isabel Wießner et al. 35 citations

Depression affects over 185 million people worldwide, with approximately one-third classified as treatment-resistant depression (TRD). Current treatments, such as oral antidepressants, often take around 3 weeks to become effective, with no immediate anti-suicidal benefits. The field urgently needs innovative therapies that provide rapid relief. Psychedelics like psilocybin and ayahuasca have...

DOI: 10.1038/s41386-025-02091-6 Full text Mental health Depression treatment Psychedelic medicine Clinical research +1

Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 1, 2025 Kyle A Brown, Musa I Ajibola, Todd D Gould 13 citations

The pharmacologically active (R,S)-ketamine (ketamine) metabolite (2 R,6 R)-hydroxynorketamine (HNK) maintains ketamine's preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination....

DOI: 10.1038/s41386-025-02085-4 Full text Mental-health Pharmacology Depression-treatment Brain-research

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