Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 1, 2022
Deborah Rudin, John D McCorvy, Grant C Glatfelter et al.
18 citations
Derivatives of (2-aminopropyl)indole and (2-aminopropyl)benzofuran are new psychoactive substances with stimulant effects. This study characterized six isomers of the sulfur-based analog (2-aminopropyl)benzo[β]thiophene (APBT) in vitro and three isomers in vivo. APBTs inhibited monoamine reuptake and induced transporter-mediated substrate release, similar to MDMA, but did not stimulate locomotion in mice. Instead, they acted as full agonists at 5-HT2 receptor subtypes and induced head-twitch responses, indicating psychedelic-like activity. Replacing oxygen with sulfur enhanced serotonin transporter release potency and 5-HT2 receptor activity, shifting the profile toward psychedelic and entactogenic effects with minimal psychomotor stimulation, suggesting potential for drug-assisted psychotherapy.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Kyle A Brown, Musa I Ajibola, Todd D Gould
13 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), maintains antidepressant-like effects in mice without adverse effects. Using brain slices from mice, researchers developed a model to study how HNK produces rapid versus sustained synaptic changes. HNK rapidly strengthened connections between neurons in the hippocampus, an effect that did not require NMDA receptor activity. However, maintaining a primed state that enhanced later long-term potentiation (a form of synaptic plasticity) did require NMDA receptors. HNK's rapid effects depended on adenylyl cyclase 1 and protein kinase A activity. The findings suggest that targeting such priming mechanisms could be a strategy for developing antidepressants.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2024
Ruth H Asch, Chadi G Abdallah, Richard E Carson et al.
11 citations
A review describes the development of PET radiotracers targeting the synaptic vesicle glycoprotein 2A (SV2A), which allows measurement of synaptic density in living brains. In depression, lower SV2A density is found in people with significant depressive symptoms. A ketamine challenge was used to examine synaptogenesis in vivo. The authors stress the value of combining clinical imaging with animal model studies, presenting preliminary findings from chronic stress models. Methodological challenges and future directions for SV2A imaging, possibly alongside other neural markers, are discussed.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
December 1, 2024
Charalampos Brakatselos, Alexia Polissidis, George Ntoulas et al.
10 citations
Repeated ketamine administration in male rats produces schizophrenia-like symptoms and alters glutamatergic and dopaminergic activity, mainly in the prefrontal cortex and dorsomedial striatum, through a bidirectional pattern. These changes are accompanied by glutamatergic/GABAergic deviations and impaired function of parvalbumin- and cholecystokinin-positive interneurons, indicating an excitation/inhibition imbalance. Cannabidiol (CBD) counteracted the schizophrenia-like behavioral phenotype, reversed prefrontal abnormalities and ventral hippocampal E/I deficits, and partially modulated dorsostriatal dysregulations. The findings suggest CBD's antipsychotic action involves region-specific modulations in corticohippocampal and corticostriatal circuitry, pointing to potential therapeutic strategies focused on restoring E/I balance.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2024
Zack Blumenfeld, Kallol Bera, Eero Castrén et al.
10 citations
Many antidepressants work by entering cells and binding to targets inside the cytoplasm or organelles, contrary to the traditional view that they act only at extracellular sites on cell surface proteins. The ability of a drug to cross membranes depends on its charge and lipid solubility, described by parameters LogP, pKa, and LogD at pH 7.4. Some antidepressants have an unusually large volume of distribution, reflecting both binding to membranes and trapping inside acidic organelles. For SSRIs and SNRIs, the exact cellular compartment where they engage their target transporters remains unknown. Rapidly acting antidepressants like ketamine and psychedelics also rely on these intracellular mechanisms, an area termed location-biased or inside-out pharmacology.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2023
Nicolas Garel, Kyle T Greenway, Lê-Anh L Dinh-Williams et al.
10 citations
A course of six sub-anesthetic ketamine infusions over four weeks helped patients with treatment-resistant depression discontinue long-term benzodiazepine or z-drug use. Of 22 patients, 91% (20/22) successfully stopped all such medications by the end of the infusions, confirmed by urine tests. Fewer than 25% experienced significant worsening of anxiety, depression, sleep problems, or suicidality during withdrawal. Over a mean follow-up of one year, 64% (14/22) remained abstinent. These preliminary results suggest ketamine infusions may facilitate benzodiazepine deprescription even in patients with active depression and significant comorbidity.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 1, 2024
Lora Khatib, Jon G Dean, Valeria Oliva et al.
9 citations
Mindfulness meditation directly reduces evoked chronic low back pain through non-opioidergic processes, not by activating the body's opioid system. In a double-blind, randomized, placebo-controlled trial with a drug crossover design, 59 individuals with chronic low back pain completed a four-session mindfulness or sham mindfulness-meditation intervention. During intravenous naloxone (an opioid blocker) or saline infusion, both mindfulness and sham mindfulness groups showed significant pain reductions during meditation compared to rest. However, the mindfulness group reported significantly lower pain than the sham group, and its effects were more pronounced, suggesting unique benefits from non-reactive appraisal processes. Pain severity and interference scores also decreased.
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
In a first-in-human trial, low to moderate doses of the synthetic cathinone 3-MMC were well tolerated and safe, with potential health risks only at high or excessive doses. 3-MMC caused dose-dependent increases in heart rate and blood pressure that were not clinically significant, along with feelings of subjective high. It also enhanced performance on several neurocognitive tasks, including processing speed, cognitive flexibility, psychomotor function, attention, and memory, while impulse control was unaffected. Participants reported mild dissociative and psychedelic effects, decreased appetite, and transient liking and wanting for the drug. The cardiovascular, psychostimulant, and psychotomimetic profile resembles that of amphetamine-related compounds.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Marcus W Meinhardt, Ivan Skorodumov, Jérôme Jeanblanc et al.
8 citations
A new approach in psychiatric drug development, the preclinical randomized controlled trial (preRCT), was tested across three European centers using a rat model of alcohol relapse. Ketamine (20 mg/kg) reduced relapse, while R-ketamine worked only in females at the same dose; a higher dose (40 mg/kg) was effective in males. The sex-dependent effects were linked to plasma R-ketamine levels, which were twice as high in females. R-ketamine produced a lasting reduction in alcohol consumption without adverse effects. The findings support moving to a clinical trial that accounts for sex differences.
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 synchronized brain oscillations involving interactions between pyramidal cells and GABAergic interneurons. NMDA receptor antagonists affect both oscillations and memory, but the link was unclear. In mice performing a touchscreen working memory task, phencyclidine (PCP) disrupted accuracy in wildtype but not GluN2D-knockout mice, indicating PCP's action requires the GluN2D subunit. MK-801, (S)-ketamine, and (R)-ketamine impaired accuracy in both genotypes. PCP increased baseline gamma power in the hippocampus only in wildtypes, while all drugs increased prefrontal gamma power. Low gamma activity during the memory maintenance phase rose when mice answered correctly, and this task-related increase was disrupted by all drugs. The GluN2D subunit mediates PCP's effects on hippocampal gamma and working memory.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Mina Kheirkhah, Wallace C Duncan, Qiaoping Yuan et al.
6 citations
People with treatment-resistant depression show higher REM density in the first REM period and shorter REM latency than healthy volunteers, while total night REM density does not differ. Ketamine treatment reduces REM density in the first REM period but does not change total night REM density or REM latency. Baseline REM density in the first REM period moderately predicts whether a person will respond to ketamine, with higher levels indicating greater likelihood of response. This marker could help identify individuals most likely to benefit from ketamine therapy.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2024
Melissa A Simon
6 citations
Psychedelics show promise for treating severe mental illness, but health equity and justice concerns must be addressed in US clinical care and research. Strategies are needed to reduce existing disparities and prevent future disparities among minoritized and marginalized populations.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2026
Isabelle Straumann, Patrick Vizeli, Isidora Avedisian et al.
5 citations
In a double-blind, placebo-controlled crossover trial with 23 healthy adults, the acute effects of MDMA, its metabolite MDA, and two lysine-conjugated prodrugs were compared. MDA produced stronger and longer-lasting subjective drug effects (6.1 vs. 4.1 hours), greater stimulant effects, more negative effects, fear, and visual alterations than MDMA at equimolar doses. The lysine-conjugated prodrug of MDA (Lys-MDA) delayed the onset and peak of effects but otherwise acted similarly to MDA. Lys-MDMA did not release MDMA into the blood and produced no effects, indicating it is not a functional prodrug. The findings suggest MDA has a less favorable therapeutic profile than MDMA, and lysine conjugation can modulate the timing but not necessarily improve tolerability of effects.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 19, 2025
Valeria Grasso, Joseph Tennyson, Raag D Airan et al.
5 citations
Ketamine, a rapid-acting treatment for depression and other neuropsychiatric disorders, works partly through the brain's opioid system, and its effects differ by sex. In rats given ketamine, blocking opioid receptors with naltrexone altered functional connectivity changes in the brain, especially in the medial prefrontal cortex (mPFC), a region of the default-mode network. These connectivity changes depended on biological sex: naltrexone affected mPFC connectivity patterns differently in males and females. Ketamine also caused a shift toward greater brain dysconnectivity and entropy, but only in male rats and only when opioid receptors were available. The findings suggest sex-specific interactions between ketamine and opioid receptors that warrant further 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
In this first-in-human Phase I clinical trial, a novel sublingual formulation of 5-MeO-DMT was tested at sub-psychedelic doses in adults with moderate to high anxiety and/or depression, but without a formal psychiatric diagnosis or ongoing treatment. The compound was well tolerated across all groups (6 mg, 9 mg, or 12 mg), with no significant adverse events or organ toxicity; mild side effects like nausea and headache were transient. Pharmacokinetics showed rapid absorption, peak plasma concentrations within a median of 20 minutes, and no drug accumulation. Dose-dependent modulation of brain activity occurred without full psychedelic effects, and participants maintained normal daily activities. These results support the safety and feasibility of repeated sub-psychedelic dosing and lay groundwork for future therapeutic trials.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Francisco Madrid-Gambin, Noemí Haro, Natasha L Mason et al.
4 citations
The metabolome—the collection of small molecules in blood—differs between occasional and chronic cannabis users both when sober and after acute THC intoxication. Fourteen metabolites, mainly involved in endocannabinoid and amino acid metabolism, distinguished the two groups with 80% accuracy. During intoxication, occasional users showed attentional impairment and elevated subjective high, accompanied by increases in organic acids, β-hydroxybutyrate, and ceramides; chronic users did not show these changes. The findings demonstrate that metabolomic profiling can identify metabolic alterations specific to the neurocognitive state of cannabis intoxication and to cannabis use frequency.
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 drug MDMA, also known as ecstasy, is being studied as a possible aid in psychotherapy for hard-to-treat mental health conditions, but how it works in the brain is not fully understood. In experiments with mice, the S(+) form of MDMA, but not the R(-) form, activated a specific serotonin receptor (5-HT2AR) and caused changes in brain cell connections in the frontal cortex of males. The R(-) form had little effect except for a head-twitch response in females. Blocking the serotonin transporter with fluoxetine prevented these effects, showing that MDMA works indirectly by increasing serotonin levels. These results reveal that MDMA's effects on brain plasticity depend on both the drug's chemical form and the sex of the animal.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2024
Ji-Woon Kim, Benjamin Kleinfelter, Ege T Kavalali et al.
3 citations
Ketamine, a rapidly acting antidepressant, works by restoring glutamate signaling in the hippocampus, countering the effects of a drug that induces depressed mood. Physostigmine, which triggers depression-like symptoms in humans, was found to cause long-term reduction of glutamate release in the mouse hippocampus. Ketamine rapidly re-establishes synaptic efficacy through postsynaptic signaling and masks the behavioral effects of physostigmine. The findings reveal that the synaptic mechanisms underlying mood changes differ from those behind antidepressant action, suggesting distinct pathways for neuropsychiatric disorders and their treatment.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 22, 2025
Briana K Chen, Alicia Whye, Louise C Matthews et al.
2 citations
A combination of two FDA-approved drugs—(R,S)-ketamine, an anesthetic and NMDAR antagonist, and prucalopride, a 5-HT4 receptor agonist used for constipation—reduced stress-induced behavioral changes in male and female rodents after various stressors (fear conditioning, learned helplessness, stress-enhanced fear learning, and chronic corticosterone exposure). The combined treatment was more effective than either drug alone, and intranasal delivery also worked. Chronic administration of the combination broadly alleviated stress-related behaviors, suggesting potential for treating stress-induced psychiatric disorders in humans.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
July 1, 2026
Denis Arikci, Joran Borgulya, Isabelle Straumann et al.
1 citation
In a double-blind, randomized, placebo-controlled crossover trial, 24 healthy adults received three doses of 2C-B (10, 20, and 30 mg), 125 mg MDMA, and 25 mg psilocybin. The 30 mg dose of 2C-B produced subjective effects comparable to MDMA but weaker than psilocybin, and increased emotional empathy similarly to MDMA. Only psilocybin caused bad drug effects and anxiety. MDMA produced the greatest cardiovascular stimulation, followed by psilocybin and then 2C-B. Only MDMA raised plasma oxytocin and neurophysin I. The average subjective effect duration of 30 mg 2C-B was 4.9 hours, similar to MDMA (4.8 h) and shorter than psilocybin (6.1 h). 2C-B had a plasma elimination half-life of about 1.3 hours.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
February 1, 2026
Dongsun Park, Gwangho Lee, Bokyum Kim et al.
1 citation
Ketamine works as a rapid antidepressant by enhancing synaptic plasticity in the hippocampus, not by normalizing stress hormone systems. It acts through multiple mechanisms including blocking NMDA receptors, activating BDNF-TrkB signaling, and promoting adult neurogenesis. These hippocampal changes coordinate with other brain regions like the medial prefrontal cortex and lateral habenula. The review synthesizes evidence that ketamine's therapeutic effects are separate from HPA axis function, shifting focus from neuroendocrine models to circuit-level plasticity. This framework suggests new strategies for developing fast-acting antidepressants.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 16, 2026
Nadia Hejazi, Mina Kheirkhah, Brady Riedner et al.
Slow-wave activity (SWA) during early non-rapid eye movement sleep is lower in people with treatment-resistant depression (TRD) than in healthy volunteers. Ketamine, but not placebo, increases SWA in TRD patients, especially those who respond to treatment, while having no effect on SWA in healthy volunteers. Ketamine also improves overall sleep in TRD patients by increasing total sleep time and sleep efficiency and reducing sleep latency. The increase in SWA after ketamine lessens with age. The findings suggest that ketamine's antidepressant effects are closely tied to its modulation of early sleep SWA and its ability to improve sleep architecture in TRD.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 1, 2026
Ted Obi, Kerry J Ressler
PTSD remains difficult to treat; only two medications are FDA-approved and have modest efficacy, and even first-line psychotherapies leave up to half of patients with persistent symptoms. Advances in neurobiology now frame PTSD as a disorder of maladaptive stress circuitry, neuroplasticity, and memory reconsolidation, opening new therapeutic possibilities. This review examines current pharmacotherapy, emerging targets, and 45 actively enrolling clinical trials. Rapid-acting interventions such as ketamine (producing symptom reductions within hours) and MDMA-assisted psychotherapy (demonstrating Phase 3 efficacy) represent major advances, though questions remain about durability, dosing, and safety. Many mechanistically plausible candidates have failed in late-stage trials due to high placebo responses, patient heterogeneity, and translational gaps.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 1, 2026
Trevonn M Gyles, Eric M Parise, Molly Estill et al.
Treatment-resistant depression (TRD) affects about one-third of people with major depressive disorder, but its molecular basis is unclear. In a mouse model, chronic social defeat stress was followed by sequential treatment with fluoxetine and ketamine, allowing classification into antidepressant-responsive and non-responsive animals. RNA sequencing of the nucleus accumbens and prefrontal cortex revealed distinct transcriptional signatures. Prior fluoxetine exposure primed some mice for molecular and behavioral response to ketamine, but this priming was absent in non-responders, indicating that resistance stems not from treatment failure alone but from a lack of adaptive molecular priming. Gene co-expression network analysis identified modules linked to stress susceptibility and antidepressant resistance, offering insight into gene networks underlying TRD.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 25, 2026
Sheida Shadani, Kaspar McCoy, Lina Ong et al.
A single dose of psilocybin (1.5 mg/kg) in C57BL/6 J mice produces sex-specific effects on social behavior and dopamine signaling. In females, psilocybin acutely increased huddling and induced hypothermia, and post-acutely enhanced novelty-seeking and grooming, with no comparable effects in males. By 24 hours, males showed reduced grooming and rearing but increased sociability toward a cage-mate, accompanied by blunted novelty-evoked nucleus accumbens dopamine responses lasting up to 7 days. At 7 days, females shifted social preference toward familiarity, associated with prolonged dopamine release during familiar interactions, while males increased grooming. Both 5-HT1A and 5-HT2A receptors contributed to these sex-specific behavioral effects.