BACKGROUND Increases in cannabis use, potency, and legal liberalization have raised concerns about psychiatric consequences. Previous studies suggest an association between cannabis use and earlier age at onset (AAO) of psychosis, but an updated meta-analysis is needed. METHODS MEDLINE, Embase, and PsycInfo were searched from inception to April 2025. Peer-reviewed cohort and case-control...
Ketamine produces rapid antidepressant and antidepressant-like effects in both humans and animal models. However, its therapeutic benefits are tempered by psychoactive side effects, such as hyperlocomotion associated with enhanced dopaminergic activity in the ventral tegmental area (VTA). We tested the therapeutic effect of cannabidiol (CBD) on locomotor activity after systemic (30 mg/kg) or...
Psilocybin and 3,4-methylenedioxymethamphetamine (MDMA) produce rapid, enduring therapeutic effects in post-traumatic stress disorder (PTSD); however, the underlying cellular mechanisms remain incompletely understood. This study investigated whether adult myelin plasticity contributes to the therapeutic actions of psilocybin and MDMA in a rat model of contextual fear conditioning. Adult male...
Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain, offering novel therapeutic strategies for neuropsychiatric disorders. Recent findings reveal that beyond their transient psychotropic effects, these compounds activate serotonin 5-HT2A receptors...
Background The impact of acute cannabis exposure on brain function and cognitive performance varies among individuals. Acute effects of cannabis on behavior may be absent or benign in chronic users, while occasional users experience significant impairment in day-to-day operations. It is hypothesized that repeated cannabis use induces neuroadaptations leading to tolerance and desensitization,...
Contradictory evidence has emerged regarding the role of the mu opioid receptor (MOR) in the antidepressant actions of (R,S)-ketamine. Here, we used the long-acting MOR-selective antagonist methocinnamox (MCAM) to determine the contribution of MOR to the actions of (R,S)-ketamine and the more selective N-methyl-D-aspartate receptor (NMDAR) antagonist fluoroethylnormemantine (FENM) against...
Biological PsychiatryJune 25, 2025Kevin G Mulvihill, Gemma J Cockcroft, Angela C Roberts2 citations
Individual variability in pharmacological treatment efficacy remains a persistent obstacle to ameliorating clinical anxiety. This may originate, in part, from the different neural aetiologies underlying pathological anxiety. To provide novel insights into patient heterogeneity in anxiolytic responsiveness we compare the efficacy of distinct anxiolytic drugs, a Selective Serotonin Re-uptake...
Biological PsychiatryJune 13, 2025Shaoqiang Han, Ya Tian, Huiting Yang et al.1 citation
Although numerous studies have attempted to identify the functional pathways underlying the rapid antidepressant effects of ketamine, their findings remain inconsistent, limiting our understanding of the neural mechanisms involved. This study aims to delineate a specific brain circuit by integrating diverse functional findings related to ketamine's efficacy in depression. We conducted a...
Social disequilibrium, or disrupted social homeostasis, underlies many behavioral disorders, including problematic drug use. One way to study the relationship between drug use and social homeostasis is to determine whether single doses of psychoactive drugs relieve some of the discomfort of social isolation and promote social connection. In this narrative review, we discuss challenges and...
Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. This mechanism may differentiate ketamine from other NMDA receptor antagonists. Animal models that reflect OR-dependent behavioral effects of ketamine may shed light on the...
We previously reported that a single injection of (R,S)-ketamine or its metabolite (2S,6S)-hydroxynorketamine (HNK) prior to stress attenuated learned fear. However, whether these drugs attenuate learned fear through divergent or convergent effects on neural activity remains to be determined. 129S6/SvEv male mice were injected with saline, (R,S)-ketamine, or (2S,6S)-HNK 1 week before a 3-shock...
Ketamine is known for its rapid antidepressant effect, but its impact on affective information processing (including attentional bias [AB], a putative cognitive mechanism of depression) remains largely unexplored. We leveraged a novel measurement of AB and sought to 1) establish adequate test-retest reliability and validity among participants with depression prior to ketamine treatment and 2)...
The prevalence of stress-induced disorders, including depression, anxiety, posttraumatic stress disorder, and postpartum depression, has been increasing, while current treatment approaches are limited. As a result, researchers are exploring alternative treatments that include ketamine as a prophylactic against these disorders. This review provides an overview of the current knowledge on the use...
Opioid use disorder (OUD) has reached epidemic proportions, with many countries facing high levels of opioid use and related fatalities. Although currently prescribed medications for OUD are considered lifesaving, they inadequately address negative affect and cognitive impairment, resulting in high relapse rates to nonmedical opioid use even years after drug cessation (protracted abstinence)....
Biological PsychiatryMarch 8, 2025Jonathan Repple, Maximilian Bayas, Chiara Möser et al.8 citations
After decades of limited progress in depression treatment, recent advancements have sparked renewed interest in developing novel antidepressants, particularly rapid-acting antidepressants (RAADs). Despite these promising developments, there remains a significant gap in research on bipolar depression. While several antipsychotics have been investigated for their efficacy in bipolar depression...
This brief review article will describe treatment approaches for posttraumatic stress disorder (PTSD) based on findings from basic research. The focus of this review will be fear conditioning and extinction models, which provide a translational model of PTSD that can help translate basic research in nonhuman animals through well-controlled trials confirming the efficacy of treatment approaches...
Diverse antidepressants were recently described to bind to TrkB (tyrosine kinase B) and drive a positive allosteric modulation of endogenous BDNF (brain-derived neurotrophic factor). Although neurotrophins such as BDNF can bind to p75NTR (p75 neurotrophin receptor), their precursors are the high-affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely...
Rather than a passive reflection of nociception, pain is shaped by the interplay between one's experiences, current cognitive-affective states, and expectations. The placebo response, a paradoxical yet reliable phenomenon, is postulated to reduce pain by engaging mechanisms shared with active therapies. It has been assumed that mindfulness meditation, practiced by sustaining nonjudgmental...
1 Summary The relationship between the acute effects of psychedelics and their persisting neurobiological and psychological effects is poorly understood. Here, we tracked brain changes with longitudinal precision functional mapping in healthy adults before, during, and for up to 3 weeks after oral psilocybin and methylphenidate (17 MRI visits per participant) and again 6+ months later....
Our findings suggest that temporary amygdala signal attenuation is associated with mechanistic changes to resting-state network connectivity. These changes are significant for altered cognition and perception and suggest targets for research investigating the efficacy of psychedelic therapy for internalizing psychiatric disorders. More broadly, our study suggests the value of quantifying the...
Biological markers for anxiety disorders may further understanding of disorder pathophysiology and suggest potential targeted treatments. The fear-potentiated startle (FPS) (a measure of startle to predictable threat) and anxiety-potentiated startle (APS) (startle to unpredictable threat) laboratory paradigm has been used to detect physiological differences in individuals with anxiety disorders...
Microdosing psychedelic drugs is a widespread social phenomenon with diverse benefits claimed for mood and cognition. Randomized controlled trials have failed to support these claims, but the laboratory-based dosing in trials conducted to date may have limited ecological validity. Healthy male volunteers were randomized into lysergic acid diethylamide (LSD) (n = 40) and placebo (n = 40) groups...
Background: Despite increasingly re fi ned tools for identi-fying individuals at clinical high-risk for psychosis (CHR-P), less is known about the effectiveness of interventions for CHR-P. The signi fi cant clinical heterogeneity among CHR-P individuals is a notable barrier, suggesting that interventions may need to be personalized during this emerging phase of illness. To address these gaps, the...
Background: Physical activity (PA) has shown to have beneficial effects on children's health and development. However, a reduced focus on PA programming in schools and home environments may contribute to the increasing prevalence of mental health problems among youth, particularly following the onset of the COVID-19 pandemic. Here, we report preliminary findings from an ongoing randomized...