Major depressive disorder (MDD) shows marked sex differences in prevalence, symptomatology, and treatment response. However, females remain underrepresented in many clinical trials, and sex-specific treatment outcomes are rarely examined. This study reanalyzed data from a randomized controlled trial comparing psilocybin and escitalopram for MDD to evaluate sex differences across multiple psychological domains. We conducted a post hoc Bayesian analysis of a six-week, double-blind trial in adults with moderate-to-severe MDD (N = 59; 20 female; psilocybin n = 30, 11 female; escitalopram n = 29, 9 female). Post-treatment depression, anhedonia, anxiety, thought suppression, and well-being were modeled by sex, treatment, sex-by-treatment interaction, and baseline score. Sexual dysfunction, measured post-treatment only, was analyzed ordinally. Prior-sensitivity analyses used narrower and wider priors. No outcome showed an overall sex difference across treatments. Within psilocybin, females had lower post-treatment anxiety than males (STAI adjusted difference = -8.77, 95
Rationale Ketamine has emerged as a rapid-acting antidepressant drug for treatment-resistant depression in adults and is currently evaluated for adolescent depression. However, the long-term effects of ketamine exposure during this period of brain development remain unclear, particularly regarding addiction liability. Objectives To investigate whether repeated ketamine exposure during adolescence may influence the long-term risk of addiction following subsequent exposure to commonly abused drugs (alcohol and cocaine) in adulthood. Methods Male and female Sprague-Dawley rats received daily i.p. injections of ketamine (10 mg/kg) or saline for 7 consecutive days during mid adolescence. The dose paradigm of ketamine administered was selected based on its antidepressant-like properties in adolescent rats. In adulthood, addiction liability was measured by voluntary ethanol consumption, using a two-bottle choice paradigm, and by assessing cocaine reward using a single-exposure place preference protocol. Results The main results suggested that a therapeutic dose of ketamine exposure during adolescence did not enhance addictive liability in adulthood as measured by voluntary ethanol consumption or cocaine reward in rats of both sexes. Conclusions Ketamine, administered during adolescence at a dose known to induce antidepressant-like effects did not impact the long-term risk of addiction caused by exposure to commonly abused drugs (i.e., alcohol and cocaine). These results suggested a good long-term safety profile following the therapeutic use of ketamine in adolescence.
Alcohol subjective response (SR) predicts drinking behaviour and risk for alcohol use disorder, but there is limited consensus on how SR differs across contexts, research settings, and alcohol problem severity. This systematic review and meta-analysis examined how alcohol SR differs across (1) commercial (e.g., bar/club/restaurant) versus non-commercial (e.g., home) settings and (2) social versus solitary drinking contexts, and if these effects are moderated by (3) laboratory versus naturalistic study setting and (4) non-problem versus problem alcohol use. Studies assessing alcohol SR across drinking contexts were systematically identified and synthesized. Outcomes included four SR quadrants (HIGH+, HIGH-, LOW+, LOW-) and alcohol reward (hedonic, motivational) and were analysed using random-effects Bayesian meta-analytic models. Across k = 15 studies, social and commercial contexts (versus solitary, non-commercial) were associated with enhanced HIGH + and alcohol reward (hedonic, motivational) effects, with potential LOW- attenuated effects. HIGH+ effects were stronger when drinking socially (versus alone) across research settings, with naturalistic environments possibly enhancing this effect. LOW- effects were potentially attenuated during social drinking only in naturalistic settings. Participants with problem alcohol use (versus non-problem) showed possible attenuation of LOW- effects while drinking socially (versus alone). Several planned analyses were limited by insufficient data. Alcohol SR varies by context and may be underestimated in laboratory settings. Limited studies, including heterogeneous effects (e.g., LOW+), were identified, underscoring the need to refine laboratory context manipulations, integrate ecologically valid approaches, and address gaps in how contextual features, SR domains, and problem severity shape alcohol SR.
Schizophrenia and related psychoses are accompanied by poor stress adaptation and a high prevalence of cigarette smoking, contributing to reduced treatment adherence and poor quality of life. The mechanistic contributions to stress-induced drug-seeking in psychosis remain poorly understood. The present study evaluated nicotine conditioned place preference (CPP) stress reinstatement in a heritable rodent model of dopamine dysregulation relevant to psychosis, alongside molecular and epigenetic alterations associated with drug use vulnerability. Adolescent offspring (F1) of Sprague–Dawley rats treated neonatally with saline (MSxFS) or quinpirole (MQxFQ) were assessed for nicotine CPP expression, extinction, and restraint stress–induced reinstatement. One hour following stress, nucleus accumbens (NAc) and amygdala tissue were analyzed for CREB and dynorphin expression, with complementary single-nucleus RNA sequencing used to identify cell-type–specific genetic adaptations in the medial prefrontal cortex (mPFC) of adolescent rats. MQxFQ rats exhibited enhanced nicotine CPP, resistance to extinction, and robust stress-induced reinstatement relative to MSxFS controls. Following nicotine and stress exposure, MQxFQ rats showed reduced CREB in the NAc and increased CREB and dynorphin in the amygdala. Differential gene expression profiling in the mPFC revealed cell-type specific metabolic and plasticity-related neuroadaptations consistent with cortical vulnerability to psychosis and drug use. These findings demonstrate significant expression of stress-induced reinstatement in a heritable model of dopamine dysregulation. Convergent molecular and genetic adaptations implicate dysregulated stress and reward circuitry, providing a mechanistic framework linking genetic risk for psychosis to maladaptive drug-seeking and vulnerability to stress.
Existing research on biological markers of intoxication while under the influence of cannabis is expansive. We aimed to characterize these parameters across different commercially available products, such as cannabis edibles with both conventional and advanced delivery systems (i.e., fast-acting). Therefore, we sought to examine changes in blood pressure, heart rate, and temperature throughout the administration and intoxication associated with the consumption of a fast-acting cannabis edible, a standard cannabis edible, and a placebo edible. We hypothesized that these biological markers would be significantly different throughout the time course of intoxication for the fast-acting and standard edible compared to the placebo edible. 20 participants completed all 3 conditions of the within-subjects design. Post ingestion of the cannabis edibles, changes in blood pressure over time for the standard edible and the fast-acting edible indicated similar effects on blood pressure. Additionally, significant changes in heart rate were observed in both the standard edible condition and the fast-acting edible condition. We observed similar pharmacodynamic effects of cannabis consumption across both standard- and fast-acting edibles, with small but significant differences in blood pressure and heart rate across fast-acting and standard edibles. Heart rate was higher for participants at the onset of and across all conditions, including the placebo, and interestingly decreased over the course of the session. There were no significant differences in temperature across time or condition. These results provide insight to the biological effects of cannabis edibles, furthering our knowledge of physiological responses to cannabis edible products.
