Treatment-resistant depression affects about one-third of patients with major depressive disorder and remains a major unmet need. Mebufotenin (5-methoxy-N,N-dimethyltryptamine; 5-MeO-DMT), the principal psychoactive constituent of Incilius alvarius parotoid secretion and of several Amazonian plants, is a pharmacologically atypical serotonergic psychedelic in clinical development for this indication. This narrative review analyses its clinical pharmacology, drawing on a structured search of PubMed/MEDLINE, EMBASE, Scopus, ClinicalTrials.gov and grey literature through 15 August 2026, supplemented by regulatory and sponsor disclosures. Mebufotenin is a non-selective serotonin agonist with high affinity at 5-hydroxytryptamine receptor 1A (5-HT1A, Ki 3.0 nM) and markedly lower affinity at 5-HT2A, with reported selectivity spanning approximately 30-fold to 300-fold depending on whether the 5-HT2A receptor is agonist- or antagonist-labelled. Clearance is dominated by monoamine oxidase A; the cytochrome P450 2D6 (CYP2D6)-derived metabolite bufotenine has a receptor profile comparable to the parent compound rather than a distinct 5-HT2A-preferring one, and was below the limit of quantification in the only human study to measure it. In the pivotal phase 2b trial (GH001-TRD-201), inhaled GH001 produced a day 8 placebo-adjusted Montgomery–Åsberg Depression Rating Scale (MADRS) reduction of − 15.5 points (p < 0.001; d = − 2.0) and day 8 remission in 23/40 (57.5
Children and adolescents treated with antipsychotics are at increased risk of cardiometabolic adverse events (CMAEs). It is unclear how far this risk is shaped by parental CMAE history or socioeconomic status. We examined whether parental CMAE history and family income modify the cardiometabolic risk associated with antipsychotic use in children, adolescents, and young adults. We conducted a nationwide cohort study of Danish children and adolescents (aged 6–17 years) and young adults (aged 18–31 years) with psychiatric diagnoses treated with antipsychotics in 2000–2021. Each exposed individual was age/sex-matched to up to 10 controls. The outcome was any CMAE, identified through hospital contacts or related prescriptions. Using propensity score weighting, we estimated weighted incidence rates (wIR) and incidence rate ratios (wIRR) with 95
Antiseizure medications (ASMs) are the mainstay of epilepsy treatment but may adversely affect cognitive functions, deepening the cognitive and psychosocial burden intrinsic to epilepsy. Cognitive side effects vary widely across drug classes, doses, treatment regimens, and individual susceptibility, typically affecting attention, processing speed, memory, language, and executive function. This narrative review provides an updated synthesis of the clinical evidence on the cognitive effects of ASMs, mostly in adults, building on a prior 2009 review and focusing on agents introduced into clinical practice since then. A literature search of PubMed identified studies published between January 2009 and December 2025, yielding data from randomised controlled trials, observational studies, meta-analyses, and systematic reviews. Overall, newer-generation ASMs, including rufinamide, lacosamide, brivaracetam, cannabidiol, fenfluramine, and ganaxolone, demonstrate generally favourable cognitive profiles when used at recommended doses, particularly in monotherapy or rational polytherapy. Eslicarbazepine and cenobamate may be associated with mild, dose-dependent cognitive effects, occurring only at the upper end of the recommended dose range. In contrast, old ASMs and certain second-generation agents, notably topiramate and zonisamide, remain consistently associated with higher cognitive risks. Special populations, including older adults and individuals with intellectual disabilities, are particularly vulnerable to cognitive adverse effects and benefit from agents with low interaction potential and benign neuropsychological profiles. Cognitive dysfunction in epilepsy is multifactorial, reflecting the interaction between disease-related neurobiological mechanisms and treatment effects. Optimal management requires balancing seizure control with cognitive preservation through individualised drug selection, cautious titration, and minimisation of polytherapy to achieve the best functional and quality-of-life outcomes.
Psychedelic microdosing has gained increasing popularity for enhancing mood and cognition, yet its effects on psychological outcomes in healthy adults remain unclear. We aim to evaluate the efficacy and safety of psychedelic microdosing on psychological outcomes in healthy/non-clinical adult population. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251035294). We searched Embase, MEDLINE, and PsycINFO from inception to February 2026 for original studies in healthy adults using sub-hallucinogenic psychedelic doses on separate days. We included randomized studies, nonrandomized prospective studies, cross-sectional studies, and observational longitudinal designs and stratified meta-analyses by design. Random-effects models were used; safety in randomized controlled trials (RCTs) was pooled as risk differences (RDs). Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools appropriate for each study design. 24 studies (3,681 participants) met inclusion criteria, 6 contributed to meta-analyses. RCTs of psilocybin and LSD microdosing showed subjective and neurophysiological effects but minimal impact on cognition, creativity, or sustained mood. Psilocybin altered EEG and speech with little behavioral change, while LSD caused transient mood and minor physiological effects without lasting cognitive or personality benefits. Observational studies indicated mood and personality improvements, likely influenced by expectancy or lifestyle factors. Meta-analyses included two parallel RCTs (3 comparisons; n = 117) and three non-RCT studies (n = 1,013). Adverse event analyses included two RCTs (4 comparisons; n = 109). RCTs showed no clear evidence of immediate symptom reduction: depressive symptoms (SMD = −0.19; 95
