What’s Legal, Where — Psychedelic Law in 2026

Sleep stage classification from electrophysiological signals is essential for studying brain function in preclinical neuroscience, yet models often fail to generalize across subjects and experimental conditions, particularly under pharmacological interventions that alter neural and muscular activity. We propose a robustness-oriented deep learning framework that integrates multi-branch feature extraction, global contextual representation, sequence modeling, and training strategies designed to reduce sensitivity to subject- and treatment-specific variability. The approach is evaluated on a large rodent dataset comprising over one million annotated EEG and EMG segments collected from multiple animals across several pharmacological conditions. It achieves strong classification performance, substantially outperforming both classical methods and standard deep learning baselines. Notably, the model maintains stable performance across treatments, showing minimal degradation when trained on limited conditions, and remains effective even with relatively small amounts of annotated data. These findings demonstrate that accurate and robust sleep stage classification is achievable despite pronounced experimental variability. The proposed framework reduces reliance on extensive annotation and improves the reliability of automated sleep analysis, supporting more scalable and reproducible preclinical research.

By fostering certain self-transcendent experiences (STE)—those characterized by interconnectedness and other-oriented emotions—3,4-Methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) has been hypothesized to disrupt social anxiety disorder maintenance processes, including negative self-focus, self-criticism, and isolation, thereby enhancing wellbeing. This secondary analysis used data from a randomized waitlist controlled trial of MDMA-AT for generalized social anxiety disorder (N = 20; NCT05138068). It characterized STE during MDMA-AT and examined their relationships with social anxiety symptoms and wellbeing outcomes. Participants reported on STE following two MDMA sessions. Outcomes (social anxiety, gratitude, belonging, purpose in life) were measured at baseline and post-treatment (16 weeks). Paired-samples t-tests examined changes across sessions and pre-to-post treatment, and regression analyses tested whether in-session experiences predicted outcome improvements. Sessions elicited blissful states, and positive and ST emotions, with few negative emotions reported. In-session experiences, especially connection-oriented STE, predicted greater post-treatment belonging, gratitude, and purpose in life, though not social anxiety reduction. STE involving a sense of self-loss were infrequently endorsed and did not predict outcomes. Findings highlight the potential importance of connection-focused STE and emotions during MDMA-AT for promoting psychological flourishing and eudaimonic wellbeing, laying the groundwork for future larger-scale mechanistic trials.

This preprint presents a focused critical narrative review of how safety findings for Cannabis and Psilocybe preparations are transferred across products, formulations, exposures, test systems, populations, and conditions of use. The central question is not whether safety evidence can ever be extrapolated, but when such extrapolation is justified and what information is needed to support it. The review examines selected analytical, cellular, pharmacokinetic, clinical, and regulatory examples to show why category-level terms such as “Cannabis,” “CBD,” “Psilocybe,” or “psilocybin” may conceal important differences in product identity, composition, formulation, dose, route, storage, contaminants, and use conditions. Examples include: discrepancies between labelled and measured cannabinoid content; preparation- and storage-dependent variation in Psilocybe cubensis biomass; extract-specific in vitro responses; differences in systemic Δ9-THC exposure despite the same nominal THC dose; and the limits of transferring findings from a controlled synthetic-psilocybin trial to fungal biomass or other use contexts. The review argues that safety findings should remain linked to the characterized product, exposure, endpoint, population or test system, observation period, and conditions actually studied. It also distinguishes product quality from clinical safety. Conformity with compositional, manufacturing, or contaminant-related specifications does not, by itself, establish clinical interchangeability, therapeutic efficacy, or overall safety. The importance of product characterization also depends on the type of claim being made and the context in which a product is supplied. Self-produced personal use, commercial supply, and therapeutic or medicinal use do not necessarily require identical levels of quality assurance. Rather, the strength of characterization and supporting evidence should be proportionate to the specificity and consequence of the claims being made. To make safety-claim transfer more transparent, the paper proposes a claim-linked extrapolation record that explicitly documents: the source safety claim; the source and target products; composition and measurement; exposure; test system or population; endpoint and ascertainment; use, support, and observation conditions; relevant source-to-target differences; bridging evidence and justification; and residual uncertainty and disposition of the claim. This record is presented as an application of existing product-characterization and evidence-bridging principles, not as a validated checklist, universal safety score, or new regulatory standard. The review is intentionally focused rather than systematic. Its conclusions are limited to the selected and accessible evidence. Missing evidence is treated as uncertainty—not as proof of harm, but also not as evidence of equivalence. Keywords Cannabis; Psilocybe; psilocybin; cannabidiol; THC; product characterization; safety; cytotoxicity; extrapolation; evidence transfer; quality assurance; botanical drugs; psychedelic research; critical narrative review Suggested hashtags #Cannabis #Psilocybe #Psilocybin #Psychedelics #PatientSafety #DrugSafety #ProductQuality #EvidenceBasedMedicine #Toxicology #Pharmacology #OpenScience #Preprint

Abstract Rationale Alcohol use disorder is defined by drinking alcohol despite knowledge of negative consequences, often referred to as aversion-resistant drinking (The dorsomedial (DMS) and dorsolateral striatum (DLS) are necessary for goal-directed and habitual action selection, respectively. Leading hypotheses posit that once drug use becomes compulsive, DMS dependence degrades while DLS dependence increases. This shift may be mediated by changes in synaptic weights from glutamatergic inputs. Objectives Using a combination of western-blot, micro-injections, and ex-vivo electrophysiology in male and female C57BL/6J mice, we investigated the role of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors AMPAR, which drive glutamatergic transmission, during quinine-adulterated alcohol drinking in the DMS and DLS across the development of aversion-resistant drinking. Results We found that AMPAR subunit composition and function change in the DMS across the development of aversion-resistant drinking whereby, calcium permeable (CP) - AMPARs drive behavior. Western blots revealed a negative relationship between DMS GluA1 and quinine-adulterated alcohol drinking in alcohol naive mice and a positive relationship between DMS Glu A1/A2 ratios and quinine-adulterated alcohol drinking in aversion-resistant mice indicating that aversion-resistance positively predicts likelihood for CP-AMPAR expression in the DMS. Female aversion-resistant mice also had significant positive relationships with DMS or DLS Glu A1/A2 ratios and female aversion-resistant mice had a significant negative relationship with GluA2 and aversion-resistant alcohol drinking. DMS CP-AMPAR antagonism caused an increase in quinine-adulterated alcohol drinking in alcohol naïve mice suggesting that CP-AMPARs in the DMS prevent aversion-resistant drinking. Ex-vivo electrophysiology of DMS spiny projection neurons revealed that aversion-resistant drinking mice had greater inward rectification and CP-AMPAR antagonist sensitivity than alcohol naïve mice indicating that spiny projection neurons in the DMS express more CP-AMPARs following the development of aversion-resistant drinking. However, sensitivity to CP-AMPAR antagonism negatively predicted aversion-resistant drinking in alcohol history mice. Conclusions These data provide evidence that repeated alcohol binges alter DMS CP-AMPAR activity, where initial DMS activity acts to causally prevent aversion-resistant drinking but after repeated binges that result in aversion-resistant alcohol drinking, DMS spiny projection neurons recruit CP-AMPARs. CP-AMPAR antagonism was negatively association with aversion-resistant drinking within the alcohol history mice suggesting that plasticity of DMS CP-AMPARs is not related to quinine-sensitivity. These data provide evidence for a causal role of the DMS in aversion-resistant drinking and open questions as to the functional role of CP-AMPARs across the drinking history and striatal cell types.

OBJECTIVES: To describe the demographic, clinical, and treatment characteristics of individuals admitted with hexahydrocannabinol (HHC)-associated psychosis and compare with cannabis-associated psychosis. METHODS: A retrospective chart review was undertaken of all admissions to the Adult Acute Mental Health Unit at University Hospital Galway, Ireland, between 1 May 2023 and 31 July 2025, with psychosis and documented HHC or cannabis use in the seven days preceding admission. Demographic, clinical, and treatment variables were compared across three groups: HHC-only, cannabis-only, and combined HHC + cannabis associated psychosis. Group differences were examined using ANOVA for continuous variables and Fisher's exact tests for categorical variables, with repeated-measures ANOVA used to examine antipsychotic dosing. Analyses were exploratory in nature. RESULTS: Thirty-three individuals (79% male) met inclusion criteria. All HHC-related cases occurred in a first episode of psychosis. Affective symptoms were more frequent in the HHC-only group (89%) than in the cannabis-only (54%) and combined HHC + cannabis groups (27%) (p = 0.024). Formal thought disorder appeared more common in HHC-exposed groups (80%) compared with cannabis-only presentations (38%), reaching statistical significance in an exploratory comparison between cannabis-only and combined HHC-exposed groups (p = 0.027). Urine toxicology screening for THC metabolites, length of stay and maximum antipsychotic dose were similar across groups. CONCLUSION: In this cohort, HHC-associated psychosis was associated with higher rates of affective symptoms and formal thought disorder than cannabis-related presentations, despite otherwise similar clinical features. Findings are hypothesis-generating, given the exploratory analyses, small sample and uncorrected multiple testing. They suggest a potential role for novel cannabinoid screening to support earlier identification and management.

Abstract Chronic stress has lasting adverse consequences that can lead, over time, to depressive disorders1‑4 yet identifying the optimal timeframe for effective therapies remains an unmet challenge. Enhanced neuronal activity and disrupted aversion-encoding in lateral habenula (LHb) are important mediators of stress-related behavioral repercussions5‑10, although the precise timing of its contribution is not understood. Here, we identified an antidepressant-sensitive onset of stress consequences in mice, observable across multiple levels of biological complexity – behavioral, functional, and molecular. Using spatial transcriptomics11,12, we generated a spatially-resolved molecular atlas of the LHb, revealing a topographically-organized and temporally-defined remodeling of gene expression in chronic stress. Longitudinal in vivo two-photon calcium imaging to survey the encoding properties of individual LHb neurons revealed progressively heightened excitatory responses to aversive stimuli. These neuronal adaptations were reversed by the antidepressant ketamine and mirrored both the progression of transcriptional changes as well as the emergence of depression-related behavioral phenotypes. Finally, both chemogenetically limiting LHb neuronal activity and administering ketamine at the onset of the remodeling processes exerted antidepressant effects. Together, these findings associate shared spatiotemporal signatures of LHb neuronal ensembles and genetic landscape with the onset of stress-induced depression-related states. This has implications for temporally tailoring therapeutical interventions in clinical practice.