Abstract The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis of psilocybin-induced changes in a cohort of detoxified patients with AUD. The longitudinal study design included three assessment days in 37 patients with blood sampling and acquisition of psychometrics – at baseline, 24 h after administration of psilocybin (25 mg) or placebo (mannitol), and one month after treatment. As the primary endpoints (duration of abstinence and mean alcohol use) in this trial were not reached, our investigation included secondary psychometrics that differed significantly between groups: Beck’s Depression Inventory and Beck’s Hopelessness Scale. The epigenome-wide association study (EWAS) identified one CpG site in TLE4 (p = 1.1e-7) associated with psilocybin treatment. Screening for differentially methylated regions, we observed altered methylation in the gene RASGRP4 (pFDR = 3.2e-4). Network analysis revealed co-methylation modules related to psilocybin treatment, as well as modules associated with the reduction of depressive symptoms and drinking behavior. Gene ontology analysis indicated involvement of these modules in neuroplasticity and immune functions, suggesting that they may reflect abstinence-related recovery processes. Investigating candidate genes at nominal significance (p < 0.05) uncovered promoter-associated methylation changes in HTR2A and TNF. Interestingly, several of the reported analyses point to immunomodulatory actions of psilocybin. While the findings of this pilot study are limited by the modest sample size, they align well with previous literature and might provide starting points for further, large-scale investigations or hypothesis-driven experiments.

Ketamine has been shown to modulate glutamate signaling in animals and may therefore have the potential to restore glutamate imbalances in the brain. Impaired glutamate homeostasis has been implicated in mental health disorders such as substance use disorders (SUDs). Thus, we investigated ketamine’s potential to increase glutamate levels in the nucleus accumbens (NAc), a key region for the development and maintenance of SUD. We further examined whether glutamate changes are associated with ketamine’s potential to induce altered states of consciousness. A single intravenous dose of R,S-ketamine (0.71 mg/kg bodyweight) was administered to 10 healthy volunteers over 40 min. Glutamate levels were measured by using a tailored proton magnetic resonance spectroscopy (1H-MRS) sequence in the left NAc on a 3 T scanner, before and during the infusion. Subjective effects were measured by using the Five-Dimensional Altered States of Consciousness (5D-ASC) questionnaire. Glutamate levels were considered from the overall spectrum average (22 min) as well as three shorter, overlapping sub-blocks (each 10 min), to capture the progression of glutamate over time. Mean glutamate levels in the NAc were not significantly altered between baseline and ketamine 1H-MRS measurement. However, glutamate changes were positively associated with anxious ego dissolution and reductions in vigilance. In conclusion, ketamine did not significantly increase glutamate levels across our sample of 10 healthy volunteers, but individual glutamate changes induced by ketamine correlate with anxious ego dissolution and reductions in vigilance, indicating that ketamine-induced glutamate alterations in the NAc underly specific alterations in perception and consciousness.

Introduction: Many countries are exploring regulations for non-medical cannabis markets to mitigate cannabis-related health risks. Regulations such as restricting opening hours or product variability may be useful tools, yet their effects on cannabis purchases remain understudied due to a lack of comprehensive sales data. Methods: The Züri Can study implements a framework for strictly regulated cannabis sales, with a fixed product portfolio and a maximum purchase volume. The dataset contains all tracked purchases of 2,507 participants from August 22, 2023, to January 17, 2025, across ten Cannabis Social Clubs (CSCs), ten pharmacies, and the municipal Drug Information Centre Zurich (DIZ). It captures detailed information on sales conditions (opening hours, product variety, customers per hour) and purchase behaviour (purchase frequency, number of packages per purchase, THC volume, and expenditure per package). Generalised estimating equations provided means and confidence intervals by type of point of sale (POS). Multilevel survival analysis and random coefficient models examined how sales conditions influenced purchase behaviour, and how purchase behaviour evolved over time. Results: Pharmacies had notably more weekly operating days (5.66), longer daily opening hours (6.16), and fewer customers per hour (1.08) than CSCs (3.81 days; 3.76 h; 4.62 customers per hour) and the DIZ (2.85 days; 3.28 h, 3.37 customers per hour). However, compared to the POS average, longer opening hours and more customers per hour only slightly increased purchase frequency; their impact on purchase amount was negligible. Variations in the number of available products only marginally affected purchasing behaviour. Purchase frequency was higher in the 30 days following the first purchase and declined over 12 months (CSCs, pharmacies) or remained stable (DIZ) while amount obtained per purchase remained stable. Conclusion: These findings suggest that in a strictly regulated non-medical cannabis market similar to the framework of the Züri Can study, variations in sales conditions only have a small impact on purchase behaviour. Legal access to cannabis does not inherently lead to increased purchasing and may even contribute to a decline in purchase frequency.

Substance use disorders (SUD) are chronic conditions with devastating effects on brain health, functioning, and survival. In this study, we compared brain morphometry of 2,782 individuals with SUD to 1,951 controls and assessed the topographic overlap of these differences with brain connectivity and receptor architecture. Across SUD, we identified a morphometric signature involving frontal, parietal, temporal and limbic systems that overlapped with cortical hub regions and harbored cortical and subcortical disease epicenters. Findings were highly consistent across six substances and numerous robustness and generalizability analyses. Transdiagnostic comparisons showed high spatial overlap of SUD epicenters with those of schizophrenia and bipolar disorder, suggesting shared network-constrained cortical differences. Finally, multivariate mapping revealed that SUD brain differences aligned with two neurotransmitter axes contrasting cannabinoid-opioid and dopaminergic systems. These findings indicate that addiction-related brain differences are shaped by connectome and neurotransmitter architecture, positioning brain network and neurochemical organization as key principles of SUD-related brain alterations.

Background: Chronic cocaine use is associated with physical, neuropsychiatric, and social consequences. While cocaine‑induced neuroplasticity is well-studied in animal models, less is known about recovery of the human brain after prolonged exposure. This longitudinal functional MRI (fMRI) study therefore examined whether (1) whole‑brain and fronto‑striatal resting‑state functional connectivity (rsFC) are modulated by reduced cocaine use and (2) baseline fronto‑striatal rsFC predicts future cocaine intake in individuals with chronic cocaine use (ICCU). Methods: We analysed rsFC data from 32 ICCU (15 sustained users [SU], 17 decreased users [DU]) and 38 matched cocaine‑naive controls (CNC) collected at baseline and long-term follow-up (median interval: 10.3 months). Whole‑brain rsFC was compared between ICCU and CNC and fronto‑striatal rsFC was examined within ICCU subgroups. Additionally, we tested whether baseline rsFC predicted future cocaine use and intensity or craving. Results: At TP1, no striatal‑prefrontal rsFC differences emerged between SU and DU. At TP2, SU exhibited widespread whole‑brain hyperconnectivity versus CNC and stronger striatal rsFC (pallidum/nucleus accumbens to superior frontal gyrus; caudate anti‑correlation to inferior frontal gyrus) versus DU (rm‑ANCOVA, p<0.05, cluster‑corrected). Baseline TP1 striatal‑prefrontal rsFC significantly predicted TP2 cocaine use (R²=0.892; caudate fronto‑striatal connectivity surviving FDR correction), whereas the craving model showed high in‑sample fit (R²=0.975) but no single seed survived FDR correction. Conclusion: Our findings indicate that altered rsFC in ICCU reflects widespread network disruption, while rsFC changes partially normalize toward control‑like patterns with reduced cocaine use. Finally, fronto‑striatal rsFC might be useful to predict cocaine use trajectories for individualized treatment of cocaine use disorder.

Background: Despite increasing international adoption of cannabis regulatory models, comparative evidence on how regulated cannabis access via distinct sales models affects health outcomes in real-world settings is scarce. We present two-year findings from an ongoing longitudinal study examining mental and physical health trajectories among people who use cannabis (PWUC) within a strictly regulated, harm-reduction–oriented framework. Methods: We used data from Züri Can, a longitudinal observational trial of regulated non-medical cannabis sales in Zurich, Switzerland, comparing three types of points of sale (POS): 10 pharmacies, a municipal drug information center, and 10 cannabis social clubs. Participants were required to complete an initial online survey prior to their first cannabis purchase followed by subsequent surveys at six-months intervals. Across five survey waves, changes in the prevalence of health outcomes were analyzed using generalized estimating equations (GEE). Cannabis use disorder (CUD, CUDIT-R), depression (PHQ-9), anxiety (GAD-7), ADHD (ASRS), insomnia (ISI), physical complaints (SCL-90 items), chronic health conditions, and health-care consultations were assessed. Models included time (years since access to regulated cannabis) as main predictor, and POS type as covariate. Annual odds ratios (OR) with 95% confidence intervals (CI) were estimated. PWUC were involved in study design. Outcomes: Using data from 3 102 participants (2 436 [78·5%] male, 627 [20·2%] female, 39 [1·3%] non-binary) gathered between mid-2023 and end of 2025, we found that the odds of CUD (OR 0·80, CI 0·76–0·85), insomnia (OR 0·79, 0·74–0·84), and anxiety (OR 0·64, 0·52–0·80) decreased significanty with each year of participation. Smaller but significant reductions were found for ADHD, physical complaints, and health-care consultations, with depression and chronic health conditions remaining stable. Findings were consistent across all three POS types. Interpretation: Trajectories in health outcomes suggest that strictly regulated, harm-reduction–oriented cannabis access can achieve its intended harm-reduction goals via different POS types.

IntroductionCannabis use is linked to the risk of developing a Cannabis Use Disorder (CUD), which can often be chronic. Early identification of problematic cannabis use is crucial to lower the risk of CUD and associated adverse effects. However, the factor structure of the widely used Cannabis Use Disorder Identification Test (CUDIT) remains ambiguous. Furthermore, the impact of age and gender on CUD assessed with CUDIT is unknown. Exploring cannabis use motives has been proposed to better understand susceptibility to CUD. This study aims to clarify the CUDIT’s factor structure, its links to cannabis use motives, and the influence of age and gender on CUD.Materials and MethodsWe analyzed data from 3454 people who use cannabis (20.5% women; mean age = 30.31 years), collected from a Swiss online survey. Participants were categorized into four groups: younger men, younger women, older men, older women. Principal Component Analysis and Confirmatory Factor Analysis tested the factor structure of the revised CUDIT version (CUDIT-R). Structural Equation Modeling explored whether the influence of use motives on the CUDIT-R factors differs between demographic groups.ResultsThe results suggest that the CUDIT-R scale is best represented by two factors: Use Intensity (Cronbach’s α = 0.71) and Awareness of Problematic Use (Cronbach’s α = 0.72). Use Intensity was lowest for younger women, and younger participants were more aware of negative effects. Gender, age, and use motives uniquely relate with both CUDIT-R factors, highlighting the CUDIT-R’s potential to guide early identification and treatment of individuals at risk for CUD.

Substance use disorders (SUD) are associated with a high global burden of disease, with 5.4% of all disability-adjusted life years lost due to alcohol and illicit drugs. Highly prevalent multimorbidity includes polysubstance use, mental health conditions, and other non-communicable and infectious diseases. Where traditional treatments are insufficient alone, music therapy (MT) is highly engaging and improves motivation and reduces craving; however, its long-term effects are unknown. The present study aims to examine long-term effects of active music groups (AMG) and music listening groups (MLG) versus treatment as usual (TAU) on addiction severity, recovery, and other outcomes in people with SUD Immediate and short-term effects, as well as mechanisms of these interventions, will also be examined. In individuals with SUD across a wide range of age, gender, socioeconomic, and cultural backgrounds, a parallel 3-arm assessor-blinded pragmatic multinational randomised controlled trial (RCT) with embedded exploratory trials and mechanistic studies will determine long-term effects of AMG and MLG versus TAU on addiction severity (primary endpoint: 1 year), recovery, and other outcomes. Embedded trials will examine immediate effects of AMG or MLG combined with individual components of TAU combined to determine the best combinations of interventions. Experimental studies will examine mechanisms using cognitive testing and brain imaging. With 600 participants in 7 countries randomised, the trial will have 80% power on the primary outcome. Patient representatives, health technology assessment (HTA) bodies, and interventionists have been involved from conception and will ensure feasibility and applicability of the intervention across Europe. This document describes the FALCO RCT, the main part of the FALCO project, which aims to reduce disease burden through innovative, effective, and affordable treatment, and will strengthen research and innovation expertise. Recommendations from FALCO will inform intervention delivery across Europe and beyond, leading to increased safety, effectiveness, and cost-effectiveness, and improved quality of life for individuals with SUD. Stakeholders will be involved in communicating findings across all European countries and regions and ensuring that findings are effectively implemented. ClinicalTrials.gov , NCT07028983 , registered 11 th of June 2025. https://clinicaltrials.gov/study/NCT07028983

Metabotropic glutamate receptor 5 (mGluR5) is involved in cocaine reward processing and addiction. Preclinical studies suggest that blocking this receptor inhibits cocaine self-administration and seeking behavior in rodents. We assessed a selective noncompetitive antagonist of mGluR5 called mavoglurant in a phase 2 randomized, placebo-controlled clinical trial of 68 adults with cocaine use disorder. Study participants were randomly assigned in a 1:1 ratio to an up-titrating schedule of oral mavoglurant twice daily up to 200 mg for 98 days or placebo. The primary end point was the proportion of cocaine use days over the treatment period assessed by a retrospective self-report using Timeline Followback. Secondary end points were urine analysis of the cocaine metabolite benzoylecgonine and alcohol use measured by Timeline Followback assessment. Exploratory end points included testing for cocaine and alcohol metabolites in hair samples. The posterior probability of mavoglurant reducing cocaine use at the end of treatment was ≥99.0% for a treatment difference <0 and ≥36.6% for a treatment difference <−10%. The difference between mavoglurant and placebo was also assessed using analysis of covariance ( P = 0.021). Urine benzoylecgonine concentration was lower in the mavoglurant-treated group versus placebo ( P = 0.025); there was reduced alcohol consumption in the treatment group ( P = 0.072). Seventy-six percent (randomized set) and 79% (safety analysis set) of patients completed the final treatment visit. Adverse events in the treatment group were headache, dizziness, and nausea. In this small and short trial, mavoglurant reduced cocaine and alcohol use in patients with chronic cocaine use disorder.

Serotonergic psychedelics are being explored as treatments for a range of psychiatric conditions. Promising results in mood disorders indicate that their effects on emotional processing may play a central role in their therapeutic potential. However, mechanistic and clinical studies paint a complex picture of the impact of psychedelics on emotions and mood. Here, we review recent findings on the effects of psychedelics on emotion, emotional empathy, and mood. We discuss how psychedelics may impact long-term emotion management strategies, the significance of challenging experiences, and neuroplastic changes. More precise characterization of emotional states and greater attention to the temporal dynamics of psychedelic-induced effects will be critical for clarifying their mechanisms of action and optimizing their therapeutic impact.

Background:Despite the promising therapeutic effects of psilocybin, its efficacy in preventing relapse after withdrawal treatment for alcohol use disorder (AUD) remains unknown. This study aims to assess whether a single dose of psilocybin combined with brief psychotherapy could reduce relapse rates and alcohol use in AUD patients. Methods:This single-center, double-blind, randomized clinical trial was conducted in Switzerland. We recruited participants with AUD between June 8, 2020, and August 16, 2023 who completed withdrawal treatment within six weeks prior to enrollment. Participants were randomized (1:1) to receive either a single oral dose of psilocybin (25 mg) or placebo (mannitol), combined with brief psychotherapy. The primary outcomes were abstinence and mean alcohol use at 4-week follow-up. Participants completed the timeline followback to assess daily alcohol use. The trial is registered on ClinicalTrials.gov (NCT04141501). Findings:We included 37 participants who completed the 4-week follow-up (female:male = 14:23; psilocybin = 18, placebo = 19) in the analysis. There were no significant differences between groups in abstinence duration (p = 0.55, psilocybin mean = 16.80 days, 95% CI: 14.31-19.29; placebo mean = 13.80 days, 95% CI: 10.97-16.63; Cohen's d = 0.151) or mean alcohol use per day (p = 0.51, psilocybin: median = 0.48 standard alcohol units, range: 0-3.99, placebo: median = 0.54 standard alcohol units, range: 0-5.96; Cohen's d = 0.11) at 4-week or 6-month follow-up (abstinence: Cohen's d = 0.10, alcohol use: Cohen's d = 0.075). Participants in both groups reported reduced craving and temptation to drink alcohol after the dosing visit, with an additional reduction observed in the psilocybin group. Thirteen adverse events occurred in the psilocybin and seven in the placebo group. One serious adverse event occurred in the psilocybin and four in the placebo group, all related to inpatient withdrawal treatments. Interpretation:A single dose of psilocybin combined with five psychotherapy sessions may not be sufficient to reduce relapse rates and alcohol use in severely affected AUD patients following withdrawal treatment. However, given the limited sample size of our study, larger trials are needed in the future to confirm these findings. Funding:Swiss National Science Foundation under the framework of Neuron Cofund, Swiss Neuromatrix Foundation, and Heffter Young Investigator Fellowship Award.

BackgroundIndividuals with cocaine use disorder experience heightened motivation to pursue rewards tied to cocaine, often triggered by associated cues. Cue reactivity and subsequent craving significantly elevate the risk of substance use, creating a pressing need for treatments that can help alleviate cravings. However, no pharmaceutical therapies for treating cocaine use disorder have been approved. Preclinical findings reveal dysfunctions in the glutamatergic pathway connecting prefrontal regions with the nucleus accumbens, which are correlated with cue-induced substance-seeking behaviour. These alterations, at both molecular and behavioural levels, can be reversed in rodents with N-acetylcysteine, a modulator of glutamatergic signalling. In contrast, the therapeutic potential for humans remains uncertain.MethodsHere, we assessed the impact of a short-term challenge with N-acetylcysteine on neural responses to cocaine cues and cue-induced craving in a randomised, placebo-controlled cross-over trial using a fMRI cue reactivity paradigm. In total, 44 fMRI cue reactivity scans of 22 individuals with cocaine use disorder were recorded—once after the administration of 2,400 mg of N-acetylcysteine/day for 2 days and once after placebo intake.ResultsIn the placebo condition, participants showed increased cue reactivity towards cocaine pictures, accompanied by significantly higher cravings as compared to neutral images. In accordance with recent meta-analyses, cue reactivity was evident in parietal regions such as the posterior cingulate and precuneus, temporal regions like the hippocampus, the bilateral insula, and medial prefrontal regions, namely the inferior, middle, and superior frontal gyrus. Cue-induced activity in the superior frontal gyrus was strongly predicted by the individual duration of cocaine use. While N-acetylcysteine showed no impact on subjectively rated cocaine craving, neural cue reactivity in the superior frontal gyrus was significantly decreased under N-acetylcysteine compared to placebo.ConclusionsOur findings show that prefrontal reactivity to cocaine cues can be reduced even by a brief pharmacological challenge with N-acetylcysteine. Since neural drug cue reactivity has been shown to be a precursor of relapse behaviour, N-acetylcysteine’s therapeutic potential should be further investigated in future studies by extending treatment periods.Clinical Trial Registrationhttps://clinicaltrials.gov, identifier NCT02626494.

Cocaine is the most frequently used stimulant worldwide, with increasing consumption rates in Europe. Cocaine use is associated with great harm to individuals and society. As of today, psychotherapeutic interventions for cocaine use disorder (CUD) demonstrate only modest effect sizes, and no pharmacotherapy has been approved due to gaps in understanding the disease. However, a novel pharmacotherapeutic target, i.e. glutamatergic neurotransmission, emerged from animal models of addiction. Specifically, after chronic cocaine administration, glutamate concentrations in the nucleus accumbens (NAcc) of rodents are reduced, while there is an overflow of glutamate during cue-induced cocaine-seeking. Recently, this glutamatergic imbalance has also been observed in humans with CUD. Additionally, promising findings with regard to novel psychotherapeutic approaches came from neurofeedback training (NFT) studies where participants use cognitive strategies to regulate their activity within a specific brain region based on “real-time” feedback about its activity as assessed by real-time functional magnetic resonance imaging (rt-fMRI). For example, participants with CUD successfully learned to regulate their brain activity in reward areas of the midbrain using reward imagery and to reconstitute reward sensitivity to non-drug related reinforcers like, e.g. social interactions, athletic or professional achievements. We therefore investigate the therapeutic potential and the underlying mechanisms of two interventions, a single dose of ketamine and a reward imagery rt-fMRI NFT in 120 participants with CUD. We examine a single ketamine infusion, three sessions of reward imagery rt-fMRI NFT, and the combination of those interventions contrasted to a placebo infusion or a sham NFT in 120 participants with CUD. The study is designed in a randomized, placebo-controlled, double-blind fashion with four study arms. We expect both interventions to have a positive effect on the proportion of cocaine use days. We predict glutamate levels in the reward system to increase with the ketamine infusion and to reduce craving, a re-enhanced sensitivity towards natural rewards resulting from the rt-fMRI NFT, and synergistic effects of the combined interventions. This neurobiologically informed approach has the potential to open new avenues for the treatment of CUD through individualised and integrated pharmaco-psychotherapy. Trial registration. NCT06125054 ClinicalTrials.gov. Registered on October 26, 2023.

As more countries explore regulatory models for non-medical cannabis, concerns persist about its mental health impact. While frequent use has been linked to depression and anxiety, the strength and direction of these associations remain uncertain. This study presents baseline data from Züri Can, a longitudinal observational study in Zurich, Switzerland, evaluating cannabis access under a strictly regulated framework. We conducted a cross-sectional analysis of 2207 participants who completed assessments prior to purchasing cannabis. Mental health was assessed using the PHQ-9 and GAD-7, and substance use with the CUDIT-R and AUDIT-C. Despite high cannabis use (56.4

Background The Incentive-Sensitization Theory postulates that addiction is primarily driven by the sensitization of the brain’s reward system to addictive substances, such as nicotine. According to this theory, exposure to such substances leads to an increase in ‘wanting’, while ‘liking’ the experience remains relatively unchanged. Although this candidate mechanism has been well substantiated through animal brain research, its translational validity for humans has only been partially demonstrated so far, with evidence from human neuroscience data being very limited. Methods From fMRI data of N=31 individuals with Nicotine Use Disorder, we created multivoxel patterns capable of capturing wanting and liking-related dimensions from a smoking cue-reactivity task. Using these patterns, we then designed a novel resting-state ‘reading’ method to evaluate how much wanting or liking still persist as a neural trace after watching the cues. Results We found that the persistence of wanting-related brain patterns at rest increases with longer smoking history but this was not the case for liking-related patterns. Interestingly, such behavior has not been observed for non-temporal measures of smoking intensity. Conclusion This study provides basic human neuroscience evidence that the dissociation between liking and wanting escalates over time, further substantiating the Incentive-Sensitization Theory, at least for Nicotine Use Disorder. These results suggest that treatment approaches could be personalized to account for the variability in individuals’ neural adaptation to addiction by considering how individuals differ in the extent to which their incentive salience system is sensitized. ### Competing Interest Statement The authors have declared no competing interest.

Tobacco smoking is one of the main causes of premature death worldwide and quitting success remains low, highlighting the need to understand the neurobiological mechanisms underlying relapse. Preclinical models have shown that the amygdala and glutamate play an important role in nicotine addiction. The aims of this study were to compare glutamate and other metabolites in the amygdala between smokers and controls, and between different smoking states. Furthermore, associations between amygdalar metabolite levels and smoking characteristics were explored. A novel non -water -suppressed proton magnetic resonance spectroscopy protocol was applied to quantify neurometabolites in 28 male smokers (>= 15 cigarettes/day) and 21 non-smoking controls, matched in age, education, verbal IQ, and weekly alcohol consumption. Controls were measured once (baseline) and smokers were measured in a baseline state (1-3 h abstinence), during withdrawal (24 h abstinence) and in a satiation state (directly after smoking). Baseline spectroscopy data were compared between groups by independent t -tests or Mann -Whitney -U tests. Smoking state differences were investigated by repeated -measures analyses of variance (ANOVAs). Associations between spectroscopy data and smoking characteristics were explored using Spearman correlations. Good spectral quality, high anatomical specificity (98% mean gray matter) and reliable quantification of most metabolites of interest were achieved in the amygdala. Metabolite levels did not differ between groups, but smokers showed significantly higher glutamine levels at baseline than satiation. Glx levels were negatively associated with pack -years and smoking duration. In summary, this study provides first insights into the neurometabolic profile of the amygdala in smokers with high anatomical specificity. By applying proton magnetic resonance spectroscopy, neurometabolites in smokers during different smoking states and non-smoking controls were quantified reliably. A significant shift in glutamine levels between smoking states was detected, with lower concentrations in satiation than baseline. The negative association between Glx levels and smoking quantity and duration may imply altered glutamate homeostasis with more severe nicotine addiction.

Background and Aims Recreational use of cannabis is illegal in most countries. Despite this, it is the third most commonly used psychoactive substance worldwide. As a result of this discrepancy, a growing number of countries have begun to reassess their legal approach to cannabis in recent years. While the health risks of cannabis and potential harm reduction measures are increasingly well understood, there are still significant gaps in knowledge about which regulatory and supply models are effective in promoting lower-risk cannabis use.In this paper, we outline the Züri Can study, which implements and evaluates a regulatory framework for cannabis sales in the city of Zurich, Switzerland, between 2023 and 2026. In addition, we illustrate how the study addresses current knowledge gaps to provide further insight into the potential future regulation of cannabis in Switzerland.To embed the study in the present scientific and political context, we first provide a brief overview of the state of knowledge on cannabis-related health risks and means of reducing them, along with lessons learned from other countries that have implemented varying regulatory systems. Design and Measurements 2,100 participants will be able to legally purchase cannabis either at a pharmacy, a cannabis social club, or the municipal drug information center over a three-year period. As part of this observational study, participants will be evaluated regarding their cannabis use habits and motives, their knowledge of lower-risk use, and their mental and physical health, among other parameters.Established harm reduction strategies are implemented as an integral part of the study design. Comments The study will contribute to a better understanding of the impact of different cannabis distribution models on cannabis use patterns and related health outcomes. The results are expected to assist Swiss and international policy makers in developing evidence-based and public health-oriented regulatory frameworks for cannabis.

Impulsivity transcends psychiatric diagnoses and is often related to anhedonia. This ad hoc cross-sectional investigation explored 1) whether self-reported trait impulsivity mapped onto a common structural brain substrate across healthy controls (HCs) and psychiatric patients, and 2) in a more exploratory fashion, whether impulsivity and anhedonia were related to each other and shared overlapping brain correlates. Structural magnetic resonance imaging (sMRI) datasets from 234 participants including HCs (n = 109) and patients with opioid use disorder (OUD, n = 22), cocaine use disorder (CUD, n = 43), borderline personality disorder (BPD, n = 45) and schizophrenia (SZ, n = 15) were included. Trait impulsivity was measured with the Barratt Impulsiveness Scale (BIS-11) and anhedonia with a subscore of the Beck Depression Inventory (BDI). BIS-11 global score data were available for the entire sample, while data on the BIS-11 2nd order factors attentional, motor and non-planning were additionally in hand for a subsample consisting of HCs, OUD and BPD patients (n = 116). Voxel-based morphometry analyses were conducted for identifying dimensional associations between grey matter volume and impulsivity/anhedonia. Partial correlations were further performed to exploratory test the relationships between impulsivity and anhedonia and their corresponding volumetric brain substrates. Volume of the left opercular part of the inferior frontal gyrus (IFG) was negatively related to global impulsivity across the entire sample and specifically to motor impulsivity in the subsample of HCs, OUD and BPD patients. Across patients anhedonia expression was negatively correlated with left putamen volume. Although there was no relationship between global impulsivity and anhedonia across all patients, only across OUD and BPD patients anhedonia was positively associated with attentional impulsivity. Finally, also across OUD and BPD patients, motor impulsivity associated left IFG volume was positively linked with anhedonia-associated volume in the left putamen. Our findings suggest a critical role of left IFG volume in self-reported global impulsivity across healthy participants and patients with substance use disorder, BPD and SZ. Preliminary findings in OUD and BPD patients further suggests associations between impulsivity and anhedonia that are related to grey matter reductions in the left IFG and putamen.