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RationaleDepressed patients robustly exhibit affective biases in emotional processing which are altered by SSRIs and predict clinical outcome.ObjectivesThe objective of this study is to investigate whether psilocybin, recently shown to rapidly improve mood in treatment-resistant depression (TRD), alters patients' emotional processing biases.MethodsSeventeen patients with treatment-resistant depression completed a dynamic emotional face recognition task at baseline and 1 month later after two doses of psilocybin with psychological support. Sixteen controls completed the emotional recognition task over the same time frame but did not receive psilocybin.ResultsWe found evidence for a group × time interaction on speed of emotion recognition (p = .035). At baseline, patients were slower at recognising facial emotions compared with controls (p

RationaleRecent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.ObjectivesHere, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.MethodsTwenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.ResultsTreatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p

Background 'Recreational' use of ketamine is spreading rapidly among young people. In healthy individuals an acute dose of the N-methyl D-aspartate (NMDA) receptor antagonist ketamine induces marked psychosis-like effects and cognitive impairments, but little is known about the long-term effects of the drug. Aims To evaluate the long-term neuropsychiatric or cognitive consequences. Methods A total of 150 individuals were assessed, 30 in each of five groups: frequent ketamine users, infrequent ketamine users, abstinent users, polydrug controls and non-users of illicit drugs. Twelve months later, 80% of these individuals were re-tested. Results Cognitive deficits were mainly observed only in frequent users. In this group, increasing ketamine use over the year was correlated with decreasing performance on spatial working memory and pattern recognition memory tasks. Assessments of psychological wellbeing showed greater dissociative symptoms in frequent users and a dose-response effect on delusional symptoms, with frequent users scoring higher than infrequent, abstinent users and non-users, respectively. Both frequent and abstinent using groups showed increased depression scores over the 12 months. Conclusions These findings imply that heavy use of ketamine is harmful to aspects of both cognitive function and psychological wellbeing. Health education campaigns need to raise awareness among young people and clinicians about these negative consequences of ketamine use. [ABSTRACT FROM AUTHOR]

BACKGROUND: The attention-grabbing properties of drugs to drug-using individuals have been well documented and recent research has begun to suggest that such attentional bias may be related to the severity of drug dependency. Dependence on ketamine has been reported anecdotally but no systematic study has investigated this phenomenon. We aimed to explore attentional biases to incentive stimuli in different populations of ketamine users. METHOD: Using a dot-probe paradigm, attentional bias to both drug-related and money-related stimuli was investigated in 150 participants: 30 frequent ketamine users, 30 infrequent ketamine users, 30 ex-ketamine users, 30 poly-drug users and 30 non-drug-using controls. Two stimulus presentation times were used (200 and 2000 ms) to investigate whether attentional bias was as a result of an automatic or a more conscious attentional shift. Participants also rated the degree to which stimuli used in the dot-probe paradigm were pleasurable. RESULTS: Frequent ketamine users demonstrated an attentional bias to both types of incentive stimuli only at the short stimulus presentation interval and this was significantly correlated with degree of ketamine use. No attentional biases were observed in any of the other groups. All groups rated money stimuli as more pleasurable than neutral stimuli. CONCLUSIONS: These data support incentive models of drug use and demonstrate the ability of the attentional bias paradigm to discriminate recreational drug users from those with more dependent patterns of use. Ketamine is a potentially dependence-forming drug. [ABSTRACT FROM AUTHOR]

RATIONALE: There is evidence that serotonergic processes may modulate the processing of fearful facial expressions. It is therefore possible that the recreational drug 'ecstasy' (MDMA), which has marked serotonergic effects, may affect people's ability to recognise human facial expressions portraying fear. OBJECTIVE: The present study therefore aimed to determine whether ecstasy users differed from controls in fear recognition at two time points: shortly after taking the drug and a few days later. METHODS: Sixteen ecstasy users and 21 controls were compared on a facial expression recognition task involving the 6 basic emotions (happiness, surprise, sadness, anger, fear and disgust) and on self-ratings of mood on the night of drug use (day 0) and 4 days later (day 4). RESULTS: In recognising fearful facial expressions, ecstasy users were more accurate than controls on day 0 but less accurate than them on day 4 when compared with their overall ability to recognise other basic emotions. Accuracy of fear recognition on day 4 was negatively correlated with both years of ecstasy use and number of ecstasy tablets taken on a typical session. On self-rated aggression scales, ecstasy users scored lower than controls on day 0 and higher on day 4. CONCLUSIONS: These results support the notion that 5-HT plays a role in modulating the recognition of fearful facial expressions. Increased accuracy of fear recognition may relate to 5-HT release following ecstasy use on day 0, and decreased accuracy may reflect subsequent depletion of 5-HT mid-week. [ABSTRACT FROM AUTHOR]

CONTEXT: As a multidimensional phenomenon, pain is influenced by various psychological factors. One such factor is catastrophizing, which is associated with higher pain intensity and emotional distress in cancer and noncancer pain. One possibility is that catastrophizing represents a general cognitive style that preferentially supports the processing of negative affective stimuli. Such preferential processing of threat-toward negative facial expressions, for example-is seen in emotional disorders and is sensitive to pharmacological treatment. Whether pharmacological (analgesic) treatment might also influence the processing of threat in pain patients is currently unclear. OBJECTIVES: This study investigates the effects catastrophizing on processing of facial affect in those receiving an acute opioid dose. METHODS: In a double-blind crossover design, the performance of 20 palliative care patients after their usual dose of immediate-release opioid was compared with their performance following matched-placebo administration on a facial affect recognition (i.e., speed and accuracy) and threat-pain estimation task (i.e., ratings of pain intensity). The influence of catastrophizing was examined by splitting the sample according to their score on the Pain Catastrophizing Scale (PCS). RESULTS: Opioid administration had no effect on facial affect processing compared with placebo. However, the main finding was that enhanced processing of fear, sadness, and disgust was found only in patients who scored highly on the PCS. There was no difference in performance between the two PCS groups on the other emotions (i.e., happiness, surprise, and anger). CONCLUSION: These findings suggest that catastrophizing is associated with an affective information-processing bias in patients with severe pain conditions. [ABSTRACT FROM AUTHOR]

Adolescence is a time of rapid neurodevelopment and the endocannabinoid system is particularly prone to change during this time. Cannabis is a commonly used drug with a particularly high prevalence of use among adolescents. The two predominant phytocannabinoids are Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which affect the endocannabinoid system. It is unknown whether this period of rapid development makes adolescents more or less vulnerable to the effects of cannabis on brain-network connectivity, and whether CBD may attenuate the effects of THC. Using fMRI, we explored the impact of vaporized cannabis (placebo, THC: 8 mg/75 kg, THC + CBD: 8 mg/75 kg THC & 24 mg/75 kg CBD) on resting-state networks in groups of semi-regular cannabis users (usage frequency between 0.5 and 3 days/week), consisting of 22 adolescents (16-17 years) and 24 young adults (26-29 years) matched for cannabis use frequency. Cannabis caused reductions in within-network connectivity in the default mode (F[2,88] = 3.97, P = 0.022, η² = 0.018), executive control (F[2,88] = 18.62, P < 0.001, η² = 0.123), salience (F[2,88] = 12.12, P < 0.001, η² = 0.076), hippocampal (F[2,88] = 14.65, P < 0.001, η² = 0.087), and limbic striatal (F[2,88] = 16.19, P < 0.001, η² = 0.102) networks compared to placebo. Whole-brain analysis showed cannabis significantly disrupted functional connectivity with cortical regions and the executive control, salience, hippocampal, and limbic striatal networks compared to placebo. CBD did not counteract THC's effects and further reduced connectivity both within networks and the whole brain. While age-related differences were observed, there were no interactions between age group and cannabis treatment in any brain network. Overall, these results challenge the assumption that CBD can make cannabis safer, as CBD did not attenuate THC effects (and in some cases potentiated them); furthermore, they show that cannabis causes similar disruption to resting-state connectivity in the adolescent and adult brain., (© 2024. The Author(s).)

Rationale: Attentional bias to drug-related stimuli is hypothesised to contribute towards addiction. However, the acute effects of Δ9-tetrahydrocannabinol (THC) on attentional bias to cannabis cues, the differential response in adults and adolescents, and the moderating effect of cannabidiol (CBD) are unknown., Objectives: Our study investigated (1) the acute effects of vaporised cannabis on attentional bias to cannabis-related images in adults and adolescents and (2) the moderating influences of age and CBD., Methods: We conducted a randomised, double-blind, placebo-controlled, cross-over study where three weight-adjusted vaporised cannabis preparations: 'THC' (8 mg THC for a 75-kg person), 'THC + CBD' (8 mg THC and 24 mg CBD for a 75-kg person) and PLA (matched placebo). Cannabis was administered on 3 separate days to 48 participants, who used cannabis 0.5-3 days/week: 24 adolescents (12 females, aged 16-17) and 24 adults (12 females, aged 26-29). Participants completed a visual probe task with cannabis cues. Our primary outcome was attentional bias to cannabis stimuli, measured using the differential reaction time to a cannabis vs. neutral probe, on 200-ms trials., Results: In contrast to hypotheses, attention was directed away from cannabis cues on placebo, and there was a main effect of the drug (F(2,92) = 3.865, p = 0.024, η 2 p  = 0.077), indicating THC administration eliminated this bias. There was no significant impact of CBD nor an age-by-drug interaction., Conclusions: Acute THC intoxication eliminated attentional bias away from cannabis cues. There was no evidence of differential response in adolescents compared to adults and no evidence that a moderate vaporised dose of CBD altered the impact of cannabis on attentional bias., Trial Registration: This study was listed with the US National Library of Medicine and registered on ClinicalTrials.gov, URL: Do Adolescents and Adults Differ in Their Acute Response to Cannabis?-Full Text View-ClinicalTrials.gov, registration number: NCT04851392., (© 2024. The Author(s).)

Adolescence is a developmental period characterised by increased vulnerability to cannabis use disorder (CUD). However, previous investigations of this vulnerability have relied on cross-sectional comparisons and lack a detailed assessment of cannabis quantity, a potentially important confounding factor. Here, we aimed to investigate the one-year course of CUD in adolescents compared to adults who currently use cannabis, adjusting for a comprehensive measure of cannabis quantity. Data are from a one-year observational longitudinal study (CannTeen) of adolescents and adults who currently used cannabis regularly with five waves of assessment at 3-monthly intervals, based in London, UK. Participants were n = 70 adults (26-29, 45.7% female), who did not regularly use cannabis when they were under age 18, and n = 76 adolescents (16-17, 50.0% female). The exposure was adolescent (compared to adult) frequent cannabis use. The primary outcome was CUD symptoms measured using the cannabis use disorder identification test revised (CUDIT-R) at five time points. Models were adjusted for cannabis quantity using mean weekly standard THC units (one unit = 5 mg THC). Other covariates included gender, and whether each session occurred before or during the COVID-19 pandemic. In models adjusted for pre-registered covariates, adolescents scored 3.7 points higher on the CUDIT-R compared to the adult group across the 5 assessment waves (3.66 95% CIs 1.99, 5.34). There was also evidence of a linear reduction in symptoms over time in both groups (-0.47, 95%CIs -0.67, -0.27). Adolescents had persistently increased CUD symptoms compared to adults across the 12-month period. This association was robust after adjusting for the quantity of cannabis consumed and other covariates., (© 2024. The Author(s).)

Aims: The aims of this study were to present an enhanced cannabis timeline followback (EC-TLFB) enabling comprehensive assessment of cannabis use measures, including standard tetrahydrocannabinol (THC) units, and to validate these against objectively indexed urinary 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH) concentrations., Design: We used cross-sectional baseline data from the 'CannTeen' observational longitudinal study., Setting: The study was conducted in London, UK., Participants: A total of 147 participants who used cannabis regularly took part in the study (n = 71 female, n = 76 male; mean age = 21.90, standard deviation = 5.32)., Measurements: The EC-TLFB was used to calculate frequency of cannabis use, method of administration, including co-administration with tobacco, amount of cannabis used (measured with unaided self-report and also using pictorial aided self-report) and type of cannabis product (flower, hash) which was used to estimate THC concentration (both from published data on THC concentration of products and analysis of cannabis samples donated by participants in this study). We calculated total weekly standard THC units (i.e. 5 mg THC for all cannabis products and methods of administration) using the EC-TLFB. The outcome variable for validation of past week EC-TLFB assessments was creatinine-normalized carboxy-tetrahydrocannabinol (THC-COOH) in urine., Findings: All measures of cannabis exposure included in this analysis were positively correlated with levels of THC-COOH in urine (r = 0.41-0.52). Standard THC units, calculated with average concentrations of THC in cannabis in the UK and unaided self-report measures of amount of cannabis used in grams showed the strongest correlation with THC-COOH in urine (r = 0.52, 95% bias-corrected and accelerated = 0.26-0.70)., Conclusions: The enhanced cannabis timeline followback (EC-TLFB) can provide a valid assessment of a comprehensive set of cannabis use measures including standard tetrahydrocannabinol units as well as and traditional TLFB assessments (e.g. frequency of use and grams of cannabis use)., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background/aim: Cannabis use is highly prevalent in adolescents; however, little is known about its effects on adolescent brain function., Method: Resting-state functional magnetic resonance imaging was used in matched groups of regular cannabis users ( N  = 70, 35 adolescents: 16-17 years old, 35 adults: 26-29 years old) and non-regular-using controls ( N  = 70, 35 adolescents/35 adults). Pre-registered analyses examined the connectivity of seven major cortical and sub-cortical brain networks (default mode network, executive control network (ECN), salience network, hippocampal network and three striatal networks) using seed-based analysis methods with cross-sectional comparisons between user groups and age groups., Results: The regular cannabis use group (across both age groups), relative to controls, showed localised increases in connectivity only in the ECN analysis. All networks showed localised connectivity differences based on age group, with the adolescents generally showing weaker connectivity than adults, consistent with the developmental effects. Mean connectivity across entire network regions of interest (ROIs) was also significantly decreased in the ECN in adolescents. However, there were no significant interactions found between age group and user group in any of the seed-based or ROI analyses. There were also no associations found between cannabis use frequency and any of the derived connectivity measures., Conclusion: Regular cannabis use is associated with changes in connectivity of the ECN, which may reflect allostatic or compensatory changes in response to regular cannabis intoxication. However, these associations were not significantly different in adolescents compared to adults.

Background: Cannabis potency (concentration of Δ-9-Tetrahydrocannabinol) has been associated with risks of adverse mental health outcomes and addiction but no studies have triangulated evidence from self-report and objective measures of cannabis potency. We hypothesised that users of high potency cannabis would have higher levels of (a) anxiety, (b) depression and (c) psychosis-like symptoms (d) cannabis dependence than users of lower potency cannabis., Methods: A cross-sectional study of 410 participants donated a sample of cannabis for analysis of THC concentration and reported their cannabis potency preference. These two exposure measures were investigated for their association with cannabis dependence, depression, anxiety, and psychosis-like symptoms in separate linear/logistic regression models., Results: High potency cannabis preference was associated with a slight increased risk of cannabis dependence after adjusting for confounding, with the exception of cannabis use frequency (OR = 1.16, 95% CI 1.04-1.28). No association was found between THC concentration in cannabis and cannabis dependence. There was weak evidence of a small association between cannabis potency and depression and anxiety. There was no association between high potency cannabis preference or THC concentration in cannabis and psychosis-like symptoms., Conclusions: Users of cannabis who preferred high potency types might be at increased risk of problematic cannabis use. This should be considered with caution as we were not able to triangulate these results with an objective measure of cannabis potency. More research is needed to understand the association between high potency cannabis use and depression and anxiety., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Long-term harms of cannabis may be exacerbated in adolescence, but little is known about the acute effects of cannabis in adolescents. We aimed to (i) compare the acute effects of cannabis in adolescent and adult cannabis users and (ii) determine if cannabidiol (CBD) acutely modulates the effects of delta-9-tetrahydocannabinol (THC)., Design: Randomised, double-blind, placebo-controlled, crossover experiment. The experiment was registered on ClinicalTrials.gov (NCT04851392)., Setting: Laboratory in London, United Kingdom., Participants: Twenty-four adolescents (12 women, 16- to 17-year-olds) and 24 adults (12 women, 26- to 29-year-olds) who used cannabis 0.5-3 days/week and were matched on cannabis use frequency (mean = 1.5 days/week)., Intervention: We administered three weight-adjusted vaporised cannabis flower preparations: 'THC' (8 mg THC for 75 kg person); 'THC + CBD' (8 mg THC and 24 mg CBD for 75 kg person); and 'PLA' (matched placebo)., Measurements: Primary outcomes were (i) subjective 'feel drug effect'; (ii) verbal episodic memory (delayed prose recall); and (iii) psychotomimetic effect (Psychotomimetic States Inventory)., Findings: Compared with 'PLA', 'THC' and 'THC + CBD' significantly (P < 0.001) increased 'feel drug effect' (mean difference [MD] = 6.3, 95% CI = 5.3-7.2; MD = 6.8, 95% CI = 6.0-7.7), impaired verbal episodic memory (MD = -2.7, 95% CI = -4.1 to -1.4; MD = -2.9, 95% CI = -4.1 to -1.7) and increased psychotomimetic effects (MD = 7.8, 95% CI = 2.8-12.7; MD = 10.8, 95% CI = 6.2-15.4). There was no evidence that adolescents differed from adults in their responses to cannabis (interaction P ≥ 0.4). Bayesian analyses supported equivalent effects of cannabis in adolescents and adults (Bayes factor [BF 01 ] >3). There was no evidence that CBD significantly modulated the acute effects of THC., Conclusions: Adolescent cannabis users are neither more resilient nor more vulnerable than adult cannabis users to the acute psychotomimetic, verbal memory-impairing or subjective effects of cannabis. Furthermore, in adolescents and adults, vaporised cannabidiol does not mitigate the acute harms caused by delta-9-tetrahydocannabinol., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Alcohol intoxication disrupts many aspects of cognition, including the generation of phenomenological characteristics of future events (a component of episodic foresight), and the execution of directed preparatory behaviours (a component of prospective memory). However, no study has tested whether alcohol intoxication is also associated with deficits engaging episodic foresight to guide future-directed behaviour., Aims: This study was designed to provide the first test of how alcohol intoxication influences the functional application of episodic foresight. The secondary aim was to establish the degree to which any observed episodic foresight difficulties associated with alcohol use might reflect broader problems in retrospective memory and executive control. Sex differences were also examined., Methods: Healthy adult social drinkers randomly received either a moderate dose of 0.6 g/kg alcohol ( n  = 61) or a matched placebo drink ( n  = 63) and then completed a validated measure that met strict criteria for assessing the functional application of episodic foresight as well as a broader cognitive test battery., Results: Relative to the placebo condition, episodic foresight was impaired by acute alcohol consumption, with this impairment related to poorer retrospective memory, but not executive control. The negative effects of alcohol intoxication on episodic foresight did not differ as a function of sex., Conclusions: Even a moderate level of intoxication impairs the ability to use episodic foresight in a functionally adaptive way. These findings have implications for understanding many of the maladaptive behaviours that are often associated with acute alcohol use.

Cannabidiol (CBD) has shown promise in treating psychiatric disorders, including cannabis use disorder - a major public health burden with no approved pharmacotherapies. However, the mechanisms through which CBD acts are poorly understood. One potential mechanism of CBD is increasing levels of anandamide, which has been implicated in psychiatric disorders including depression and cannabis use disorder. However, there is a lack of placebo-controlled human trials investigating this in psychiatric disorders. We therefore assessed whether CBD affects plasma anandamide levels compared to placebo, within a randomised clinical trial of CBD for the treatment of cannabis use disorder. Individuals meeting criteria for cannabis use disorder and attempting cannabis cessation were randomised to 28-day administration with placebo (n = 23), 400 mg CBD/day (n = 24) or 800 mg CBD/day (n = 23). We estimated the effects of each CBD dose compared to placebo on anandamide levels from baseline to day 28. Analyses were conducted both unadjusted and adjusted for cannabis use during the trial to account for effects of cannabis on the endocannabinoid system. We also investigated whether changes in plasma anandamide levels were associated with clinical outcomes relevant for cannabis use disorder (cannabis use, withdrawal, anxiety, depression). There was an effect of 800 mg CBD compared to placebo on anandamide levels from baseline to day 28 after adjusting for cannabis use. Pairwise comparisons indicated that anandamide levels unexpectedly reduced from baseline to day 28 in the placebo group (-0.048, 95% CI [-0.089, -0.007]), but did not change in the 800 mg CBD group (0.005, 95% CI [-0.036, 0.047]). There was no evidence for an effect of 400 mg CBD compared to placebo. Changes in anandamide levels were not associated with clinical outcomes. In conclusion, this study found preliminary evidence that 28-day treatment with CBD modulates anandamide levels in individuals with cannabis use disorder at doses of 800 mg/day but not 400 mg/day compared to placebo., (© 2023. The Author(s).)

Rationale: Chronic cannabis use is associated with impaired cognitive function. Evidence indicates cannabidiol (CBD) might be beneficial for treating cannabis use disorder. CBD may also have pro-cognitive effects; however, its effect on cognition in people with cannabis use disorder is currently unclear., Objectives: We aimed to assess whether a 4-week CBD treatment impacted cognitive function. We hypothesised that CBD treatment would improve cognition from baseline to week 4, compared to placebo., Methods: Cognition was assessed as a secondary outcome in a phase 2a randomised, double-blind, parallel-group and placebo-controlled clinical trial of 4-week daily 200 mg, 400 mg and 800 mg CBD for the treatment of cannabis use disorder. Participants had moderate or severe DSM-5 cannabis use disorder and intended to quit cannabis use. Our pre-registered primary cognitive outcome was delayed prose recall. Secondary cognitive outcomes were immediate prose recall, stop signal reaction time, trail-making task performance, verbal fluency and digit span., Results: Seventy participants were randomly assigned to placebo (n = 23), 400 mg CBD (n = 24) and 800 mg CBD (n = 23). A 200 mg group was eliminated from the trial because it was an inefficacious dose at interim analysis (n = 12) and was not analysed here. For the primary cognitive outcome, there was no effect of CBD compared to placebo, evidenced by a lack of dose-by-time interaction at 400 mg (0.46, 95%CIs: - 1.41, 2.54) and 800 mg (0.89, 95%CIs: - 0.99, 2.81). There was no effect of CBD compared to placebo on secondary cognitive outcomes, except backwards digit span which increased following 800 mg CBD (0.30, 95%CIs: 0.02, 0.58)., Conclusions: In this clinical trial for cannabis use disorder, CBD did not influence delayed verbal memory. CBD did not have broad cognitive effects but 800 mg daily treatment may improve working memory manipulation., Clinical Trial Registration: The trial was registered with ClinicalTrials.gov (NCT02044809) and the EU Clinical Trials Register (2013-000,361-36)., (© 2022. The Author(s).)

Background: Adolescents may respond differently to cannabis than adults, yet no previous functional magnetic resonance imaging study has examined acute cannabis effects in this age group. In this study, we investigated the neural correlates of reward anticipation after acute exposure to cannabis in adolescents and adults., Methods: This was a double-blind, placebo-controlled, randomized, crossover experiment. Forty-seven adolescents (n = 24, 12 females, ages 16-17 years) and adults (n = 23, 11 females, ages 26-29 years) matched on cannabis use frequency (0.5-3 days/week) completed the Monetary Incentive Delay task during functional magnetic resonance imaging after inhaling cannabis with 0.107 mg/kg Δ⁹-tetrahydrocannabinol ("THC") (8 mg THC for a 75-kg person) or with THC plus 0.320 mg/kg cannabidiol ("THC+CBD") (24 mg CBD for a 75-kg person), or placebo cannabis. We investigated reward anticipation activity with whole-brain analyses and region of interest analyses in the right and left ventral striatum, right and left anterior cingulate cortex, and right insula., Results: THC reduced anticipation activity compared with placebo in the right (p = .005, d= 0.49) and left (p = .003, d = 0.50) ventral striatum and the right insula (p = .01, d = 0.42). THC+CBD reduced activity compared with placebo in the right ventral striatum (p = .01, d = 0.41) and right insula (p = .002, d = 0.49). There were no differences between "THC" and "THC+CBD" conditions and no significant drug by age group interaction effect, supported by Bayesian analyses. There were no significant effects in the whole-brain analyses., Conclusions: In weekly cannabis users, cannabis suppresses the brain's anticipatory reward response to money, and CBD does not modulate this effect. Furthermore, the adolescent reward circuitry is not differentially sensitive to acute effects of cannabis on reward anticipation., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

EDM event attendees are a high-risk population for substance use and associated adverse effects. The aim of this study was to examine substance use at EDM events, focusing on associations between attendance motives and substance use. Sociodemographic characteristics, event specifics, past-year use, and attendance motives were assessed through an online survey. Participants were 1345 Belgian EDM event attendees (69.44% male, M age = 22.63, SD age = 4.03). Ecstasy/MDMA/Molly (52.28%), other synthetic hallucinogens (53.68%), ketamine (42.13%), amphetamines (40.45%), and alkyl nitrites (poppers) (32.76%) were most frequently used at festivals/outdoor parties/raves. In nightclubs, cocaine (32.29%) was shown to be prevalent as well, while other synthetic hallucinogens (15.79%) were less often consumed. At events with a more private character, cannabis (68.88%) and magic mushrooms (66.44%) were most frequently used. Aside from alcohol (47.76%), substance use in pubs/bars was negligible. Overall enjoyment was demonstrated to be the key attendance motive, which was succeeded by those relating to music and socialization. A wide range of motives proved to be more important to users (e.g., dance, exploration, escapism, excitement, alcohol, drugs) than non-users, while some were associated with the use of particular substances. The prevalence of substance use was shown to be dependent on the specifics of the setting. Moreover, the idea of a three-dimensional classification of the most principal motives for music event attendance was supported. Finally, correlations were estimated between attendance motives and substance use as well as specific substances. Results could enable more tailored approaches in prevention and harm reduction efforts as well as event management strategies.

Background: Cannabis use may be linked with anhedonia and apathy. However, previous studies have shown mixed results, and few have examined the association between cannabis use and specific reward sub-processes. Adolescents may be more vulnerable than adults to harmful effects of cannabis. This study investigated (1) the association between non-acute cannabis use and apathy, anhedonia, pleasure, and effort-based decision-making for reward; and (2) whether these relationships were moderated by age group., Methods: We used data from the "CannTeen" study. Participants were 274 adult (26-29 years) and adolescent (16-17 years) cannabis users (1-7 d/wk use in the past 3 months) and gender- and age-matched controls. Anhedonia was measured with the Snaith-Hamilton Pleasure Scale (n = 274), and apathy was measured with the Apathy Evaluation Scale (n = 215). Effort-based decision-making for reward was measured with the Physical Effort task (n = 139), and subjective wanting and liking of rewards was measured with the novel Real Reward Pleasure task (n = 137)., Results: Controls had higher levels of anhedonia than cannabis users (F1,258 = 5.35, P = .02, η p2 = .02). There were no other significant effects of user-group and no significant user-group*age-group interactions. Null findings were supported by post hoc Bayesian analyses., Conclusion: Our results suggest that cannabis use at a frequency of 3 to 4 d/wk is not associated with apathy, effort-based decision-making for reward, reward wanting, or reward liking in adults or adolescents. Cannabis users had lower anhedonia than controls, albeit at a small effect size. These findings are not consistent with the hypothesis that non-acute cannabis use is associated with amotivation., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Background: Adolescence is characterised by psychological and neural development. Cannabis harms may be accentuated during adolescence. We hypothesised that adolescents would be more vulnerable to the associations between cannabis use and mental health and addiction problems than adults., Method: As part of the 'CannTeen' study, we conducted a cross-sectional analysis. There were 274 participants: split into groups of adolescent users ( n  = 76; 16-17 years old) and controls ( n  = 63), and adult users ( n  = 71; 26-29 years old) and controls ( n  = 64). Among users, cannabis use frequency ranged from 1 to 7 days/week, while controls had 0-10 lifetime exposures to cannabis. Adolescent and adult cannabis users were matched on cannabis use frequency (mean=4 days/week). We measured Diagnostic and Statistical Manual (DSM-5) Cannabis Use Disorder (CUD), Beck Depression Inventory, Beck Anxiety Inventory and Psychotomimetic States Inventory-adapted., Results: After adjustment for covariates, adolescent users were more likely to have severe CUD than adult users (odd ratio = 3.474, 95% confidence interval (CI) = 1.501-8.036). Users reported greater psychotic-like symptoms than controls ( b  = 6.004, 95% CI = 1.211-10.796) and adolescents reported greater psychotic-like symptoms than adults ( b  = 5.509, 95% CI = 1.070-9.947). User-group was not associated with depression or anxiety. No significant interactions between age-group and user-group were identified. Exploratory analyses suggested that cannabis users with severe CUD had greater depression and anxiety levels than cannabis users without severe CUD., Conclusion: Adolescent cannabis users are more likely than adult cannabis users to have severe CUD. Adolescent cannabis users have greater psychotic-like symptoms than adult cannabis users and adolescent controls, through an additive effect. There was no evidence of an amplified vulnerability to cannabis-related increases in subclinical depression, anxiety or psychotic-like symptoms in adolescence. However, poorer mental health was associated with the presence of severe CUD.

Chronic use of drugs may alter the brain's reward system, though the extant literature concerning long-term cannabis use and neural correlates of reward processing has shown mixed results. Adolescents may be more vulnerable to the adverse effects of cannabis than adults; however, this has not been investigated for reward processing. As part of the 'CannTeen' study, in the largest functional magnetic resonance imaging study of reward processing and cannabis use to date, we investigated reward anticipation and feedback in 125 adult (26-29 years) and adolescent (16-17 years) cannabis users (1-7 days/week cannabis use) and gender- and age-matched controls, using the Monetary Incentive Delay task. Blood-oxygen-level-dependent responses were examined using region of interest (ROI) analyses in the bilateral ventral striatum for reward anticipation and right ventral striatum and left ventromedial prefrontal cortex for feedback, and exploratory whole-brain analyses. Results showed no User-Group or User-Group × Age-Group effects during reward anticipation or feedback in pre-defined ROIs. These null findings were supported by post hoc Bayesian analyses. However, in the whole-brain analysis, cannabis users had greater feedback activity in the prefrontal and inferior parietal cortex compared to controls. In conclusion, cannabis users and controls had similar neural responses during reward anticipation and in hypothesised reward-related regions during reward feedback. The whole-brain analysis revealed tentative evidence of greater fronto-parietal activity in cannabis users during feedback. Adolescents showed no increased vulnerability compared with adults. Overall, reward anticipation and feedback processing appear spared in adolescent and adult cannabis users, but future longitudinal studies are needed to corroborate this., (© 2022. The Author(s).)

Background: Adolescence is a period of psychological and neural development in which harms associated with cannabis use may be heightened. We hypothesised that adolescent who use cannabis (adolescentsWUC) would have steeper delay discounting (preference for immediate over future rewards) and greater demand (relative valuation) for cannabis than adults who use cannabis (adultsWUC)., Methods: This cross-sectional study, part of the 'CannTeen' project, compared adultsWUC (n = 71, 26-29 years old) and adolescentsWUC (n = 76, 16-17 years old), and gender- and age-matched adolescent (n = 63) and adult (n = 64) controls. AdolescentsWUC and adultsWUC used cannabis 1-7 days/week and were matched on cannabis use frequency (4 days/week). The Monetary Choice Questionnaire assessed delay discounting. A modified Marijuana Purchase Task (MPT) assessed cannabis demand in adolescentsWUC and adultsWUC. The MPT yielded five indices: intensity (amount of cannabis used at zero cost), O max (total peak expenditure), P max (price at peak expenditure), breakpoint (cost at which cannabis demand is suppressed to zero) and elasticity (degree to which cannabis use decreases with increasing price). Analyses were adjusted for covariates of gender, socioeconomic status, other illicit drug use., Results: Both adolescentsWUC and adultsWUC had steeper delay discounting than controls (F, (1,254)= 9.13, p = 0.003, η p 2 = 0.04), with no significant age effect or interaction. AdolescentsWUC showed higher intensity (F, (1,138)= 9.76, p = 0.002, η p 2 = 0.07) and lower elasticity (F, (1,138)= 15.25, p < 0.001, η p 2 = 0.10) than adultsWUC. There were no significant differences in P max , O max or breakpoint., Conclusion: Individuals who use cannabis prefer immediate rewards more than controls. AdolescentsWUC, compared to adultsWUC, may be in a high-risk category with diminished sensitivity to cannabis price increases and a greater consumption of cannabis when it is free., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit-safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. Methods: A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Findings: Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit-safety balances remain better than those of the noncannabinoid drugs. Interpretation: The benefit-safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.

Rationale: Acute alcohol consumption adversely affects many cognitive abilities, including episodic memory and executive functioning. However, no study to date has tested whether these acute effects of alcohol also extend to episodic future thinking (EFT). This is a surprising omission given that EFT refers to the ability to imagine oneself experiencing the future, a highly adaptive ability that has been implicated in many important functional behaviours. EFT is also thought to impose demands on episodic memory and executive control., Objectives: The current study was designed to provide the first test of whether a moderate dose of alcohol influences EFT and whether any observed EFT difficulties are secondary to broader problems in episodic memory and executive functioning. Sex differences in EFT following acute alcohol consumption were also examined., Methods: One hundred and twenty-four healthy adult social drinkers were recruited and randomly assigned to either the alcohol (n = 61) or placebo (n = 63) condition. Participants were administered a dose of 0.6 g/kg alcohol or a matched placebo drink., Results: Relative to the placebo condition, EFT was impaired by acute alcohol consumption. This impairment was underpinned by broader difficulties with episodic memory, but not executive functioning. There were no sex differences in EFT performance following acute alcohol use., Conclusion: These data provide novel insights into the effects of acute alcohol consumption on EFT and the broader cognitive mechanisms that contribute to these difficulties. The results are discussed in relation to their implications for understanding many of the maladaptive behaviours commonly associated with acute alcohol use., (© 2022. The Author(s).)

Background: Cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity., Aims: To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor)., Method: Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach., Results: Study 1 ( N  = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 ( N  = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks., Outcomes: THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

Background: The lack of an agreed international minimum approach to measuring cannabis use hinders the integration of multidisciplinary evidence on the psychosocial, neurocognitive, clinical and public health consequences of cannabis use., Methods: A group of 25 international expert cannabis researchers convened to discuss a multidisciplinary framework for minimum standards to measure cannabis use globally in diverse settings., Results: The expert-based consensus agreed upon a three-layered hierarchical framework. Each layer-universal measures, detailed self-report and biological measures-reflected different research priorities and minimum standards, costs and ease of implementation. Additional work is needed to develop valid and precise assessments., Conclusions: Consistent use of the proposed framework across research, public health, clinical practice and medical settings would facilitate harmonisation of international evidence on cannabis consumption, related harms and approaches to their mitigation., (© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Preclinical and human studies suggest that adolescent cannabis use may be associated with worse cognitive outcomes than adult cannabis use. We investigated the associations between chronic cannabis use and cognitive function in adolescent and adult cannabis users and controls. We hypothesised user-status would be negatively associated with cognitive function and this relationship would be stronger in adolescents than adults., Methods: As part of the 'CannTeen' project, this cross-sectional study assessed cognitive performance in adolescent cannabis users (n = 76; 16-17-year-olds), adolescent controls (n = 63), adult cannabis users (n = 71; 26-29-year-olds) and adult controls (n = 64). Users used cannabis 1-7 days/week. Adolescent and adult cannabis users were matched on cannabis use frequency (4 days/week) and time since last use (2.5 days). Verbal episodic memory (VEM) was assessed using the prose recall task, spatial working memory (SWM) was assessed using the spatial n-back task, and response inhibition was assessed with the stop-signal task. Primary outcome variables were: delayed recall, 3-back discriminability, and stop signal reaction time, respectively., Results: Users had worse VEM than controls (F(1,268) = 7.423, p = 0.007). There were no significant differences between user-groups on SWM or response inhibition. Null differences were supported by Bayesian analyses. No significant interactions between age-group and user-group were found for VEM, SWM, or response inhibition., Conclusions: Consistent with previous research, there was an association between chronic cannabis use and poorer VEM, but chronic cannabis use was not associated with SWM or response inhibition. We did not find evidence for heightened adolescent vulnerability to cannabis-related cognitive impairment., (© 2022. The Author(s).)

Background: Esketamine was licensed for use in treatment resistant depression by the European Medicines Agency in December 2019. It is unclear whether this new approval has lowered the risk perception of recreational ketamine use. This is important given a recent increase in recreational ketamine use., Methods: This study expanded on an existing longitudinal online study of the nightlife scene, by adding an additional longitudinal assessment as well as a new cross-sectional sample. Participants had to be aged 18-34 years, reside in the UK and have attended at least 6 electronic music events in the past year. The likelihood of increasing recreational ketamine use due to the approval, attitudes towards and risk perception of medical ketamine use and experiences resulting from recreational ketamine use were collected after the approval. Changes in ketamine use and frequency were assessed longitudinally before and after the approval., Results: The overall sample size was 2415: 414 longitudinal (57% retention rate) and 2001 new cross-sectional participants. The majority indicated no change in their likelihood of using recreational ketamine due to the approval of esketamine (87%). Longitudinal participants did not indicate an increase in past 12 month use or frequency after the approval. Only one-third of participants reported being aware of the approval. Participants previously aware showed greater overall support for medical use of ketamine than participants previously unaware of the change. However, an equally high risk was assigned to the recreational use of ketamine in both groups. Ketamine users indicated both increases as well as decreases in depression and anxiety as a result of ketamine use., Conclusion: The introduction of esketamine as an antidepressant was not associated with a change in the risk perception of recreational ketamine use in most participants, nor was it longitudinally associated with increased use. Potential negative effects of recreational ketamine use on mental health, as users in this sample reported, should be clearly communicated when discussing the benefits of (es-) ketamine in a therapeutic context., Competing Interests: Declarations of Interest HVC is also supported by grants from the UK MRC and by the National Institute for Health Research UCLH Biomedical Research Centre; she has consulted for Janssen Research and Development., (Copyright © 2022. Published by Elsevier B.V.)

Background: Ketamine as an antidepressant improves anhedonia as early as 2 hours after infusion. These drug effects are thought to be exerted via actions on reward-related brain areas-yet these actions remain largely unknown. Our study investigates ketamine's effects during the anticipation and receipt of an expected reward, after the psychotomimetic effects of ketamine have passed, when early antidepressant effects are reported., Methods: We examined ketamine's effects during the anticipation and receipt of expected rewards on predefined brain areas, namely, the dorsal and ventral striatum, ventral tegmental area, amygdala, and insula. We recruited 37 male and female participants with remitted depression who were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned 2 hours after drug administration in a double-blind crossover design (ketamine: 0.5 mg/kg and placebo) while performing a monetary reward task., Results: A significant main effect of ketamine was observed across all regions of interest during the anticipation and feedback phases of win and no-win trials. The drug effects were particularly prominent in the nucleus accumbens and putamen, which showed increased activation on the receipt of smaller rewards compared with neutral. The levels of (2R,6R)-hydroxynorketamine 2 hours after infusion significantly correlated with the activation observed in the ventral tegmental area for that contrast., Conclusions: These findings demonstrate that ketamine can produce detectable changes in reward-related brain areas 2 hours after infusion, which occur without symptom changes and support the idea that ketamine might improve reward-related symptoms via modulation of response to feedback., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Background: Incorporating 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy has shown promise in recent years for treating various mental health conditions, particularly those involving trauma. However, concerns about declines in mood and cognition during the days following dosing, also known as 'Blue Mondays', have been raised as limitations to its clinical use. Although these changes have been well-documented among recreational users, there are critical confounds to these reports that limit generalizability to clinically administered MDMA., Aims: Here, we aimed to evaluate the evidence basis for the negative side effects associated with MDMA as well as inform our understanding of the drug's post-acute effects in a clinical context with an open-label study., Methods: The current open-label study examined MDMA therapy for alcohol use disorder (AUD; N = 14) and measured mood, sleep quality, illicit MDMA consumption and anecdotal reports after the acute drug effects had worn off., Results: Participants maintained a positive mood during the week following drug administration in a clinical context. Relative to baseline, self-reported sleep quality improved at the 3- and 6-month follow-ups. Finally, no participants reported using or desiring to use illicit MDMA, and the anecdotal reports indicated that they perceived the treatment favourably., Conclusion: The results support the overall safety and tolerability of clinically administered MDMA and, importantly, suggest that the 'come downs' previously associated with the substance may be explained by confounds in research relating to the illicit sourcing of the drug and specific environmental setting for recreational consumption.

Objective: Early evidence suggests that ketamine may be an effective treatment to sustain abstinence from alcohol. The authors investigated the safety and efficacy of ketamine compared with placebo in increasing abstinence in patients with alcohol use disorder. An additional aim was to pilot ketamine combined with mindfulness-based relapse prevention therapy compared with ketamine and alcohol education as a therapy control., Methods: In a double-blind placebo-controlled phase 2 clinical trial, 96 patients with severe alcohol use disorder were randomly assigned to one of four conditions: 1) three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education. The primary outcomes were self-reported percentage of days abstinent and confirmed alcohol relapse at 6-month follow-up., Results: Ninety-six participants (35 women; mean age, 44.07 years [SD=10.59]) were included in the intention-to-treat analysis. The treatment was well tolerated, and no serious adverse events were associated with the study drug. Although confidence intervals were wide, consistent with a proof-of-concept study, there were a significantly greater number of days abstinent from alcohol in the ketamine group compared with the placebo group at 6-month follow-up (mean difference=10.1%, 95% CI=1.1, 19.0), with the greatest reduction in the ketamine plus therapy group compared with the saline plus education group (15.9%, 95% CI=3.8, 28.1). There was no significant difference in relapse rate between the ketamine and placebo groups., Conclusions: This study demonstrated that treatment with three infusions of ketamine was well tolerated in patients with alcohol use disorder and was associated with more days of abstinence from alcohol at 6-month follow-up. The findings suggest a possible beneficial effect of adding psychological therapy alongside ketamine treatment.