AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers.

This is the final version of the article. Available from Springer Nature via the DOI in this record.Smoking cannabis daily doubles an individual's risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual's acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis-which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content-and also ± 7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis.This research was funded by grants to HVC and CJAM from the Medical Research Council UK (G0800268/P4844; MRCL023032/1)

Impaired empathy and increased anger following social exclusion in non-intoxicated opioid users

This is the final version. Available from Springer Verlag via the DOI in this record.Rationale: Social functioning is modulated by the endogenous opioid system. In opioid use disorder, social functioning appears disrupted, but little research has delineated the nature of these deficits and their relationship to acute opioid use. Objectives: The current study aimed to assess both emotional and cognitive empathy, along with subjective and physiological responses to social exclusion in opioid users who were either acutely intoxicated or non-intoxicated from using opioids. Methods: Individuals on an opioid substitution medication (OSM) were divided into ‘intoxicated users’ (had taken their OSM the same day as testing, n = 20) and ‘non-intoxicated users’ (had taken their OSM > 12 h ago, n = 20) and compared with opioid-naïve controls (n = 24). Empathy was assessed using the multifaceted empathy test and self-report questionnaire. Participants also underwent a period of social exclusion (Cyberball Game) and completed measures of mood and physiological responses (salivary cortisol and heart rate). Results: Non-intoxicated users had significantly lower emotional empathy (the ability to experience others’ emotions), as well as greater anger after social exclusion when compared with the intoxicated users and controls. Anger did not change with social exclusion in the intoxicated user group and cortisol levels were lower overall. Conclusions: Reduced ability to spontaneously share the emotions of others was reported in non-intoxicated users, particularly regarding positive emotions. There was some support for the idea of hyperalgesia to social pain, but this was restricted to an enhanced anger response in non-intoxicated users. Equivalent rates of empathy between the intoxicated users and controls could indicate some remediating effects of acute opioids.University of Exete

Acute effects of cannabinoids on addiction endophenotypes are moderated by genes encoding the CB1 receptor and FAAH enzyme

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordUnderstanding genetic factors that contribute to cannabis use disorder (CUD) is important, but to date, findings have been equivocal. Single-nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 gene (CNR1; rs1049353 and rs806378) and fatty acid amide hydrolase (FAAH) gene (rs324420) have been implicated in CUD. Their relationship to addiction endophenotypes such as cannabis-related state satiety, the salience of appetitive cues, and craving after acute cannabinoid administration has not been investigated. Forty-eight cannabis users participated in a double-blind, placebo-controlled, four-way crossover experiment where they were administered treatments in a randomized order via vaporization: placebo, Δ 9 -tetrahydrocannabinol (THC) (8 mg), THC + cannabidiol (THC + CBD) (8 + 16 mg), and CBD (16 mg). Cannabis-related state satiety, appetitive cue salience (cannabis and food), and cannabis craving were assessed each day. Participants were genotyped for rs1049353, rs806378, and rs324420. Results indicated that CNR1 rs1049353 GG carriers showed increased state satiety after THC/THC + CBD administration in comparison with placebo and reduced the salience of appetitive cues after THC in comparison with CBD administration; A carriers did not vary on either of these measures indicative of a vulnerability to CUD. CNR1 rs806378 CC carriers showed greater salience to appetitive cues in comparison with T carriers, but there was no evidence for changes in state satiety. FAAH rs324420 A carriers showed greater bias to appetitive cues after THC, in comparison with CC carriers. FAAH CC carriers showed reduced bias after THC in comparison with CBD. No SNPs modulated craving. These findings identify candidate neurocognitive mechanisms through which endocannabinoid system genetics may influence vulnerability to CUD.Medical Research Council (MRC)Economic and Social Research Council (ESRC)Society for the Study of AddictionBritish Medical Association Foundation for Medical ResearchUCLNational Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC

The Acute Effects of a Dopamine D3 Receptor Preferring Agonist on Motivation for Cigarettes in Dependent and Occasional Cigarette Smokers.

This is the final version of the article. Available from OUP via the DOI in this record.Background: Dopaminergic functioning is thought to play critical roles in both motivation and addiction. There is preliminary evidence that dopamine agonists reduce the motivation for cigarettes in smokers. However, the effects of pramipexole, a dopamine D3 receptor preferring agonist, have not been investigated. The aim of this study was to examine the effects of an acute dose of pramipexole on the motivation to earn cigarettes and nondrug rewards. Methods: Twenty dependent and 20 occasional smokers received 0.5 mg pramipexole using a double-blind, placebo-controlled crossover design. Motivation for cigarettes and consummatory nondrug rewards was measured using the DReaM-Choice task, in which participants earned, and later "consumed," cigarettes, music, and chocolate. Demand for cigarettes was measured using the Cigarette Purchase Task (CPT). Self-reported craving, withdrawal, and drug effects were also recorded. Results: Dependent smokers chose (p < .001) and button-pressed for (p < .001) cigarettes more, and chose chocolate less (p < .001), than occasional smokers. Pramipexole did not affect the number of choices for or amount of button-pressing for any reward including cigarettes, which was supported by a Bayesian analysis. The dependent smokers had greater demand for cigarettes than occasional smokers across all CPT outcomes (ps < .021), apart from elasticity. Pramipexole did not affect demand for cigarettes, and this was supported by Bayesian analyses. Pramipexole produced greater subjective "feel drug" and "dislike drug" effects than placebo. Conclusions: Dependent and occasional cigarette smokers differed in their motivation for cigarettes but not for the nondrug rewards. Pramipexole did not acutely alter motivation for cigarettes. These findings question the role of dopamine D3 receptors in cigarette-seeking behavior in dependent and occasional smokers. Implications: This study adds to the growing literature about cigarette versus nondrug reward processing in nicotine dependence and the role of dopamine in cigarette-seeking behavior. Our results suggest nicotine dependence is associated with a hypersensitivity to cigarette rewards but not a hyposensitivity to nondrug rewards. Furthermore, our results question the importance of dopamine D3 receptors in motivational processing of cigarettes in occasional and dependent smokers.This study was funded by BBSRC PhD funding

Value-based decision-making of cigarette and nondrug rewards in dependent and occasional cigarette smokers: An FMRI study

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordLittle is known about the neural functioning that underpins drug valuation and choice in addiction, including nicotine dependence. Following ad libitum smoking, 19 dependent smokers (smoked≥10/day) and 19 occasional smokers (smoked 0.5-5/week) completed a decision-making task. First, participants stated how much they were willing-to-pay for various amounts of cigarettes and shop vouchers. Second, during functional magnetic resonance imaging, participants decided if they wanted to buy these cigarettes and vouchers for a set amount of money. We examined decision-making behaviour and brain activity when faced with cigarette and voucher decisions, purchasing (vs not purchasing) cigarettes and vouchers, and “value signals” where brain activity correlated with cigarette and voucher value. Dependent smokers had a higher willingness-to-pay for cigarettes and greater activity in the bilateral middle temporal gyrus when faced with cigarette decisions than occasional smokers. Across both groups, the decision to buy cigarettes was associated with activity in the left paracingulate gyrus, right nucleus accumbens, and left amygdala. The decision to buy vouchers was associated with activity in the left superior frontal gyrus, but dependent smokers showed weaker activity in the left posterior cingulate gyrus than occasional smokers. Across both groups, cigarette value signals were observed in the left striatum and ventromedial prefrontal cortex. To summarise, nicotine dependence was associated with greater behavioural valuation of cigarettes and brain activity during cigarette decisions. When purchasing cigarettes and vouchers, reward and decision-related brain regions were activated in both groups. For the first time, we identified value signals for cigarettes in the brain.Biotechnology and Biological Sciences Research Council (BBSRC)Medical Research Council (MRC)Society for the Study of AddictionUniversity College London, National Institute of Health Research Biomedical Research Centr

Enhancement drugs: are there limits to what we should enhance and why?

Substances, such as alcohol, opiates and cannabis, have been used by humans for millennia. Today, a much wider range of substances are used for a range of purposes, including the enhancement of performance during university studies, sexual experiences, sports, exercise, at celebrations, socializing and the experience of art and music. Substance use is also associated with a range of harmful effects to the individual and society as a whole. Prohibitions, regulation, prevention and treatment have all been used to protect against this harm. In this commentary, it is argued that public health interventions should target relevant harms and not to evaluate which aspects of human endeavors and experiences should be enhanced and which should not. It is argued that interventions should directly target the harmful effects, using the best available evidence. Two examples are given of substances that may be altered to prevent serious harm - one for alcohol and one for cannabis. In the case of alcohol, the addition of dissolved oxygen could reduce both the risk of accidents and the risk of liver damage associated with alcohol consumption. In the case of cannabis, there is strong indication that the reduction of content Δ-tetrahydrocannabinol and the increase of cannabidiol could reduce the risk of psychoses and the addiction associated with its use. The aim of this article is to show that responsible regulation should not necessarily be restricted to preventing the use and/or (in the case of alcohol) a reduction in the amounts and frequency of its use, but should also aim to include a range of other strategies that could reduce the burden of illness associated with illicit substance use

Which biological and self-report measures of cannabis use predict cannabis dependency and acute psychotic-like effects?

BACKGROUND: Changes in cannabis regulation globally make it increasingly important to determine what predicts an individual's risk of experiencing adverse drug effects. Relevant studies have used diverse self-report measures of cannabis use, and few include multiple biological measures. Here we aimed to determine which biological and self-report measures of cannabis use predict cannabis dependency and acute psychotic-like symptoms. METHOD: In a naturalistic study, 410 young cannabis users were assessed once when intoxicated with their own cannabis and once when drug-free in counterbalanced order. Biological measures of cannabinoids [(Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN) and their metabolites)] were derived from three samples: each participant's own cannabis (THC, CBD), a sample of their hair (THC, THC-OH, THC-COOH, CBN, CBD) and their urine (THC-COOH/creatinine). Comprehensive self-report measures were also obtained. Self-reported and clinician-rated assessments were taken for cannabis dependency [Severity of Dependence Scale (SDS), DSM-IV-TR] and acute psychotic-like symptoms [Psychotomimetic State Inventory (PSI) and Brief Psychiatric Rating Scale (BPRS)]. RESULTS: Cannabis dependency was positively associated with days per month of cannabis use on both measures, and with urinary THC-COOH/creatinine for the SDS. Acute psychotic-like symptoms were positively associated with age of first cannabis use and negatively with urinary THC-COOH/creatinine; no predictors emerged for BPRS. CONCLUSIONS: Levels of THC exposure are positively associated with both cannabis dependency and tolerance to the acute psychotic-like effects of cannabis. Combining urinary and self-report assessments (use frequency; age first used) enhances the measurement of cannabis use and its association with adverse outcomes

Which biological and self-report measures of cannabis use predict cannabis dependency and acute psychotic-like effects?

This is the final version. Available from the publisher via the DOI in this record.BACKGROUND: Changes in cannabis regulation globally make it increasingly important to determine what predicts an individual's risk of experiencing adverse drug effects. Relevant studies have used diverse self-report measures of cannabis use, and few include multiple biological measures. Here we aimed to determine which biological and self-report measures of cannabis use predict cannabis dependency and acute psychotic-like symptoms. METHOD: In a naturalistic study, 410 young cannabis users were assessed once when intoxicated with their own cannabis and once when drug-free in counterbalanced order. Biological measures of cannabinoids [(Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN) and their metabolites)] were derived from three samples: each participant's own cannabis (THC, CBD), a sample of their hair (THC, THC-OH, THC-COOH, CBN, CBD) and their urine (THC-COOH/creatinine). Comprehensive self-report measures were also obtained. Self-reported and clinician-rated assessments were taken for cannabis dependency [Severity of Dependence Scale (SDS), DSM-IV-TR] and acute psychotic-like symptoms [Psychotomimetic State Inventory (PSI) and Brief Psychiatric Rating Scale (BPRS)]. RESULTS: Cannabis dependency was positively associated with days per month of cannabis use on both measures, and with urinary THC-COOH/creatinine for the SDS. Acute psychotic-like symptoms were positively associated with age of first cannabis use and negatively with urinary THC-COOH/creatinine; no predictors emerged for BPRS. CONCLUSIONS: Levels of THC exposure are positively associated with both cannabis dependency and tolerance to the acute psychotic-like effects of cannabis. Combining urinary and self-report assessments (use frequency; age first used) enhances the measurement of cannabis use and its association with adverse outcomes

The effects of cannabidiol on impulsivity and memory during abstinence in cigarette dependent smokers

This is the final version of the article. Available from Springer Nature via the DOI in this record.The dataset generated during the current study are available from the corresponding author on reasonable request.Acute nicotine abstinence in cigarette smokers results in deficits in performance on specific cognitive processes, including working memory and impulsivity which are important in relapse. Cannabidiol (CBD), the non-intoxicating cannabinoid found in cannabis, has shown pro-cognitive effects and preliminary evidence has indicated it can reduce the number of cigarettes smoked in dependent smokers. However, the effects of CBD on cognition have never been tested during acute nicotine withdrawal. The present study therefore aimed to investigate if CBD can improve memory and reduce impulsivity during acute tobacco abstinence. Thirty, non-treatment seeking, dependent, cigarette smokers attended two laboratory-based sessions after overnight abstinence, in which they received either 800 mg oral CBD or placebo (PBO), in a randomised order. Abstinence was biologically verified. Participants were assessed on go/no-go, delay discounting, prose recall and N-back (0-back, 1-back, 2-back) tasks. The effects of CBD on delay discounting, prose recall and the N-back (correct responses, maintenance or manipulation) were null, confirmed by a Bayesian analysis, which found evidence for the null hypothesis. Contrary to our predictions, CBD increased commission errors on the go/no-go task. In conclusion, a single 800 mg dose of CBD does not improve verbal or spatial working memory, or impulsivity during tobacco abstinence.This research was funded by a PhD Studentship from the Medical Research Council (MRC) to the C.H. and an MRC DPFS award (MR/K015524/1) to HVC and CJAM.TPF is funded by a Senior Academic Fellowship from the Society for the Study of Addiction

Do AKT1, COMT and FAAH influence reports of acute cannabis intoxication experiences in patients with first episode psychosis, controls and young adult cannabis users?

This is the final version. Available from the publisher via the DOI in this record.Epidemiological and biological evidence support the association between heavy cannabis use and psychosis. However, it is unclear which cannabis users are susceptible to its psychotogenic effect. Therefore, understanding genetic factors contributing to this relationship might prove an important strategy to identify the mechanisms underlying cannabis-associated psychotic experiences. We aimed to determine how variation in AKT1, COMT and FAAH genotypes, and their interaction with three different groups (first episode psychosis (FEP) patients (n = 143), controls (n = 92) and young adult (YA) cannabis users n = 485)) influenced cannabis experiences, in those who had used cannabis at least once. We investigated the role of AKT1 (rs2494732), COMT Val158Met (rs4680) and FAAH (rs324420) on cannabis experiences by combining data from a large case-control study of FEP patients, with a naturalistic study of YA cannabis users (n = 720). Outcome measures were cannabis-induced psychotic-like experiences (cPLEs) and euphoric experiences (cEEs). We used linear mixed effects models to assess the effects of each genotype and their interaction with group, adjusting for age, sex, ethnicity, age of first cannabis use, years of use and frequency. cPLEs were more frequent in FEP patients than controls and YA cannabis users. cEEs were more prevalent in YA cannabis users than FEP patients or controls. Variation in AKT1, COMT or FAAH was not associated with cPLEs/cEEs. There was no interaction between genotype and group (FEP cases, controls and YA cannabis users) on cPLEs/cEEs. In conclusion, AKT1, COMT or FAAH did not modulate specific psychotomimetic response to cannabis and did not interact with group, contrary to previous research.Medical Research Council (MRC