Persistent increased severity of cannabis use disorder symptoms in adolescents compared to adults: a one-year longitudinal study.

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.

Anhedonia, Apathy, Pleasure, and Effort-Based Decision-Making in Adult and Adolescent Cannabis Users and Controls.

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.

Apathy and Anhedonia in Adult and Adolescent Cannabis Users and Controls Before and During the COVID-19 Pandemic Lockdown.

BACKGROUND: COVID-19 lockdown measures have caused severe disruptions to work and education and prevented people from engaging in many rewarding activities. Cannabis users may be especially vulnerable, having been previously shown to have higher levels of apathy and anhedonia than non-users. METHODS: In this survey study, we measured apathy and anhedonia, before and after lockdown measures were implemented, in n = 256 adult and n = 200 adolescent cannabis users and n = 170 adult and n = 172 adolescent controls. Scores on the Apathy Evaluation Scale (AES) and Snaith-Hamilton Pleasure Scale (SHAPS) were investigated with mixed-measures ANCOVA, with factors user group, age group, and time, controlling for depression, anxiety, and other drug use. RESULTS: Adolescent cannabis users had significantly higher SHAPS scores before lockdown, indicative of greater anhedonia, compared with adolescent controls (P = .03, η p2 = .013). Contrastingly, adult users had significantly lower scores on both the SHAPS (P < .001, η p2 = .030) and AES (P < .001, η p2 = .048) after lockdown compared with adult controls. Scores on both scales increased during lockdown across groups, and this increase was significantly smaller for cannabis users (AES: P = .001, η p2 = .014; SHAPS: P = .01, η p2 = .008). Exploratory analyses revealed that dependent cannabis users had significantly higher scores overall (AES: P < .001, η p2 = .037; SHAPS: P < .001, η p2 = .029) and a larger increase in scores (AES: P = .04, η p2 =.010; SHAPS: P = .04, η p2 = .010), compared with non-dependent users. CONCLUSIONS: Our results suggest that adolescents and adults have differential associations between cannabis use as well as apathy and anhedonia. Within users, dependence may be associated with higher levels of apathy and anhedonia regardless of age and a greater increase in levels during the COVID-19 lockdown.

Acute effects of cannabis on speech illusions and psychotic-like symptoms: two studies testing the moderating effects of cannabidiol and adolescence.

BACKGROUND: Acute cannabis administration can produce transient psychotic-like effects in healthy individuals. However, the mechanisms through which this occurs and which factors predict vulnerability remain unclear. We investigate whether cannabis inhalation leads to psychotic-like symptoms and speech illusion; and whether cannabidiol (CBD) blunts such effects (study 1) and adolescence heightens such effects (study 2). METHODS: Two double-blind placebo-controlled studies, assessing speech illusion in a white noise task, and psychotic-like symptoms on the Psychotomimetic States Inventory (PSI). Study 1 compared effects of Cann-CBD (cannabis containing Δ-9-tetrahydrocannabinol (THC) and negligible levels of CBD) with Cann+CBD (cannabis containing THC and CBD) in 17 adults. Study 2 compared effects of Cann-CBD in 20 adolescents and 20 adults. All participants were healthy individuals who currently used cannabis. RESULTS: In study 1, relative to placebo, both Cann-CBD and Cann+CBD increased PSI scores but not speech illusion. No differences between Cann-CBD and Cann+CBD emerged. In study 2, relative to placebo, Cann-CBD increased PSI scores and incidence of speech illusion, with the odds of experiencing speech illusion 3.1 (95% CIs 1.3-7.2) times higher after Cann-CBD. No age group differences were found for speech illusion, but adults showed heightened effects on the PSI. CONCLUSIONS: Inhalation of cannabis reliably increases psychotic-like symptoms in healthy cannabis users and may increase the incidence of speech illusion. CBD did not influence psychotic-like effects of cannabis. Adolescents may be less vulnerable to acute psychotic-like effects of cannabis than adults.

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

Little 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.

Substance-Linked Sex in Heterosexual, Homosexual, and Bisexual Men and Women: An Online, Cross-Sectional "Global Drug Survey" Report.

INTRODUCTION: Substance use in sexual contexts has received recent attention, but it has mostly been restricted to men who have sex with men and the so-called "chemsex" phenomenon. AIM: To explore the use of licit and illicit substances in combination with sex in heterosexual, homosexual, and bisexual men and women; to explore substance-linked sex (SLS) differences across sexual orientation and sexes. METHODS: An international online self-selecting cross-sectional drugs survey, the Global Drug Survey 2013 (n = 22,289), was conducted. Respondents were asked about which drugs (including alcohol) they had had sex while on; how frequently they used drugs to enhance sex; and how different drugs changed different aspects of the sexual experience. We report descriptive statistics and test differences between men and women and between different sexual orientations. MAIN OUTCOME MEASURES: The following outcome measures were recorded: (i) Percentage of each group reporting last-year use of each drug with sex, (ii) Mean subjective rating (-10 to +10) from each group for each drug on each aspect of the sexual experience. RESULTS: SLS occurred across sexual orientations and in both men and women. All groups reported that alcohol, cannabis, and 3,4-methylenedioxymethamphetamine (MDMA) were the most while commonly used drugs with sex. Larger proportions of homosexual and bisexual men had sex while on most drugs than heterosexual men (P < .001); and larger proportions of bisexual women had sex while on most drugs than heterosexual women (P < .004). ≥20% of each group reported having used drugs with the intention of enhancing a sexual experience; larger proportions of homosexual and bisexual men reported this behavior than heterosexual men (P < .001). There were clear dissociations between the effects of different drugs on different aspects of the sexual experience; although γ-hydroxybutyric acid/γ-butyrolactone and MDMA were rated consistently highly. CLINICAL IMPLICATIONS: Men and women of different sexual orientations must be considered when forming harm reduction and treatment strategies. However, "chemsex" drugs were most commonly used by homosexual men; targeted messages to this group should continue. STRENGTH & LIMITATIONS: Our study is highly novel; no previous study has investigated the combination of sex with this range of drugs. However, our survey is self-selecting, and some groups have a small sample size. CONCLUSIONS: All groups reported SLS to some degree. However, differences in SLS between men and women and sexual orientations were found. Alcohol, cannabis, and MDMA were most commonly used with sex. "Chemsex" drugs were more commonly used by homosexual and bisexual men than heterosexual men. Lawn W, Aldridge A, Xia R, et al. Substance-Linked Sex in Heterosexual, Homosexual, and Bisexual Men and Women: An Online, Cross-Sectional "Global Drug Survey" Report. J Sex Med 2019;16:721-732.

Cannabis Dampens the Effects of Music in Brain Regions Sensitive to Reward and Emotion.

Background: Despite the current shift towards permissive cannabis policies, few studies have investigated the pleasurable effects users seek. Here, we investigate the effects of cannabis on listening to music, a rewarding activity that frequently occurs in the context of recreational cannabis use. We additionally tested how these effects are influenced by cannabidiol, which may offset cannabis-related harms. Methods: Across 3 sessions, 16 cannabis users inhaled cannabis with cannabidiol, cannabis without cannabidiol, and placebo. We compared their response to music relative to control excerpts of scrambled sound during functional Magnetic Resonance Imaging within regions identified in a meta-analysis of music-evoked reward and emotion. All results were False Discovery Rate corrected (P<.05). Results: Compared with placebo, cannabis without cannabidiol dampened response to music in bilateral auditory cortex (right: P=.005, left: P=.008), right hippocampus/parahippocampal gyrus (P=.025), right amygdala (P=.025), and right ventral striatum (P=.033). Across all sessions, the effects of music in this ventral striatal region correlated with pleasure ratings (P=.002) and increased functional connectivity with auditory cortex (right: P< .001, left: P< .001), supporting its involvement in music reward. Functional connectivity between right ventral striatum and auditory cortex was increased by cannabidiol (right: P=.003, left: P=.030), and cannabis with cannabidiol did not differ from placebo on any functional Magnetic Resonance Imaging measures. Both types of cannabis increased ratings of wanting to listen to music (P<.002) and enhanced sound perception (P<.001). Conclusions: Cannabis dampens the effects of music in brain regions sensitive to reward and emotion. These effects were offset by a key cannabis constituent, cannabidol.

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

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.

Assessing Cannabis Use in People with Psychosis.

Introduction: Cannabis use is common in people with psychotic disorders and is associated with the exacerbation of symptoms, poor treatment adherence, and an increased risk of relapse. Accurate assessment of cannabis use is thus critical to the clinical management of psychosis. Discussion: Cannabis use is usually assessed with self-report questionnaires that were originally developed for healthy individuals or people with a cannabis use disorder. Compared to these groups, the pattern of cannabis use and the associated harms in patients with psychosis are quite different. Moreover, in people with psychosis, the accuracy of self-reported use may be impaired by psychotic symptoms, cognitive deficits, and a desire to conceal use when clinicians have advised against it. Although urinary screening for delta-9-tetrahydrocannabinol is sometimes used in the assessment of acute psychotic episodes, it is not used in routinely. Cannabis use could be assessed by measuring the concentration of cannabinoids in urine and blood, but this is rarely done in either clinical settings or research. Conclusion: Using quantitative biological measures could provide a more accurate guide to the effects of use on the disorder than asking patients or using questionnaires.

What impacts the acceptability of wearable devices that detect opioid overdose in people who use opioids? A qualitative study.

INTRODUCTION: Drug-related deaths involving an opioid are at all-time highs across the United Kingdom. Current overdose antidotes (naloxone) require events to be witnessed and recognised for reversal. Wearable technologies have potential for remote overdose detection or response but their acceptability among people who use opioids (PWUO) is not well understood. This study explored facilitators and barriers to wearable technology acceptability to PWUO. METHODS: Twenty-four participants (79% male, average age 46 years) with current (n = 15) and past (n = 9) illicit heroin use and 54% (n = 13) who were engaged in opioid substitution therapy participated in semi-structured interviews (n = 7) and three focus groups (n = 17) in London and Nottingham from March to June 2022. Participants evaluated real devices, discussing characteristics, engagement factors, target populations, implementation strategies and preferences. Conversations were recorded, transcribed and thematically analysed. RESULTS: Three themes emerged: device-, person- and environment-specific factors impacting acceptability. Facilitators included inconspicuousness under the device theme and targeting subpopulations of PWUO at the individual theme. Barriers included affordability of devices and limited technology access within the environment theme. Trust in device accuracy for high and overdose differentiation was a crucial facilitator, while trust between technology and PWUO was a significant environmental barrier. DISCUSSION AND CONCLUSIONS: Determinants of acceptability can be categorised into device, person and environmental factors. PWUO, on the whole, require devices that are inconspicuous, comfortable, accessible, easy to use, controlled by trustworthy organisations and highly accurate. Device developers must consider how the type of end-user and their environment moderate acceptability of the device.

Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks.

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.

Enhanced cannabis timeline followback (EC-TLFB): Comprehensive assessment of cannabis use including standard THC units and validation through biological measures.

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).

The acute effects of cannabis, with and without cannabidiol, on attentional bias to cannabis related cues: a randomised, double-blind, placebo-controlled, cross-over study.

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, η2p = 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.

A scoping review of mHealth technologies for opioid overdose prevention, detection and response.

ISSUES: Opioid overdose kills over 100,000 people each year globally. Mobile health (mHealth) technologies and devices, including wearables, with the capacity to prevent, detect or respond to opioid overdose exist in early form, or could be re-purposed or designed. These technologies may particularly help those who use alone. For technologies to be successful, they must be effective and acceptable to the at-risk population. The aim of this scoping review is to identify published studies on mHealth technologies that attempt to prevent, detect or respond to opioid overdose. APPROACH: A systematic scoping review of literature was conducted up to October 2022. APA PsychInfo, Embase, Web of Science and Medline databases were searched. INCLUSION CRITERIA: articles had to report on (i) mHealth technologies that deal with (ii) opioid (iii) overdose. KEY FINDINGS: A total of 348 records were identified, with 14 studies eligible for this review across four domains: (i) technologies that require intervention/response from others (four); (ii) devices that use biometric data to detect overdose (five); (iii) devices that automatically respond to an overdose with administration of an antidote (three); (iv) acceptability/willingness to use overdose-related technologies/devices (five). IMPLICATIONS: There are multiple routes in which these technologies may be deployed, but several factors impact acceptability (e.g., discretion or size) and accuracy of detection (e.g., sensitive parameter/threshold with low false positive rate). CONCLUSION: mHealth technologies for opioid overdose may play a crucial role in responding to the ongoing global opioid crises. This scoping review identifies vital research that will determine the future success of these technologies.

The acute effects of cannabis with and without cannabidiol in adults and adolescents: A randomised, double-blind, placebo-controlled, crossover experiment.

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 [BF01 ] >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.

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults.

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.

The Effects of Acute Cannabis With and Without Cannabidiol on Neural Reward Anticipation in Adults and Adolescents.

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.

Clinical outcome data of anxiety patients treated with cannabis-based medicinal products in the United Kingdom: a cohort study from the UK Medical Cannabis Registry.

RATIONALE: Cannabis-based medicinal products (CBMPs) have been identified as novel therapeutics for generalised anxiety disorder (GAD) based on pre-clinical models; however, there is a paucity of high-quality evidence on their effectiveness and safety. OBJECTIVES: This study aimed to evaluate the clinical outcomes of patients with GAD treated with dried flower, oil-based preparations, or a combination of both CBMPs. METHODS: A prospective cohort study of patients with GAD (n = 302) enrolled in the UK Medical Cannabis Registry prescribed oil or flower-based CBMPs was performed. Primary outcomes were changes in generalised anxiety disorder-7 (GAD-7) questionnaires at 1, 3, and 6 months compared to baseline. Secondary outcomes were single-item sleep quality scale (SQS) and health-related quality of life index (EQ-5D-5L) questionnaires at the same time points. These changes were assessed by paired t-tests. Adverse events were assessed in line with CTCAE (Common Terminology Criteria for Adverse Events) v4.0. RESULTS: Improvements in anxiety, sleep quality and quality of life were observed at each time point (p < 0.001). Patients receiving CBMPs had improvements in GAD-7 at all time points (1 month: difference -5.3 (95% CI -4.6 to -6.1), 3 months: difference -5.5 (95% CI -4.7 to -6.4), 6 months: difference -4.5 (95% CI -3.2 to -5.7)). Thirty-nine participants (12.9%) reported 269 adverse events in the follow-up period. CONCLUSIONS: Prescription of CBMPs in those with GAD is associated with clinically significant improvements in anxiety with an acceptable safety profile in a real-world setting. Randomised trials are required as a next step to investigate the efficacy of CBMPs.

The CannTeen Study: Cannabis use disorder, depression, anxiety, and psychotic-like symptoms in adolescent and adult cannabis users and age-matched controls.

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.

Neural responses to reward anticipation and feedback in adult and adolescent cannabis users and controls.

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.