Delta-9-tetrahydrocannabinol intoxication is associated with increased prefrontal activation as assessed with functional near-infrared spectroscopy: A report of a potential biomarker of intoxication.

The primary psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), binds to cannabinoid receptors (CB1) present in high concentrations in the prefrontal cortex (PFC). It is unknown whether the PFC hemodynamic response changes with THC intoxication. We conducted the first double-blind, placebo-controlled, cross-over study of the effect of THC intoxication on functional near infrared spectroscopy (fNIRS) measures of PFC activation. Fifty-four adult, regular (at least weekly) cannabis users received a single oral dose of synthetic THC (dronabinol; 5-50 mg, dose individually tailored to produce intoxication) and identical placebo on two visits at least one week apart. fNIRS recordings were obtained during a working memory task (N-Back) at three timepoints: before THC/placebo, at 100 min (when peak effects were expected), and at 200 min after THC/placebo administration. Functional data were collected using a continuous-wave NIRS device, with 8 sources and 7 detectors arrayed over the forehead, resulting in 20 channels covering PFC regions. Participants also completed frequent heart rate measures and subjective ratings of intoxication. Approximately half of participants reported significant intoxication. Intoxication ratings were not correlated with dose of THC. Increases in heart rate significantly correlated with intoxication ratings after THC dosing. Results indicated that 100 min after THC administration, oxygenated hemoglobin (HbO) response significantly increased from pre-dose HbO levels throughout the PFC in participants who reported significant intoxication. Changes in HbO response significantly correlated with self-reported intoxication at 100 min after THC administration. Among those who reported intoxication, HbO response decreased at 200 min after THC, when intoxication had largely resolved, compared to the peak THC time point. This study demonstrates that THC intoxication causes increased PFC activity, and fNIRS of the PFC can measure this effect. Increased neural activation in PFC represents a potential biomarker for cannabis intoxication.

Marijuana use and major depressive disorder are additively associated with reduced verbal learning and altered cortical thickness.

Marijuana (MJ) use and major depressive disorder (MDD) have both been associated with deficits in verbal learning and memory as well as structural brain abnormalities. It is not known if MJ use by those with MDD confers additional impairment. The goal of this study was to examine unique and combined effects of MDD and MJ use on verbal memory and brain structure. Young adults (n=141) aged 18-25 years with MJ use and no lifetime MDD (MJ, n=46), MDD and no MJ use (MDD, n=23), MJ use and lifetime MDD (MDD+MJ, n=24), and healthy controls without MDD or MJ use (CON, n=48) were enrolled. Participants completed the California Verbal Learning Test, Second Edition (CVLT-II), a measure of verbal learning and memory. A sub-sample of 82 participants also underwent a structural magnetic resonance imaging (MRI) scan. Group differences in CVLT-II performance, cortical thickness, and hippocampal volume were assessed. We found an additive effect of MDD and MJ on memory recall. Only MDD, but not MJ, was associated with poorer initial learning, fewer words recalled, more intrusion errors, and lower percent retention. There was also an additive effect of MDD and MJ use on reduced cortical thickness in the middle temporal gyrus. Findings indicate that MJ use and MDD have additive adverse associations with verbal recall and cortical thickness in the middle temporal gyrus, suggesting that MJ use among those with MDD may be contraindicated. Prospective studies are warranted to determine whether this association may be causal.

Neural mechanisms of sensitivity to peer information in young adult cannabis users.

Though social influence is a critical factor in the initiation and maintenance of marijuana use, the neural correlates of influence in those who use marijuana are unknown. In this study, marijuana-using young adults (MJ; n = 20) and controls (CON; n = 23) performed a decision-making task in which they made a perceptual choice after viewing the choices of unknown peers via photographs, while they underwent functional magnetic resonance imaging scans. The MJ and CON groups did not show differences in the overall number of choices that agreed with versus opposed group influence, but only the MJ group showed reaction time slowing when deciding against group choices. Longer reaction times were associated with greater activation of frontal regions. The MJ goup, compared to CON, showed significantly greater activation in the caudate when presented with peer information. Across groups, caudate activation was associated with self-reported susceptibility to influence. These findings indicate that young adults who use MJ may exhibit increased effort when confronted with opposing peer influence, as well as exhibit greater responsivity of the caudate to social information. These results not only better define the neural basis of social decisions, but also suggest that marijuana use is associated with exaggerated neural activity during decision making that involves social information.

Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.

Marijuana is the most commonly used illicit drug in the United States, but little is known about its effects on the human brain, particularly on reward/aversion regions implicated in addiction, such as the nucleus accumbens and amygdala. Animal studies show structural changes in brain regions such as the nucleus accumbens after exposure to Δ9-tetrahydrocannabinol, but less is known about cannabis use and brain morphometry in these regions in humans. We collected high-resolution MRI scans on young adult recreational marijuana users and nonusing controls and conducted three independent analyses of morphometry in these structures: (1) gray matter density using voxel-based morphometry, (2) volume (total brain and regional volumes), and (3) shape (surface morphometry). Gray matter density analyses revealed greater gray matter density in marijuana users than in control participants in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, sublenticular extended amygdala, and left amygdala, even after controlling for age, sex, alcohol use, and cigarette smoking. Trend-level effects were observed for a volume increase in the left nucleus accumbens only. Significant shape differences were detected in the left nucleus accumbens and right amygdala. The left nucleus accumbens showed salient exposure-dependent alterations across all three measures and an altered multimodal relationship across measures in the marijuana group. These data suggest that marijuana exposure, even in young recreational users, is associated with exposure-dependent alterations of the neural matrix of core reward structures and is consistent with animal studies of changes in dendritic arborization.

Cannabis-related episodic memory deficits and hippocampal morphological differences in healthy individuals and schizophrenia subjects.

Cannabis use has been associated with episodic memory (EM) impairments and abnormal hippocampus morphology among both healthy individuals and schizophrenia subjects. Considering the hippocampus' role in EM, research is needed to evaluate the relationship between cannabis-related hippocampal morphology and EM among healthy and clinical groups. We examined differences in hippocampus morphology between control and schizophrenia subjects with and without a past (not current) cannabis use disorder (CUD). Subjects group-matched on demographics included 44 healthy controls (CON), 10 subjects with a CUD history (CON-CUD), 28 schizophrenia subjects with no history of substance use disorders (SCZ), and 15 schizophrenia subjects with a CUD history (SCZ-CUD). Large-deformation, high-dimensional brain mapping with MRI produced surface-based representations of the hippocampus that were compared across all four groups and correlated with EM and CUD history. Surface maps of the hippocampus were generated to visualize morphological differences. CON-CUD and SCZ-CUD were characterized by distinct cannabis-related hippocampal shape differences and parametric deficits in EM performance. Shape differences observed in CON-CUD were associated with poorer EM performance, while shape differences observed in SCZ-CUD were associated with a longer duration of CUD and shorter duration of CUD remission. A past history of CUD may be associated with notable differences in hippocampal morphology and EM impairments among adults with and without schizophrenia. Although the results may be compatible with a causal hypothesis, we must consider that the observed cannabis-related shape differences in the hippocampus could also be explained as biomarkers of a neurobiological susceptibility to poor memory or the effects of cannabis.

Cumulative gains enhance striatal response to reward opportunities in alcohol-dependent patients.

Substance use disorder is characterized by a transition from volitional to compulsive responding for drug reward. A possible explanation for this transition may be that alcohol-dependent patients (ADP) show a general propensity for a history of rewarded instrumental responses, and these rewarded responses may boost the activation of motivational neurocircuitry for additional reward. Brain imaging studies of decision-making have demonstrated that ADP relative to controls (CON) often show altered neural activation in response to anticipating and receiving rewards, but the majority of studies have not investigated how past performance affects activation. A potential exists for ADP to show increased sensitivity to reward as a function of reward delivery history. In the current study, we used functional magnetic resonance imaging to investigate the neural correlates of risky decision-making in ADP (n = 18) and CON (n = 18) while they played a two-choice monetary risk-taking game. In addition to investigating general neural recruitment by risky decision-making, we also modeled each participant's running total of monetary earnings in order to determine areas of activation that correlated with cumulative reward. We found that ADP and CON showed few differences in behavior or in mesolimbic activation by choice for, and receipt of, risky gains. However, when including a cumulative-earnings covariate, ADP exhibited heightened striatal activation that correlated with total earnings during the choice event in the task. The heightened contextual sensitivity of striatal responses to cumulative earnings in ADP may represent a general neurobiological affective substrate for development of automatized instrumental behavior.

The Developmental Timing but Not Magnitude of Adolescent Risk-Taking Propensity Is Consistent Across Social, Environmental, and Psychological Factors.

PURPOSE: Risk-taking is thought to peak during adolescence, but most prior studies have relied on small convenience samples lacking participant diversity. This study tested the generalizability of adolescent self-reported risk-taking propensity across a comprehensive set of participant-level social, environmental, and psychological factors. METHODS: Data (N = 1,005,421) from the National Survey on Drug Use and Health were used to test the developmental timing and magnitude of risk-taking propensity and its link to alcohol and cannabis use across 19 subgroups defined via sex, race/ethnicity, socioeconomic status, population density, religious affiliation, and mental health. RESULTS: The developmental timing of a lifespan peak in risk-taking propensity during adolescence (15-18 years old) generalized across nearly all levels of social, environmental, and psychological factors, whereas the magnitude of this peak widely varied. Nearly all adolescents with regular substance use reported higher levels of risk-taking propensity. DISCUSSION: Results support a broad generalizability of adolescence as the peak lifespan period of self-reported risk-taking but emphasize the importance of participant-level factors in determining the specific magnitude of reported risk-taking.

Intoxication due to Δ9-tetrahydrocannabinol is characterized by disrupted prefrontal cortex activity.

Neural states of impairment from intoxicating substances, including cannabis, are poorly understood. Cannabinoid 1 receptors, the main target of Δ9-tetrahydrocannabinol (THC), the primary intoxicating cannabinoid in cannabis, are densely localized within prefrontal cortex; therefore, prefrontal brain regions are key locations to examine brain changes that characterize acute intoxication. We conducted a double-blind, randomized, cross-over study in adults, aged 18-55 years, who use cannabis regularly, to determine the effects of acute intoxication on prefrontal cortex resting-state measures, assessed with portable functional near-infrared spectroscopy. Participants received oral THC (10-80 mg, individually dosed to overcome tolerance and achieve acute intoxication) and identical placebo, randomized for order; 185 adults were randomized and 128 completed both study days and had usable data. THC was associated with expected increases in subjective intoxication ratings (ES = 35.30, p < 0.001) and heart rate (ES = 11.15, p = 0.001). THC was associated with decreased correlations and anticorrelations in static resting-state functional connectivity within the prefrontal cortex relative to placebo, with weakest correlations and anticorrelations among those who reported greater severity of intoxication (RSFC between medial PFC-ventromedial PFC and DEQ scores, r = 0.32, p < 0.001; RSFC between bilateral mPFC and DEQ scores, r = -0.28, p = 0.001). Relative to placebo, THC was associated with increased variability (or reduced stability) in dynamic resting-state functional connectivity of the prefrontal cortex at p = 0.001, consistent across a range of window sizes. Finally, using frequency power spectrum analyses, we observed that relative to placebo, THC was associated with widespread reduced spectral power within the prefrontal cortex across the 0.073-0.1 Hz frequency range at p < 0.039. These neural features suggest a disruptive influence of THC on the neural dynamics of the prefrontal cortex and may underlie cognitive impairing effects of THC that are detectable with portable imaging. This study is registered in Clinicaltrials.gov (NCT03655717).

Contingency management is associated with positive changes in attitudes and reductions in cannabis use even after discontinuation of incentives among non-treatment seeking youth.

BACKGROUND: It is important to identify interventions that reduce harm in youth not motivated to change their cannabis use. This study evaluated how short-duration contingency management (CM) impacts cannabis use attitudes and behavior after abstinence incentives are discontinued among non-treatment seeking youth. METHODS: Participants (N=220) were randomized to 4 weeks of abstinence-based CM (CB-Abst; n=126) or monitoring (CB-Mon; n=94). Participants completed self-report and provided biochemical measures of cannabis exposure at baseline, end-of-intervention, and 4-week follow-up. Changes in self-reported cannabis use frequency (days/week; times/week) and biochemically verified creatinine-adjusted 11-nor-9-carboxy-tetrahydrocannabinol concentrations (CN-THCCOOH) were analyzed between groups from baseline to follow-up. In CB-Abst, cannabis use goals at end-of-intervention were described and changes in cannabis use at follow-up were explored by goals and cannabis use disorder (CUD) diagnosis. RESULTS: There was a group by visit interaction on cannabis use (days: beta=0.93, p=0.005; times: beta=0.71, p<0.001; CN-THCCOOH: beta=0.26, p=0.004), with reductions at follow-up detected only in CB-Abst. Following 4 weeks of abstinence, 68.4% of CB-Abst participants wanted to reduce or abstain from cannabis use following completion of CM. Those in CB-Abst who set end-of-intervention reduction goals and were without CUD had greater decreases in cannabis use frequency at follow-up (Goals*time on days/week: beta=-2.27, p<0.001; CUD*time on times/week: beta=0.48, SE=0.24, t=2.01, p=0.048). CONCLUSIONS: Findings support the utility of brief incentivized abstinence for generating motivation to reduce cannabis use and behavior change even after incentives end. This study supports CM as a potentially viable harm reduction strategy for those not yet ready to quit.

Associations between behavioral and self-reported impulsivity, brain structure, and genetic influences in middle childhood.

Impulsivity undergoes a normative developmental trajectory from childhood to adulthood and is thought to be driven by maturation of brain structure. However, few large-scale studies have assessed associations between impulsivity, brain structure, and genetic susceptibility in children. In 9112 children ages 9-10 from the ABCD study, we explored relationships among impulsivity (UPPS-P impulsive behavior scale; delay discounting), brain structure (cortical thickness (CT), cortical volume (CV), and cortical area (CA)), and polygenic scores for externalizing behavior (PGSEXT). Both higher UPPS-P total scores and more severe delay-discounting had widespread, low-magnitude associations with smaller CA in frontal and temporal regions. No associations were seen between impulsivity and CV or CT. Additionally, higher PGSEXT was associated with both higher UPPS-P scores and with smaller CA and CV in frontal and temporal regions, but in non-overlapping cortical regions, underscoring the complex interplay between genetics and brain structure in influencing impulsivity. These findings indicate that, within large-scale population data, CA is significantly yet weakly associated with each of these impulsivity measures and with polygenic risk for externalizing behaviors, but in distinct brain regions. Future work should longitudinally assess these associations through adolescence, and examine associated functional outcomes, such as future substance use and psychopathology.

Longitudinal Associations Between Cannabis Use and Cognitive Impairment in a Clinical Sample of Middle-Aged Adults Using Cannabis for Medical Symptoms.

Introduction: Cannabis use to alleviate medical symptoms is increasing in middle-aged and older adults. Cognitive impairment associated with cannabis use may be especially detrimental to these understudied age groups. We hypothesized that among middle-aged and older adults who used cannabis for 12 months, frequent (≥3 days/week) compared with nonfrequent (≤2 days/week) use will be associated with cognitive impairment. Materials and Methods: We performed secondary analysis on data from a clinical trial of cannabis use for medical symptoms. Participants (n=62) were ≥45 years, and completed a baseline and at least one postbaseline visit. Cognitive domains were assessed through the Cambridge Neuropsychological Test Automated Battery. Cannabis use was assessed prospectively through daily smartphone diaries. Frequency of cannabis use was a binary predictor in a mixed-effects logistic regression model predicting cognitive impairment adjusted for baseline cognitive functioning. Results: At baseline, participants were primarily nonfrequent cannabis users; however, in all other time periods, most participants were frequent users (range: 55-58%). Cognitive outcomes did not differ between frequent and nonfrequent cannabis users. However, in sensitivity analyses, respondents with problematic cannabis use scored significantly worse on one cognitive domain compared to those without problematic cannabis use. Conclusions: In a clinical sample of adults aged ≥45 years, no longitudinal associations were found between cannabis use and cognitive functioning. However, a few significant associations were observed between problematic use and cognitive functioning. Further research is needed to assess the impact of cannabis use on adults, particularly those aged ≥65 years, and to investigate potential subtler influences of cannabis use on cognition. ClinicalTrials.gov ID: NCT03224468.

The Cannabis Effects Expectancy Questionnaire-Medical (CEEQ-M): Preliminary psychometric properties and longitudinal validation within a clinical trial.

The use of cannabis for medical symptoms is increasing despite limited evidence for its efficacy. Expectancies-prior beliefs about a substance or medicine-can modulate use patterns and effects of medicines on target symptoms. To our knowledge, cannabis expectancies have not been studied for their predictive value for symptom relief. The 21-item Cannabis Effects Expectancy Questionnaire-Medical (CEEQ-M) is the first longitudinally validated measure of expectancies for cannabis used for medical symptoms. The questionnaire was developed for a randomized clinical trial of the effect of state cannabis registration (SCR) card ownership on symptoms of pain, insomnia, anxiety, and depression in adults (N = 269 across six questionnaire administrations). Item-level analyses (n = 188) demonstrated between-person stability of expectancies and no aggregate, within-person expectancy changes 3 months after individuals gained access to SCR cards. Exploratory factor analysis (n = 269) indicated a two-factor structure. Confirmatory factor analysis at a later timepoint (n = 193) demonstrated good fit and scalar invariance of the measurement model. Cross-lagged panel models across 3 and 12 months (n = 187 and 161, respectively) indicated that CEEQ-M-measured expectancies did not predict changes in self-reported cannabis use; symptoms of pain, insomnia, anxiety, and depression; and well-being. However, greater baseline cannabis use predicted more positive expectancy changes. The findings suggest that the CEEQ-M is psychometrically sound. Future work should clarify at what timescales cannabis expectancies have predictive value and how cannabis expectancies for medical symptoms are maintained and diverge from other substance use expectancies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Cannabis use for medical symptoms: Patterns over the first year of use.

BACKGROUND: As greater numbers of states in the United States and countries in the world continue to legalize cannabis for medical use, it has become increasingly important to assess patterns of cannabis use in individuals using cannabis for medical symptoms over time. A public health concern is that, like recreational cannabis, some individuals using cannabis for medical reasons may develop detrimental patterns of use, leading to the development of a cannabis use disorder (CUD). METHODS: In a 9-month longitudinal cohort study following a 12-week randomized, waitlist-controlled trial in 149 adults who used cannabis to alleviate insomnia, pain, depressed mood, or anxiety (RCT: NCT03224468), we assessed whether patterns of cannabis use for the 9 months following the RCT were associated with the development of CUD. RESULTS: We identified five unique trajectories of use; 31 participants (21%) had low stable or no use, 50 (34%) had medium stable use, 19 (13%) had high stable use, 26 (17%) showed de-escalating and 23 (15%) showed escalating use over 9 months following the RCT. Of 149 participants enrolled, 19 (13%) met diagnostic criteria for CUD at 12 months. Only the escalating cannabis use pattern predicted significantly higher rates of CUD compared to the low or no use category (OR = 4.29, 95% CI = 1.21 to 10.87, p = 0.02). CONCLUSIONS: These data indicate that most individuals using cannabis for medical symptoms have a stable pattern of use over the first year. Escalation of use may be a detrimental pattern that warrants further concern.

Cannabis use and sleep quality in daily life: An electronic daily diary study of adults starting cannabis for health concerns.

BACKGROUND: Real world patterns of cannabis use for health concerns are highly variable and rarely overseen by a physician. Pragmatic effectiveness studies with electronic daily diaries that capture person-specific patterns of cannabis use and health symptoms may help clarify risks and benefits. METHODS: As part of a larger, randomized trial (NCT03224468), adults (N = 181) seeking cannabis for insomnia, pain, or anxiety or depressive symptoms were randomized to obtain a medical cannabis card immediately (MCC) or a waitlist control (WLC) and completed 12-weeks of daily web-based surveys on cannabis use and sleep, pain, and depressive symptoms. RESULTS: Completion rates of daily surveys were moderate to high (median completed: 72 out of 90 days). Daily reports of cannabis use were consistent with monthly interview assessments and urinalysis. The MCC group increased cannabis use frequency in the 12 weeks following randomization, while WLC did not. Among the MCC group, self-reported sleep quality was significantly higher on cannabis use days, compared to nonuse days. The MCC group displayed long-term sleep improvements, consistent with increasing cannabis frequency. No improvements were found for pain or depressive symptoms. CONCLUSION: Cannabis use is associated with same day improvements in self-reported sleep quality, but not pain or depressive symptoms, although sleep improvements occurred in the context of increased frequency of cannabis use, raising the risk for cannabis use disorder. Daily web-based assessments of cannabis appear valid and feasible in adults seeking cannabis for health concerns, providing a flexible, complementary method for future real-world effectiveness studies with expanded and objective measures.

Development of cannabis use disorder in medical cannabis users: A 9-month follow-up of a randomized clinical trial testing effects of medical cannabis card ownership.

Background: Evidence for long-term effectiveness of commercial cannabis products used to treat medical symptoms is inconsistent, despite increasingly widespread use. Objective: To prospectively evaluate the effects of using cannabis on self-reported symptoms of pain, insomnia, anxiety, depression, and cannabis use disorder (CUD) after 12 months of use. Methods: This observational cohort study describes outcomes over 9 months following a 12-week randomized, waitlist-controlled trial (RCT: NCT03224468) in which adults (N = 163) who wished to use cannabis to alleviate insomnia, pain, depression, or anxiety symptoms were randomly assigned to obtain a medical marijuana card immediately (immediate card acquisition group) or to delay obtaining a card for 12 weeks delay (delayed card acquisition group). During the 9-month post-randomization period, all participants could use cannabis as they wished and choose their cannabis products, doses, and frequency of use. Insomnia, pain, depression, anxiety, and CUD symptoms were assessed over the 9-month post-randomization period. Results: After 12 months of using cannabis for medical symptoms, 11.7% of all participants (n = 19), and 17.1% of those using cannabis daily or near-daily (n = 6) developed CUD. Frequency of cannabis use was positively correlated with pain severity and number of CUD symptoms, but not significantly associated with severity of self-reported insomnia, depression, or anxiety symptoms. Depression scores improved throughout the 9 months in all participants, regardless of cannabis use frequency. Conclusions: Frequency of cannabis use was not associated with improved pain, anxiety, or depression symptoms but was associated with new-onset cannabis use disorder in a significant minority of participants. Daily or near-daily cannabis use appears to have little benefit for these symptoms after 12 months of use.

Pain catastrophizing is associated with reduced neural response to monetary reward.

Introduction: Pain catastrophizing, a measure of an individual's negative emotional and cognitive appraisals of pain, has been included as a key treatment target in many psychological interventions for pain. However, the neural correlates of pain catastrophizing have been understudied. Prior neuroimaging evidence suggests that adults with pain show altered reward processing throughout the mesocorticolimbic reward circuitry. Methods: In this study, we tested the association between Pain Catastrophizing Scale (PCS) scores and neural activation to the Monetary Incentive Delay (MID) reward neuroimaging task in 94 adults reporting a range of pain, insomnia, and mood symptoms. Results: Results indicated that PCS score but not pain intensity was significantly associated with blunted activation in the caudate and putamen in response to feedback of successful vs. unsuccessful trials on the MID task. Mediation analyses indicated that PCS score fully mediated the relationship between depression symptoms and reward activation. Discussion: These findings provide evidence that pain catastrophizing is independently associated with altered striatal function apart from depression symptoms and pain intensity. Thus, in individuals experiencing pain and/or co- morbid conditions, reward dysfunction is directly related to pain catastrophizing.

Genetic patterning for child psychopathology is distinct from that for adults and implicates fetal cerebellar development.

Childhood psychiatric symptoms are often diffuse but can coalesce into discrete mental illnesses during late adolescence. We leveraged polygenic scores (PGSs) to parse genomic risk for childhood symptoms and to uncover related neurodevelopmental mechanisms with transcriptomic and neuroimaging data. In independent samples (Adolescent Brain Cognitive Development, Generation R) a narrow cross-disorder neurodevelopmental PGS, reflecting risk for attention deficit hyperactivity disorder, autism, depression and Tourette syndrome, predicted psychiatric symptoms through early adolescence with greater sensitivity than broad cross-disorder PGSs reflecting shared risk across eight psychiatric disorders, the disorder-specific PGS individually or two other narrow cross-disorder (Compulsive, Mood-Psychotic) scores. Neurodevelopmental PGS-associated genes were preferentially expressed in the cerebellum, where their expression peaked prenatally. Further, lower gray matter volumes in cerebellum and functionally coupled cortical regions associated with psychiatric symptoms in mid-childhood. These findings demonstrate that the genetic underpinnings of pediatric psychiatric symptoms differ from those of adult illness, and implicate fetal cerebellar developmental processes that endure through childhood.

The effect of intravenous alcohol on the neural correlates of risky decision making in healthy social drinkers.

Alcohol is thought to contribute to an increase in risk-taking behavior, but the neural correlates underlying this effect are not well understood. In this study, participants were given intravenous alcohol or placebo while undergoing functional magnetic resonance imaging (fMRI) and playing a risk-taking game. The game allowed us to examine the neural response to choosing a safe or risky option, anticipating outcome and receiving feedback. We found that alcohol increased risk-taking behavior, particularly among participants who experienced more stimulating effects of alcohol. fMRI scans demonstrated that alcohol increased activation in the striatum to risky compared with safe choices and dampened the neural response to notification of both winning and losing throughout the caudate, thalamus and insula. This study suggests that alcohol may increase risk-taking behavior by both activating brain regions involved in reward when a decision is made, and dampening the response to negative and positive feedback.

Randomised, pragmatic, waitlist controlled trial of cannabis added to prescription opioid support on opioid dose reduction and pain in adults with chronic non-cancer pain: study protocol.

INTRODUCTION: Chronic, non-cancer pain impacts approximately 50 million adults in the USA (20%), approximately 25% of whom receive chronic prescription opioids for pain despite limited empirical efficacy data and strong dose-related risk for opioid use disorder and opioid overdose. Also despite lack of efficacy data, there are many reports of people using cannabis products to manage chronic pain and replace or reduce chronic opioids. Here we describe the protocol for a randomised trial of the effect of cannabis, when added to a behavioural pain management and prescription opioid taper support programme, on opioid utilisation, pain intensity and pain interference. METHODS: This is a pragmatic, single-blind, randomised, wait-list controlled trial that aims to enrol 250 adults taking prescription opioids at stable doses of ≥25 morphine milligram equivalents per day for chronic non-cancer pain who express interest in using cannabis to reduce their pain, their opioid dose or both. All participants will be offered a weekly, 24-session Prescription Opioid Taper Support group behavioural pain management intervention. Participants will be randomly assigned in 1:1 ratio to use cannabis products, primarily from commercial cannabis dispensaries or to abstain from cannabis use for 6 months. Coprimary outcomes are change in prescription monitoring programme-verified opioid dose and change in Pain, Enjoyment, General Activity scale scores. Secondary outcomes include quality of life, depression, anxiety, self-reported opioid dose and opioid and cannabis use disorder symptoms. All other outcomes will be exploratory. We will record adverse events. ETHICS AND DISSEMINATION: This study has ethical approval by the Massachusetts General Brigham Institutional Review Board (#2021P000871). Results will be published in peer-reviewed journals and presented at national conferences. TRIAL REGISTRATION NUMBER: NCT04827992.

Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging.

The primary cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC), causes intoxication and impaired function, with implications for traffic, workplace, and other situational safety risks. There are currently no evidence-based methods to detect cannabis-impaired driving, and current field sobriety tests with gold-standard, drug recognition evaluations are resource-intensive and may be prone to bias. This study evaluated the capability of a simple, portable imaging method to accurately detect individuals with THC impairment. In this double-blind, randomized, cross-over study, 169 cannabis users, aged 18-55 years, underwent functional near-infrared spectroscopy (fNIRS) before and after receiving oral THC and placebo, at study visits one week apart. Impairment was defined by convergent classification by consensus clinical ratings and an algorithm based on post-dose tachycardia and self-rated "high." Our primary outcome, prefrontal cortex (PFC) oxygenated hemoglobin concentration (HbO), was increased after THC only in participants operationalized as impaired, independent of THC dose. ML models using fNIRS time course features and connectivity matrices identified impairment with 76.4% accuracy, 69.8% positive predictive value (PPV), and 10% false-positive rate using convergent classification as ground truth, which exceeded Drug Recognition Evaluator-conducted expanded field sobriety examination (67.8% accuracy, 35.4% PPV, and 35.4% false-positive rate). These findings demonstrate that PFC response activation patterns and connectivity produce a neural signature of impairment, and that PFC signal, measured with fNIRS, can be used as a sole input to ML models to objectively determine impairment from THC intoxication at the individual level. Future work is warranted to determine the specificity of this classifier to acute THC impairment.ClinicalTrials.gov Identifier: NCT03655717.