Year-Long Cannabis Use for Medical Symptoms and Brain Activation During Cognitive Processes.

Importance: Cannabis is increasingly being used to treat medical symptoms, but the effects on brain function in those using cannabis for these symptoms are not known. Objective: To test whether 1 year of cannabis use for medical symptoms after obtaining a medical cannabis card was associated with increased brain activation during working memory, reward, and inhibitory control tasks, areas of cognition affected by cannabis. Design, Setting, and Participants: This cohort study was conducted from July 2017 to July 2020 among participants from the greater Boston area who were recruited as part of a clinical trial of individuals seeking medical cannabis cards for anxiety, depression, pain, or insomnia symptoms. Participants were aged between 18 and 65 years. Exclusion criteria were daily cannabis use and cannabis use disorder at baseline. Data analysis was conducted from August 2021 to April 2024. Main Outcomes and Measures: Outcomes were whole brain functional activation during tasks involving working memory, reward, and inhibitory control at baseline and after 1 year of medical cannabis card ownership. Results: Imaging was collected from participants before and 1 year after obtaining medical cannabis cards, with 57 participants at baseline (38 female [66.7%]; 6 [10.5%] Black and 45 [78.9%] White participants; 1 [1.8%] Hispanic participant; median [IQR] age, 34.0 [24.0-51.0] years) and 54 participants at 1 year (37 female [68.5%]; 4 [7.4%] Black and 48 [88.9%] White participants; 1 [1.9%] Hispanic participant, median [IQR] age, 36.5 [25.0-51.0] years). Imaging was also collected in 32 healthy control participants at baseline (22 female [68.8%]; 2 [6.2%] Black and 27 [84.4%] White participants; 3 [9.4%] Hispanic participants; median [IQR] age, 33.0 [24.8-38.2] years). In all groups and at both time points, functional imaging revealed canonical activations of the probed cognitive processes. No statistically significant difference in brain activation between the 2 time points (baseline and 1 year) in those with medical cannabis cards and no associations between changes in cannabis use frequency and brain activation after 1 year were found. Conclusions and Relevance: In this cohort study of adults obtaining medical cannabis cards for medical symptoms, no significant association between brain activation in the areas of cognition of working memory, reward, and inhibitory control and 1 year of cannabis use was observed. The results warrant further studies that probe the association of cannabis at higher doses, with greater frequency, in younger age groups, and with larger, more diverse cohorts.

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.

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).

Substance Use, Suicidal Thoughts, and Psychiatric Comorbidities Among High School Students.

This cross-sectional study evaluates the dose-dependent association between alcohol, cannabis, and nicotine use and psychiatric symptoms among participants in the Substance Use and Risk Factor Survey and the Youth Risk Behavior Survey.

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.

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.

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.

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).

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.

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.

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.

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.

State-Level Recreational Cannabis Legalization Is Not Differentially Associated with Cannabis Risk Perception Among Children: A Multilevel Regression Analysis.

Introduction: As more states pass recreational cannabis laws (RCLs) for adults, there is concern that increasing (and state-sanctioned) cannabis acceptance will result in a reduced perception of risk of harm from cannabis among children. We aimed to discover whether children in states with RCLs had decreased perception of risk from cannabis compared with children in states with illicit cannabis. Methods: We analyzed data from the multisite multistate Adolescent Brain and Cognitive Development Study to determine how the perception of cannabis harm among children (age at baseline: 9-10; N=10,395) changes over time in states with and without RCLs. Using multilevel modeling, we assessed survey responses from children longitudinally across 3 years, adjusting for state-, family-, and participant-level clustering and child-level factors, including demographics (sex, race, and socioeconomic status), religiosity, and trait impulsivity. Results: There was no significant main effect of state RCLs on perceived risk of cannabis use, and no differences in change over time by state RCLs, even after controlling for demographic factors and other risk (e.g., impulsivity) and protective (e.g., religiosity) factors. Conclusions: This analysis indicates that state-level RCLs are not associated with differential perception of cannabis risk among children, even after controlling for demographics, trait impulsivity, and religiosity. Future studies could assess how perception of risk from cannabis changes as children and adolescents continue to mature in states with and without RCLs.

Study protocol for a phase II, double-blind, randomised controlled trial of cannabidiol (CBD) compared with placebo for reduction of brain neuroinflammation in adults with chronic low back pain.

INTRODUCTION: Chronic pain is a debilitating medical problem that is difficult to treat. Neuroinflammatory pathways have emerged as a potential therapeutic target, as preclinical studies have demonstrated that glial cells and neuroglial interactions play a role in the establishment and maintenance of pain. Recently, we used positron emission tomography (PET) to demonstrate increased levels of 18 kDa translocator protein (TSPO) binding, a marker of glial activation, in patients with chronic low back pain (cLBP). Cannabidiol (CBD) is a glial inhibitor in animal models, but studies have not assessed whether CBD reduces neuroinflammation in humans. The principal aim of this trial is to evaluate whether CBD, compared with placebo, affects neuroinflammation, as measured by TSPO levels. METHODS AND ANALYSIS: This is a double-blind, randomised, placebo-controlled, phase II clinical trial. Eighty adults (aged 18-75) with cLBP for >6 months will be randomised to either an FDA-approved CBD medication (Epidiolex) or matching placebo for 4 weeks using a dose-escalation design. All participants will undergo integrated PET/MRI at baseline and after 4 weeks of treatment to evaluate neuroinflammation using [11C]PBR28, a second-generation radioligand for TSPO. Our primary hypothesis is that participants randomised to CBD will demonstrate larger reductions in thalamic [11C]PBR28 signal compared with those receiving placebo. We will also assess the effect of CBD on (1) [11C]PBR28 signal from limbic regions, which our prior work has linked to depressive symptoms and (2) striatal activation in response to a reward task. Additionally, we will evaluate self-report measures of cLBP intensity and bothersomeness, depression and quality of life at baseline and 4 weeks. ETHICS AND DISSEMINATION: This protocol is approved by the Massachusetts General Brigham Human Research Committee (protocol number: 2021P002617) and FDA (IND number: 143861) and registered with ClinicalTrials.gov. Results will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT05066308; ClinicalTrials.gov.

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.

Effect of Medical Marijuana Card Ownership on Pain, Insomnia, and Affective Disorder Symptoms in Adults: A Randomized Clinical Trial.

Importance: Despite the legalization and widespread use of cannabis products for a variety of medical concerns in the US, there is not yet a strong clinical literature to support such use. The risks and benefits of obtaining a medical marijuana card for common clinical outcomes are largely unknown. Objective: To evaluate the effect of obtaining a medical marijuana card on target clinical and cannabis use disorder (CUD) symptoms in adults with a chief concern of chronic pain, insomnia, or anxiety or depressive symptoms. Design, Setting, and Participants: This pragmatic, single-site, single-blind randomized clinical trial was conducted in the Greater Boston area from July 1, 2017, to July 31, 2020. Participants were adults aged 18 to 65 years with a chief concern of pain, insomnia, or anxiety or depressive symptoms. Participants were randomized 2:1 to either the immediate card acquisition group (n = 105) or the delayed card acquisition group (n = 81). Randomization was stratified by chief concern, age, and sex. The statistical analysis followed an evaluable population approach. Interventions: The immediate card acquisition group was allowed to obtain a medical marijuana card immediately after randomization. The delayed card acquisition group was asked to wait 12 weeks before obtaining a medical marijuana card. All participants could choose cannabis products from a dispensary, the dose, and the frequency of use. Participants could continue their usual medical or psychiatric care. Main Outcomes and Measures: Primary outcomes were changes in CUD symptoms, anxiety and depressive symptoms, pain severity, and insomnia symptoms during the trial. A logistic regression model was used to estimate the odds ratio (OR) for CUD diagnosis, and linear models were used for continuous outcomes to estimate the mean difference (MD) in symptom scores. Results: A total of 186 participants (mean [SD] age 37.2 [14.4] years; 122 women [65.6%]) were randomized and included in the analyses. Compared with the delayed card acquisition group, the immediate card acquisition group had more CUD symptoms (MD, 0.28; 95% CI, 0.15-0.40; P < .001); fewer self-rated insomnia symptoms (MD, -2.90; 95% CI, -4.31 to -1.51; P < .001); and reported no significant changes in pain severity or anxiety or depressive symptoms. Participants in the immediate card acquisition group also had a higher incidence of CUD during the intervention (17.1% [n = 18] in the immediate card acquisition group vs 8.6% [n = 7] in the delayed card acquisition group; adjusted odds ratio, 2.88; 95% CI, 1.17-7.07; P = .02), particularly those with a chief concern of anxiety or depressive symptoms. Conclusions and Relevance: This randomized clinical trial found that immediate acquisition of a medical marijuana card led to a higher incidence and severity of CUD; resulted in no significant improvement in pain, anxiety, or depressive symptoms; and improved self-rating of insomnia symptoms. Further investigation of the benefits of medical marijuana card ownership for insomnia and the risk of CUD are needed, particularly for individuals with anxiety or depressive symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT03224468.