The Cannabis Gray Market: A Case for Cannabis Regulatory Science Research.

The cannabis gray market poses significant public health concerns and remains a major threat to consumer and/or potential consumer uptake of regulated cannabis markets in jurisdictions with legal state-sponsored cannabis programs. In this perspective, we provide an overview of the cannabis gray market, and describe an integrated epidemiological and regulatory science framework to study the gray market. Using tobacco regulatory science as a guide, we introduce example cannabis regulatory science research activities as a means to improve the field's understanding of the cannabis gray market. Cannabis regulatory science is a developing field that can improve our understanding of the cannabis regulatory ecosystem and provide regulatory officials and policymakers alike with much needed data to inform regulatory decision-making and improve the success and uptake of state-sponsored cannabis programs.

Cigarette smoking and cognitive task performance: Experimental effects of very-low nicotine-content cigarettes.

Reductions in the nicotine content of cigarettes decrease smoking rate and dependence severity, but effects on cognition are less well established. The potential impacts of very-low nicotine-content (VLNC) cigarettes on cognitive task performance must be evaluated, especially in vulnerable populations. The aim of the present study is to experimentally examine the effects of VLNC cigarettes on cognitive performance. Adults who smoked daily (n = 775) from three vulnerable populations (socioeconomically disadvantaged reproductive-age women, individuals with opioid use disorder, affective disorders) were examined. Participants were randomly assigned to normal nicotine content (NNC; 15.8 mg nicotine/g tobacco) or VLNC (2.4 mg/g or 0.4 mg/g) cigarettes for 12 weeks. Response inhibition (stop-signal task), working memory (n-back task; n of 2-n of 0), and cognitive interference (nicotine Stroop task) were assessed at baseline, 2, 6, and 12 weeks. Results were analyzed using mixed-model repeated-measures analyses of variance. Extended exposure to VLNC cigarettes produced no significant changes in any measure of cognitive performance compared to NNC cigarettes. Over weeks, response times on the n-back task decreased across doses. No significant effects were observed on the stop-signal or nicotine Stroop tasks. All three vulnerable populations performed comparably on all three cognitive tasks. Extended exposure to VLNC cigarettes produced no impairments in cognitive performance on any of the assessed tasks compared to NNC cigarettes. These findings are consistent with the larger literature detailing other consequences following exposure to VLNC cigarettes and are encouraging for the adoption of a nicotine-reduction policy. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Changes in weight among individuals with psychiatric conditions or socioeconomic disadvantage assigned to smoke very low nicotine content cigarettes.

Nicotine abstinence leads to weight gain, which could be an unintended consequence of a nicotine reduction policy. This secondary analysis used weekly assessments of weight and ratings of "increased appetite/hunger/weight gain" collected in three 12-week, randomized controlled trials evaluating the effects of cigarettes differing in nicotine dose (15.8, 2.4, or 0.4 mg/g) among individuals with affective disorders, opioid use disorder (OUD), and socioeconomically disadvantaged women. Linear mixed models tested differences by dose and time. Analyses first collapsed across populations and then separated out individuals with OUD because biomarkers suggested they used substantially more noncombusted nicotine. Across populations, weight increased significantly over time, averaging 1.03 kg (p < .001), but did not vary by dose nor was there any interaction of dose/time. "Increased appetite/hunger/weight gain" ratings increased significantly as a function of dose, with differences between low and high doses (1.95 and 1.73, respectively, p = .01), but not by time nor any interaction. In the combined group of individuals with affective disorders and socioeconomically disadvantaged women, weight and "increased appetite/hunger/weight gain" ratings increased significantly by dose, with differences between low and high doses (1.43 vs. 0.73 kg, p = .003 and 2.00 vs. 1.76, p = .02, respectively). Among individuals with OUD, there were no significant effects of any kind on either outcome. Individuals with affective disorders and socioeconomically disadvantaged women gained weight and reported more subjective appetite/weight gain when given 0.4, but not 2.4 mg/g cigarettes, despite comparable decreases in nicotine exposure. However, neither change was clinically significant, suggesting minimal short-term adverse consequences of a nicotine reduction policy. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Randomized controlled trial of zolpidem as a pharmacotherapy for cannabis use disorder.

BACKGROUND: Sleep disturbance is commonly reported among individuals meeting criteria for cannabis use disorder (CUD), and people who use cannabis frequently report sleep disturbance as a contributor to failed quit attempts. The purpose of this study was to measure sleep in individuals enrolled in treatment for CUD, and to determine whether use of hypnotic medication during treatment increased abstinence rates. METHOD: The study enrolled 127 adults seeking treatment for CUD in a 12-week clinical trial and randomized to receive extended-release zolpidem (zolpidem-XR) or placebo. All participants received computerized behavioral therapy and abstinence-based contingency management. The study conducted in-home ambulatory polysomnography (PSG) assessments at baseline and during treatment to objectively measure sleep. Self-report measures of recent sleep, Insomnia Severity Index (ISI), and drug use (Timeline Follow-Back) were collected at each study visit, and the study confirmed self-reported abstinence via quantitative urine drug testing. RESULT: Participants randomized to placebo, but not zolpidem-XR exhibited significant sleep disturbance during week 1 of treatment. Sleep disturbance emerged in the zolpidem-XR group after study medication was stopped at the end of treatment. Though participants assigned to the zolpidem-XR condition had qualitatively greater rates of abstinence compared with placebo (27 % versus 15 % negative at end of treatment), the difference was not statistically significant. Treatment retention was poor (about 50 % drop out in both groups) and medication adherence was a challenge without the use of contingent incentives. CONCLUSION: Results from this randomized controlled trial suggest that zolpidem-XR can attenuate abstinence-induced sleep disturbance early in treatment for CUD, but that sleep problems are likely to emerge after the medication is stopped. Further research should identify alternative pharmacotherapies and behavioral treatments for CUD and elucidate the role of sleep disturbance in the development and maintenance of CUD.

The Impact of the Covid-19 Pandemic on Smoking Among Vulnerable Populations.

AIM: While accumulating evidence suggests that people modified their smoking during the ongoing COVID-19 pandemic, it remains unclear whether those most at risk for tobacco-related health disparities did so. The current study examined changes in smoking among several vulnerable smoker populations during the COVID-19 pandemic. METHODS: A web-based survey was distributed in 2020 to 709 adults with socioeconomic disadvantage, affective disorders, or opioid use disorder who participated in a previous study investigating the effects of very low nicotine content (VLNC) cigarettes on smoking. Current smoking status and rate, and adoption of protective health behaviors in response to the pandemic (eg social distancing, mask wearing) were examined. RESULTS: Among 332 survey respondents (46.8% response rate), 84.6% were current smokers. Repeated measures ANOVA showed that current cigarettes/day (CPD) was higher during COVID than pre-COVID (12.9 ± 1.0 versus 11.6 ± 1.0; p < .001). Most respondents had adopted protective health behaviors to prevent infection (>79% for all behaviors). More than half indicated that they were still leaving their homes specifically to buy cigarettes (64.6%) and were buying more packs per visit to the store (54.5%) than pre-COVID. Individuals unemployed at the time of the survey experienced greater increases in CPD (from 11.4 ± 1.4 to 13.3 ± 1.4, p = .024) as did those with higher levels of anxiety (from 11.5 ± 1.1 to 13.6 ± 1.1, p < .001). CONCLUSIONS: Smoking increased during the COVID-19 pandemic in this sample of adults from vulnerable populations, even while most adopted protective health measures to prevent infection. Unemployment and anxiety might identify those at greatest risk for increases in tobacco use. IMPLICATIONS: Individuals from populations especially vulnerable to smoking might be at risk for greater harm from cigarette smoking during times of pandemic-related stress. Public health interventions are warranted to ameliorate increases in smoking among these populations. Special attention should be paid to those experiencing unemployment and high anxiety.

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review.

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous µ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

Relating individual differences in the reinforcing value of smoking and dependence severity to nicotine exposure levels in vulnerable populations.

Cigarette smoking is overrepresented in populations with psychiatric conditions and socioeconomic disadvantage. Greater understanding of the role of reinforcement and nicotine dependence in smoking among vulnerable populations may facilitate development of better targeted interventions to reduce smoking. Prior research demonstrated that individual differences in the reinforcing value of smoking and nicotine-dependence severity predicted total nicotine-exposure in vulnerable populations. The present study uses multivariate regression to address two aims: (1) Quantify the degree to which the reinforcing value of smoking, assessed using the Cigarette Purchase Task (CPT), and dependence severity assessed using the Fagerström Test of Nicotine Dependence and Brief Wisconsin Inventory of Smoking Dependence Motives (B-WISDM) each account for individual differences in cotinine-plus-3'-hydroxycotinine (COT+3HC) levels. (2) Explore whether there is overlap in the variance accounted for by the CTP, FTND, and B-WISDM. Participants were 628 adults with co-morbid psychiatric conditions or socioeconomic disadvantage who smoked daily. The CPT, FTND, and B-WISDM models accounted for 23.76%, 32.45%, and 29.61% of the variance in COT+3HC levels, respectively. Adding CPT to the FTND model failed to increase the variance accounted for and adding it to the B-WISDM model did so by only 1.2% demonstrating considerable overlap in the variance in nicotine exposure levels accounted for by these three instruments. These results provide new knowledge on the relationship between individual differences in the reinforcing value of smoking and nicotine-exposure levels and suggest differences in reinforcing value may underpin a considerable portion of the variance in nicotine exposure accounted for by dependence severity.

Potential effects of nicotine content in cigarettes on use of other substances.

A national nicotine reduction policy has the potential to reduce cigarette smoking and associated adverse health impacts among vulnerable populations. However, possible unanticipated adverse effects of reducing nicotine content in cigarettes, such as increasing the use of alcohol or other abused substances, must be examined. The purpose of this study was to evaluate the effects of exposure to varying doses of nicotine in cigarettes on use of other substances. This was a secondary analysis (n = 753) of three simultaneous, multisite, double-blind, randomized-controlled trials examining 12 weeks of exposure to study cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco) among daily smokers from three vulnerable populations: individuals with affective disorders (n = 251), individuals with opioid use disorder (n = 256), and socioeconomically-disadvantaged women of reproductive age (n = 246). Effect of study cigarette assignment on urine toxicology screens (performed weekly) and responses to drug and alcohol use questionnaires (completed at study weeks 6 and 12) were examined using negative binomial regression, logistic regression, or repeated measures analysis of variance, controlling for sex, age, and menthol status. The most common substances identified using urine toxicology included tetrahydrocannabinol (THC; 44.8%), cocaine (9.2%), benzodiazepine (8.6%), and amphetamines (8.0%), with 57.2% of participants testing positive at least once for substance use (27.3% if excluding THC). No significant main effects of nicotine dose were found on any of the examined outcomes. These results suggest that reducing nicotine content does not systematically increase use of other substances, even among individuals at increased risk of substance use. ClinicalTrials.gov Identifiers: NCT02232737, NCT2250664, NCT2250534.

A systematic review and meta-analysis of delay discounting and cannabis use.

Delay discounting reflects the systematic reduction in the value of a consequence by delay to delivery. Theoretical and empirical work suggests that delay discounting is a key behavioral mechanism underlying substance use disorder. Existing work on cannabis use, however, is mixed with many studies reporting null results. The purpose of this review was to provide an in-depth assessment of the association between delay discounting and cannabis use. We conducted metaregression analyses to determine the omnibus correlation between delay discounting and cannabis use, and to evaluate task-based and sample-based moderators. Studies included evaluated an association between delay discounting and cannabis quantity-frequency or severity measures in human participants (27 studies, 61 effect sizes, 24,782 participants). A robust variance estimation method was used to account for dependence among effect sizes. A significant, but small, omnibus effect was observed (r = .082) in which greater cannabis use frequency or severity was associated with greater discounting. Incentive structure and outcome type were each significant moderators in a multiple moderator model such that incentivized tasks correlated with severity measures showed stronger associations (r = .234) than hypothetical tasks correlated with quantity-frequency measures (r = .029). Comparisons to historic effect size data supported the hypothesis that, at present, the relationship between cannabis use and delay discounting appears empirically smaller than for other substances. Future work should explore theoretical rationales explaining this modest relationship involving cannabis use and delay discounting, such as reflecting the smaller magnitude of perceived long-term clinical outcomes associated with cannabis compared to other substances. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Abuse liability of cigarettes with very low nicotine content in pregnant cigarette smokers.

The U.S. Food and Drug Administration has proposed reducing the nicotine content of cigarettes to a minimally-addictive level. To our knowledge, this study is the first to examine how pregnant smokers respond to very low nicotine content (VLNC) cigarettes. In Phase 1, participants blindly sampled two VLNC cigarettes (0.4 and 2.4 mg/g of tobacco) and their usual brand (UB) cigarette in separate sessions, then completed a behavioral economic simulation task and measures of subjective effects, craving/withdrawal, and smoking topography. Phase 2 directly compared the relative reinforcing effects of the cigarettes using concurrent choice testing. All possible dose-pair combinations were tested in separate sessions where puffs were earned ad libitum by clicking the code associated with their preferred cigarette 10 times. Phase 3 tested the 0.4 mg/g-UB dose-pair where UB puffs could be earned with a progressively incremented number of clicks (maximum 8400). Ten pregnant smokers in Burlington, VT and Baltimore, MD participated in 2017-2018. Regarding abuse liability, participants chose the 0.4-mg/g dose less than UB (22% vs. 78%) during concurrent choice testing and the 0.4-mg/g dose sustained less demand than the 2.4-mg/g and UB doses on the simulation task. Positive subjective effects were also lower for both VLNC cigarettes vs. UB. Each cigarette reduced nicotine craving/withdrawal and no significant changes indicative of compensatory smoking were noted. Reducing the nicotine content of cigarettes may decrease their abuse liability in pregnant smokers without causing untoward craving/withdrawal or compensatory smoking. Studies of extended exposure to VLNCs in pregnant women are warranted.

The state of clinical outcome assessments for cannabis use disorder clinical trials: A review and research agenda.

There is considerable variability in the use of outcome measures in clinical trials for cannabis use disorder (CUD), and a lack of consensus regarding optimal outcomes may have hindered development and approval of new pharmacotherapies. The goal of this paper is to summarize an evaluation of assessment measures and clinical endpoints for CUD clinical trials, and propose a research agenda and priorities to improve CUD clinical outcome assessments. The primary recommendation is that sustained abstinence from cannabis should not be considered the primary outcome for all CUD clinical trials as it has multiple limitations. However, there are multiple challenges to the development of a reliable and valid indicator of cannabis reduction, including the lack of a standard unit of measure for the various forms of cannabis and products and the limitations of currently available biological and self-report assessments. Development of a core toolkit of assessments is needed to both allow flexibility for study design, while facilitating interpretation of outcomes across trials. Four primary agenda items for future research are identified to expedite development of improved clinical outcome assessments for this toolkit: (1) determine whether minimally invasive biologic assays could identify an acute level of cannabis use associated with psychomotor impairment or other cannabis-related harms; (2) create an indicator of quantity of cannabis use that is consistent across product types; (3) examine the presence of cannabis-specific functional outcomes; and (4) identify an optimal duration to assess changes in CUD diagnostic criteria.

A web-based episodic specificity and future thinking session modulates delay discounting in cannabis users.

Episodic future thinking (EFT), a brief intervention involving mental simulation of positive future events, improves delay discounting (DD) in nicotine and alcohol dependent individuals. This study is the first to assess effects of a single-session, online episodic training (ET) on constructs that might impact cannabis use and cannabis use disorder. A sample of 200 active cannabis users recruited via Amazon Mechanical Turk were randomized to an EFT group (n = 102) or an episodic recent thinking control group (ERT; n = 98). A novel episodic specificity induction (ES) was included to enhance quality of episodic thinking for the ET group, and an ES attention control was provided to the ERT group (control training group; CT). Quality and manipulation ratings of event excitement, vividness, importance, and enjoyment of trainings were collected in addition to DD tasks (gains and losses) and readiness to change cannabis use. The ET group reported higher overall quality and manipulation ratings than did the CT group (p < .001, d = 0.79). DD of gains was lower in the ET relative to those of the CT group after controlling for relevant variables (p = .003, d = 0.48), unlike DD of losses (p = .50, d = 0.11). The ET group showed larger pre/post increases in readiness to change, but they were not statistically significant (p = .069, d = 0.26). These effects, following a session of online ET, suggests that ET may positively impact factors related to reduction in cannabis use. Differential effects of EFT and ES components on DD and the development of ET as an adjunctive mHealth intervention targeting reduction in cannabis use appears warranted. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Treatment Implications Associated with Cannabis and Tobacco Co-Use.

PURPOSE OF THE REVIEW: The goal of this article is to summarize the treatment-focused literature on cannabis and tobacco co-use and the treatment implications of co-use. This review will focus on: 1) the impact of co-use on cessation outcomes, 2) compensatory use/substitution of the non-treated substance among co-users, and 3) treatment interventions to address co-use. This article will highlight the limitations to co-use captured in the literature and offer considerations and directives for co-use research and treatment moving forward. RECENT FINDINGS: The degree to which co-use affects cessation for a single, targeted substance remains in question, as the literature is largely mixed. Cannabis treatment trials are better equipped to answer these questions given that they do not typically exclude tobacco users. While the relationship between tobacco use and poorer cannabis outcomes appears to have some evidence, the reverse relationship (cannabis use affecting tobacco outcomes) is not consistently supported. SUMMARY: The co-use of cannabis and tobacco and its impact on single substance cessation and/or compensatory substance use during cessation is generally overlooked in treatment trials, while interventions to address both substances are rare. Capturing co-use adds burden for researchers, clinicians, and participants, but is warranted given the prevalence of co-use and a rapidly changing cannabis and tobacco regulatory environment, which may further complicate co-occurring substance use. Co-users are a heterogeneous population; trials focused on co-users, in addition to better data capture and consistent terminology, will aid in an understanding of nuanced patterns of co-use critical to inform treatment interventions.

Sequential and simultaneous treatment approaches to cannabis use disorder and tobacco use.

Tobacco smoking among those seeking treatment for cannabis use disorder (CUD) is common and is a negative predictor of cannabis outcomes. Quitting tobacco may be beneficial for those seeking to quit cannabis use. This initial proof of concept, controlled trial was designed to compare a simultaneous versus sequential tobacco intervention among those seeking treatment for CUD. Sixty-seven adults received either a simultaneous (SIM) or sequential (SEQ) approach to tobacco cessation in the context of outpatient treatment for CUD. A tobacco intervention (TI) that combined web-based counseling with nicotine replacement therapy (NRT) was provided during weeks 1-12 for SIM and was delayed until weeks 13-24 for SEQ. During weeks 1-12, no between-condition significant differences were observed on treatment participation or cannabis use outcomes. The majority of SIM participants initiated TI counseling (62%), 50% made at least one quit attempt and 41% initiated NRT. Interestingly, 39% in SEQ made tobacco quit attempts and 18% initiated NRT on their own before the TI was offered to them. However, only 30% of those in SEQ continued treatment during weeks 13-24, which compromised between-condition comparisons following the TI, but illustrated a potential clinical concern with delaying the TI. Tobacco cessation outcomes generally were poor and did not differ between conditions. This initial controlled trial suggests that addressing tobacco use during CUD treatment is acceptable and generates action towards tobacco cessation. Additional trials testing more intensive TI models may be necessary to identify more efficacious interventions for co-use of cannabis and tobacco.

Emerging Trends in Cannabis Administration Among Adolescent Cannabis Users.

PURPOSE: The legal landscape of cannabis availability and use in the United States is rapidly changing. As the heterogeneity of cannabis products and methods of use increases, more information is needed on how these changes affect use, especially in vulnerable populations such as youth. METHODS: A national sample of adolescents aged 14-18 years (N = 2,630) were recruited online through advertisements displayed on Facebook and Instagram to complete a survey on cannabis. The survey assessed patterns of edible use, vaping, and smoking cannabis, and the associations among these administration routes and use of other substances. RESULTS: The most frequent and consistent route of cannabis use was smoking (99% lifetime), with substantial numbers reporting vaping (44% lifetime) and edible use (61% lifetime). The majority of those who had experimented with multiple routes of cannabis administration continued to prefer smoking, and the most common pattern of initiation was smoking, followed by edibles and then vaping. In addition to cannabis use, adolescents reported high rates of nicotine use and substantial use of other substances. Adolescents who used more cannabis administration routes tended to also report higher frequency of other substances tried. CONCLUSIONS: Additional work is needed to determine whether the observed adolescent cannabis administration patterns are similar across different samples and sampling methods as well as how these trends change over time with extended exposure to new products and methods. The combined knowledge gained via diverse sampling strategies will have important implications for the development of regulatory policy and prevention and intervention efforts.

Systematic review of outcome domains and measures used in psychosocial and pharmacological treatment trials for cannabis use disorder.

Cannabis use disorder (CUD) is prevalent and demand for treatment is increasing, yet few individuals engage in formal treatment and the efficacy of established interventions for CUD is modest. Existing clinical trials evaluating psychosocial and pharmacological treatments for CUD have incorporated a wide variety of measures for assessing cannabis use outcomes, including abstinence, self-reported frequency and quantity used, withdrawal, use/dependence severity, and other psychosocial outcomes. The heterogeneity of measures and outcomes has limited quantitative analyses of the comparative effectiveness of existing interventions. The purpose of this systematic review is to: 1) identify and characterize approaches for measuring cannabis use in existing CUD intervention trials, including abstinence, frequency and quantity of use, and 2) summarize measures used to assess treatment efficacy in other outcome domains (e.g., cannabis use severity, psychosocial functioning, cannabis withdrawal), and provide a platform for future research to evaluate which outcome measures are most likely to reflect treatment efficacy and clinically significant improvement in other outcome domains.

Co-use of cannabis, tobacco, and alcohol during adolescence: policy and regulatory implications.

Legislative reforms have legalized use of cannabis for medical and recreational purposes. Efforts to evaluate the public health impact of these changes have predominantly focused on determining whether liberalizing cannabis policies has increased cannabis use patterns. Co-use of cannabis and other licit substances, namely tobacco and alcohol, is common during the developmental period of adolescence, which is generally characterized by an increase in risk-taking and novelty-seeking. However, limited research has sought to evaluate the potential implications of reforms to medical and recreational cannabis laws on concurrent and simultaneous use of cannabis, tobacco, and alcohol during adolescence. The current report reviews the extant literature detailing the prevalence and outcomes associated with concurrent and simultaneous cannabis-tobacco and cannabis-alcohol use, including recent work that has examined how concurrent and simultaneous use may be influenced by cannabis reform. This review details how the cannabis landscape and cannabis retail marketplace have evolved and briefly summarizes the corresponding policy and regulatory challenges that have emerged. The report concludes with a focused cannabis co-use research agenda that adopts different strategies including behavioural economic, self-administration, and survey research methods.

The effect of high-dose dronabinol (oral THC) maintenance on cannabis self-administration.

BACKGROUND: There is a clear need for advancing the treatment of cannabis use disorders. Prior research has demonstrated that dronabinol (oral THC) can dose-dependently suppress cannabis withdrawal and reduce the acute effects of smoked cannabis. The present study was conducted to evaluate whether high-dose dronabinol could reduce cannabis self-administration among daily users. METHODS: Non-treatment seeking daily cannabis users (N = 13) completed a residential within-subjects crossover study and were administered placebo, low-dose dronabinol (120 mg/day; 40 mg tid), or high-dose dronabinol (180-240 mg/day; 60-80 mg tid) for 12 consecutive days (order counterbalanced). During each 12-day dronabinol maintenance phase, participants were allowed to self-administer smoked cannabis containing <1% THC (placebo) or 5.7% THC (active) under forced-choice (drug vs. money) or progressive ratio conditions. RESULTS: Participants self-administered significantly more active cannabis compared with placebo in all conditions. When active cannabis was available, self-administration was significantly reduced during periods of dronabinol maintenance compared with placebo maintenance. There was no difference in self-administration between the low- and high-dose dronabinol conditions. CONCLUSIONS: Chronic dronabinol dosing can reduce cannabis self-administration in daily cannabis users and suppress withdrawal symptoms. Cannabinoid agonist medications should continue to be explored for therapeutic utility in the treatment of cannabis use disorders.

Cannabis Withdrawal: A Review of Neurobiological Mechanisms and Sex Differences.

PURPOSE OF REVIEW: This report provides an updated overview of pre-clinical and clinical research on the etiology and biological substrates of the cannabis withdrawal syndrome. RECENT FINDINGS: Long-term cannabis use is associated with downregulation of type-1 cannabinoid receptors (CB1). Reduced CB1 receptor density is related to increased withdrawal during early abstinence, and the reduction in CB1 receptor density reverses with extended abstinence. Females have been shown to have increased rate and severity of a subset of cannabis withdrawal symptoms compared with men. SUMMARY: Recent studies have extended knowledge of the biological processes and individual difference variables that influence cannabis withdrawal. However, caveats include small sample sizes in clinical studies, participant samples that are predominantly male, and limited examinations of endocannabinoids, enzymes that degrade endocannabinoids, negative allosteric modulators, and other neurobiological systems that may directly impact cannabis withdrawal symptom expression.

U.S. cannabis legalization and use of vaping and edible products among youth.

BACKGROUND: Alternative methods for consuming cannabis (e.g., vaping and edibles) have become more popular in the wake of U.S. cannabis legalization. Specific provisions of legal cannabis laws (LCL) (e.g., dispensary regulations) may impact the likelihood that youth will use alternative methods and the age at which they first try the method - potentially magnifying or mitigating the developmental harms of cannabis use. METHODS: This study examined associations between LCL provisions and how youth consume cannabis. An online cannabis use survey was distributed using Facebook advertising, and data were collected from 2630 cannabis-using youth (ages 14-18). U.S. states were coded for LCL status and various LCL provisions. Regression analyses tested associations among lifetime use and age of onset of cannabis vaping and edibles and LCL provisions. RESULTS: Longer LCL duration (ORvaping: 2.82, 95% CI: 2.24, 3.55; ORedibles: 3.82, 95% CI: 2.96, 4.94), and higher dispensary density (ORvaping: 2.68, 95% CI: 2.12, 3.38; ORedibles: 3.31, 95% CI: 2.56, 4.26), were related to higher likelihood of trying vaping and edibles. Permitting home cultivation was related to higher likelihood (OR: 1.93, 95% CI: 1.50, 2.48) and younger age of onset (ß: -0.30, 95% CI: -0.45, -0.15) of edibles. CONCLUSION: Specific provisions of LCL appear to impact the likelihood, and age at which, youth use alternative methods to consume cannabis. These methods may carry differential risks for initiation and escalation of cannabis use. Understanding associations between LCL provisions and methods of administration can inform the design of effective cannabis regulatory strategies.