Brian J. Sherman

Treatment of Cannabis Use Disorder: Current Science and Future Outlook.

Cannabis is the most commonly used illicit substance in the United States. Rates of cannabis use and cannabis use disorder (CUD) have increased in the past decade, paralleling changes in the legal and political climate favoring legalization. Almost 20 million people 12 years or older report past‐month cannabis use, and 8 million report daily or near‐daily use. Concurrently, the perception that cannabis use poses a significant risk of negative consequences has decreased. Contrary to this perception, heavy cannabis use is associated with cognitive impairment, increased risk for psychotic disorders and other mental health problems, lower education attainment, and unemployment. Clinical trials of various treatments for CUD have likewise increased, focusing primarily on psychotherapy treatments, specifically motivational enhancement therapy, cognitive behavioral therapy, and contingency management. Their findings suggest that a combination of these three modalities produces the best abstinence outcomes, although abstinence rates remain modest and decline after treatment. More recently, pharmacotherapy trials have been conducted as adjunctive interventions to psychosocial treatment. N‐acetylcysteine and gabapentin are two of the most promising medications, although no pharmacologic treatment has emerged as clearly efficacious. In this review, we provide a detailed summary of clinical trials that evaluated psychotherapy and pharmacotherapy for treating CUD and discuss emerging areas of clinical research and cannabis‐specific barriers to treatment.

Gender differences among treatment-seeking adults with cannabis use disorder: Clinical profiles of women and men enrolled in the achieving cannabis cessation—evaluating N-acetylcysteine treatment (ACCENT) study

BACKGROUND AND OBJECTIVES Recent evidence suggests that women may fare worse than men in cannabis trials with pharmacologic interventions. Identifying baseline clinical profiles of treatment-seeking cannabis-dependent adults could inform gender-specific treatment planning and development. METHODS The current study compared baseline demographic, cannabis use, and psychiatric factors between women (n = 86) and men (n = 216) entering the Achieving Cannabis Cessation-Evaluating N-acetylcysteine Treatment (ACCENT) study, a multi-site, randomized controlled trial conducted within the National Drug Abuse Treatment Clinical Trials Network. RESULTS Women reported greater withdrawal intensity (p = .001) and negative impact of withdrawal (p = .001), predominantly due to physiological and mood symptoms. Women were more likely to have lifetime panic disorder (p = .038) and current agoraphobia (p = .022), and reported more days of poor physical health (p = .006) and cannabis-related medical problems (p = .023). Women reporting chronic pain had greater mean pain scores than men with chronic pain (p = .006). Men and women did not differ on any measures of baseline cannabis use. DISCUSSION AND CONCLUSIONS Cannabis-dependent women may present for treatment with more severe and impairing withdrawal symptoms and psychiatric conditions compared to cannabis-dependent men. This might help explain recent evidence suggesting that women fare worse than men in cannabis treatment trials of pharmacologic interventions. Baseline clinical profiles of treatment-seeking adults can inform gender-specific treatment planning and development. SCIENTIFIC SIGNIFICANCE Cannabis-dependent women may benefit from integrated treatment focusing on co-occurring psychiatric disorders and targeted treatment of cannabis withdrawal syndrome.(Am J Addict 2017;26:136-144).

Gender differences in cannabis use disorder treatment: Change readiness and taking steps predict worse cannabis outcomes for women

INTRODUCTION Gender differences in cannabis use and cannabis use disorder have been established. Regarding treatment, some evidence suggests that women are less responsive, though the mechanisms are not well understood. Motivation to change and self-efficacy are associated with better outcomes overall, and may help explain gender differences in cannabis use outcomes. METHODS A secondary data analysis of a double-blind placebo controlled trial of buspirone treatment for cannabis dependence (N=175) was conducted. Self-report assessments of motivation to change, self-efficacy, and other clinical correlates were completed at baseline, and cannabis use was measured throughout the study. RESULTS There was a significant interaction between gender and taking steps on abstinence. Counter to hypothesis, higher taking steps reduced likelihood of achieving abstinence among women; there was no association among men. Subsequently, taking steps was associated with self-efficacy and quantity of use among men, and cannabis related problems among women. There was a significant interaction between gender and readiness to change on creatinine adjusted cannabinoid levels. Change readiness was positively associated with cannabinoid levels among women, but not men. CONCLUSIONS Motivation to change and initiation of change behavior predict worse cannabis outcomes in women. Men and women differ in what motivates change behavior. Social desirability, neurobiology, and treatment type may impact these effects. Gender differences in cannabis use and treatment responsiveness must be considered in future studies.

Approach bias modification for cannabis use disorder: A proof-of-principle study

BACKGROUND More effective treatments for cannabis use disorder (CUD) are needed. Evidence suggests that biases in cognitive processing of drug-related stimuli are central to the development and maintenance of addiction. The current study examined the feasibility and effect of a novel intervention - approach bias modification (ApBM) - on cannabis approach bias and cue-reactivity. METHODS A randomized, double-blind, sham-controlled proof-of-principle laboratory experiment investigated the effect of a four-session computerized ApBM training protocol on cannabis approach bias and cue-reactivity in non-treatment seeking adults age 18-65 with CUD (N = 33). ApBM procedures involved responding to cannabis or neutral stimuli using a computer joystick to model approach or avoidance behavior. Reactivity to tactile, olfactory, and auditory cue sets was assessed with physiological (blood pressure and heart rate) and subjective (cannabis craving) measures. Cannabis use was assessed via self-report. RESULTS Participants receiving ApBM showed blunted cannabis cue-induced craving at the end of training compared to those in the sham-ApBM condition (p = .05). A preliminary gender effect on cannabis use was also found; men receiving ApBM reported fewer cannabis use sessions per day at the end of training compared to women (p = .02), while there were no differences between men and women in the sham condition. ApBM did not attenuate cannabis approach bias following training. CONCLUSION Preliminary results indicate that ApBM may be efficacious in reducing cannabis cue-reactivity and improving cannabis use outcomes. While encouraging, the results should be interpreted with caution. Investigation of ApBM as an adjunct to psychosocial treatments for treatment-seeking adults with CUD is warranted.

Effect of oxytocin pretreatment on cannabis outcomes in a brief motivational intervention

Motivational enhancement therapy (MET) is efficacious in reducing cannabis use, yet benefits are generally short-lived. Oxytocin is a hypothalamic neuropeptide that promotes prosocial behaviors and plays a role in drug-related neuroadaptations; as such, oxytocin may enhance the effect of MET on cannabis outcomes. Cannabis dependent adults were randomized to receive MET plus oxytocin (n =8) or placebo (n =8). Participants receiving oxytocin showed reductions in amount of cannabis used daily and number of sessions per day. Participants receiving placebo did not evidence significant reductions. Powered clinical trials of oxytocin-enhanced MET for cannabis use disorder are warranted.

Incremental validity of estimated cannabis grams as a predictor of problems and cannabinoid biomarkers: Evidence from a clinical trial

BACKGROUND Quantifying cannabis use is complex due to a lack of a standardized packaging system that contains specified amounts of constituents. A laboratory procedure has been developed for estimating physical quantity of cannabis use by utilizing a surrogate substance to represent cannabis, and weighing the amount of the surrogate to determine typical use in grams. METHOD This secondary analysis utilized data from a multi-site, randomized, controlled pharmacological trial for adult cannabis use disorder (N=300), sponsored by the National Drug Abuse Treatment Clinical Trials Network, to test the incremental validity of this procedure. In conjunction with the Timeline Followback, this physical scale-based procedure was used to determine whether average grams per cannabis administration predicted urine cannabinoid levels (11-nor-9-carboxy-Δ9-tetrahydrocannabinol) and problems due to use, after accounting for self-reported number of days used (in the past 30 days) and number of administrations per day in a 12-week clinical trial for cannabis use disorder. RESULTS Likelihood ratio tests suggest that model fit was significantly improved when grams per administration and relevant interactions were included in the model predicting urine cannabinoid level (X2=98.3; p<0.05) and in the model predicting problems due to cannabis use (X2=6.4; p<0.05), relative to a model that contained only simpler measures of quantity and frequency. CONCLUSIONS This study provides support for the use of a scale-based method for quantifying cannabis use in grams. This methodology may be useful when precise quantification is necessary (e.g., measuring reduction in use in a clinical trial).

Impact of endogenous progesterone on reactivity to yohimbine and cocaine cues in cocaine-dependent women

Background and objective: Data from clinical and preclinical models of relapse suggest that progesterone attenuates cocaine‐seeking behavior. In a recent study, we found that cocaine‐dependent women reported greater subjective responses to cues that were preceded by a stressor than cocaine‐dependent men. The objective of this study was to examine the impact of endogenous progesterone on the subjective and endocrine responses to a drug‐paired cue that was preceded by a stressor in cocaine‐dependent women. Methods: Cocaine‐dependent women with low (< 4 ng/ml; n = 16) and high (≥ 4 ng/ml; n = 9) plasma progesterone levels received either the alpha‐2 adrenergic receptor antagonist yohimbine (21.6 mg) or placebo before each of two cocaine‐cue exposure sessions. Participants were tested under both conditions in a counterbalanced, double‐blind fashion. Data were collected after study drug administration, immediately and at 5, 30, and 60 min after the cue. Results: The anxiety response to the cue was differentially modified by progesterone levels under the two administration conditions (condition × progesterone level interaction, F1,23 = 9.8, p = 0.005). Progesterone levels also modified the craving response to the cue differently under the placebo condition as compared to the yohimbine condition (condition × progesterone level interaction, F1,23 = 13.9, p = 0.001). In both cases, high progesterone levels attenuated craving and anxiety response to the cue following yohimbine administration. There was no effect of progesterone levels on salivary cortisol or dehydroepiandrosterone under the placebo condition or under the yohimbine condition. Conclusions: These preliminary data suggest that high levels of endogenous progesterone attenuate subjective responses to drug‐cues that are preceded by a stressor. Importantly, these data support a growing literature demonstrating the protective effects of progesterone on the vulnerability to cocaine relapse in women. HIGHLIGHTSWe examined the effect of endogenous progesterone on reactivity following a stressor.High‐progesterone cocaine‐dependent women showed attenuated subjective reactivity.Progesterone may protect against stress‐induced relapse in cocaine‐dependent women.

Impact of cannabis legalization on treatment and research priorities for cannabis use disorder

Abstract An increasing proportion of the world has legalized cannabis for medicinal or recreational use. The legalization trend appears to be continuing. These changes in the legislative landscape may have important health, treatment, and research implications. This review discusses public health outcomes that may be impacted by increases in cannabis availability and use. It additionally considers potential research and treatment priorities in the face of widespread cannabis legalization.

Biological correlates of self-reported new and continued abstinence in cannabis cessation treatment clinical trials

BACKGROUND The agreement between self-reported cannabis abstinence with urine cannabinoid concentrations in a clinical trials setting is not well characterized. We assessed the agreement between various cannabinoid cutoffs and self-reported abstinence across three clinical trials, one including contingency management for abstinence. METHODS Three cannabis cessation clinical trials where participants reported use and provided weekly urine samples for cannabis and creatinine concentration measurements were included. Bootstrapped data were assessed for agreement between self-reported 7+ day abstinence and urine cannabinoid tests using generalized linear mixed effects models for clustered binary outcomes. One study implemented contingency management for cannabis abstinence. Four hundred and seventy-three participants with 3787 valid urine specimens were included. Urine was analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol and creatinine using immunoassay methods Biological cutoffs of 50, 100, and 200 ng/ml, as well as changes in CN normalized THCCOOH (25%/50% decrease), were assessed for agreement with self-reported abstinence during the three clinical trials. RESULTS Agreement between measured THCCOOH and self-reported abstinence increases with increasing cutoff concentrations, while the agreement with self-reported non-abstinence decreases with increasing cutoff concentrations. Combining THCCOOH cutoffs with recent changes in CN-THCCOOH provides a better agreement in those self-reporting abstinence. Participants in the studies that received CM for abstinence had a lower agreement between self-reported abstinence and returned to use than those in studies that did not have a contingency management component. CONCLUSION Using combinations of biological measurements and self-reported abstinence, confirmation of study related abstinence may be verifiable earlier and with greater accuracy than relying on a single measurement.