Varenicline as a treatment for cannabis use disorder: A placebo-controlled pilot trial.

BACKGROUND: An efficacious pharmacotherapy for cannabis use disorder (CUD) has yet to be established. This study preliminarily evaluated the safety and efficacy of varenicline for CUD in a proof-of-concept clinical trial. METHODS: Participants in this 6-week randomized, placebo-controlled pilot trial received either varenicline (n = 35) or placebo (n = 37), added to a brief motivational enhancement therapy intervention. Outcomes included cannabis withdrawal, cannabis abstinence, urine cannabinoid levels, percent cannabis use days, and cannabis sessions per day. RESULTS: Both treatment groups noted significant decreases in self-reported cannabis withdrawal, percentage of days used, and use sessions per day during treatment compared to baseline. While this pilot trial was not powered to detect statistically significant between-group differences, participants randomized to varenicline evidenced numerically greater rates of self-reported abstinence at the final study visit [Week 6 intent-to-treat (ITT): Varenicline: 17.1% vs. Placebo: 5.4%; RR = 3.2 (95% CI: 0.7,14.7)]. End-of-treatment urine creatinine corrected cannabinoid levels were numerically lower in the varenicline group and higher in the placebo group compared to baseline [Change from baseline: Varenicline -1.7 ng/mg (95% CI: -4.1,0.8) vs. Placebo: 1.9 ng/mg (95% CI: -0.4,4.3); Δ = 3.5 (95% CI: 0.1,6.9)]. Adverse events related to study treatment did not reveal new safety signals. CONCLUSIONS: Findings support the feasibility of conducting clinical trials of varenicline as a candidate pharmacotherapy for CUD, and indicate that a full-scale efficacy trial, powered based on effect sizes and variability yielded in this study, is warranted.

Latency to cannabis dependence mediates the relationship between age at cannabis use initiation and cannabis use outcomes during treatment in men but not women.

BACKGROUND: Time from first cannabis use to cannabis dependence (latency) may be an important prognostic indicator of cannabis-related problems and treatment outcomes. Gender differences in latency have been found; however, research in this general area is limited. As cannabis use increases and perceived risk declines, a better understanding of how these factors interact in predicting treatment outcomes is critical. METHODS: A secondary data analysis of a randomized, double-blind, placebo-controlled pharmacotherapy trial for cannabis dependence (N = 302) examined the associations between age of cannabis use onset, time to cannabis dependence (latency), and gender on cannabis use during the trial. Mediation analysis tested whether the association between age of onset and cannabis use during the trial was mediated by latency to cannabis dependence differentially for men and women. RESULTS: Age of use initiation was inversely correlated with latency to dependence prior to treatment [HR(95% CI) = 1.18 (1.06, 1.30); p = .002] and cannabis use during treatment (ß=-1.27; SE = 0.37; p < .001). There was a significant mediation effect between age of onset, latency, and cannabis use that varied by gender. Earlier age of onset predicted longer latency, and subsequently, greater cannabis use during the trial in men (21.4% mediated; p < .05), but not women. Other substance use, race, and past psychiatric diagnosis did not predict latency either independently or in interaction models. CONCLUSION: Findings support existing evidence that early cannabis use onset is associated with worse outcomes and add new knowledge on the differential associations between age of onset, latency to cannabis dependence, and treatment outcomes for men and women.

The effect of oxytocin, gender, and ovarian hormones on stress reactivity in individuals with cocaine use disorder.

RATIONALE: Cocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction. OBJECTIVES: To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response. METHODS: One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min. RESULTS: Gender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033). CONCLUSIONS: Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect.

Self-reported cognition and marijuana use in older adults: Results from the national epidemiologic survey on alcohol and related conditions-III.

Marijuana use among older adults is on an unprecedented rise, yet little is known about its effects on cognition in this population where, due to advanced age, risk for cognitive decline is high. Thus, we investigated whether marijuana use and use characteristics were associated with self-reported cognition among older adults ages ≥ 50 years using the National Epidemiologic Survey on Alcohol and Related Conditions-III. Respondents either had never used marijuana ("never": n = 10,976), used but not in the past 12 months ("former": n = 2990), or used in the past 12 months ("current": n = 712). Self-reported cognition was measured using the Executive Function Index. Marijuana and substance use characteristics were obtained using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Covariates included demographics, mental health and disability, and comorbid mental and substance use disorder. Using general linear models of cross-sectional data, we found that current users, particularly those with cannabis use disorder, reported worse cognition than never or former users, but these effects were small in magnitude. Among both former and current users, greater duration of past use was associated with worse cognition. Frequent use within the past 12 months was associated with worse cognition among current users, but daily users reported better cognition compared to monthly or weekly users. Thus, marijuana use may impact self-reported cognition in older adulthood, although these effects may be subtle, specific to particular use characteristics, and possibly affected by self-awareness of deficits. Future work using objective measures such as neuropsychological testing or neuroimaging may better elucidate these effects.

Exogenous progesterone for cannabis withdrawal in women: Feasibility trial of a novel multimodal methodology.

BACKGROUND: Sex differences in cannabis use disorder (CUD) and its treatment have been identified. Women report more severe withdrawal and have shown worse treatment outcomes. Ovarian hormones are implicated in these differences and research suggests that exogenous progesterone may be an effective pharmacotherapy. METHODS: The current randomized, placebo-controlled, feasibility trial tested a novel multimodal methodology for administering exogenous progesterone during acute cannabis withdrawal. Eight heavy cannabis using women received micronized progesterone (200 mg bid) (n = 3) or matching placebo (n = 5) during the early follicular phase of their menstrual cycle over a 5-day study period while abstaining from cannabis. Laboratory visits (days 1 and 5) included biological and self-report assessments, while home-based procedures (days 2-4) included ambulatory assessments, video data capture and tele-drug testing, and biological assessments. Primary outcomes were medication adherence and salivary hormone levels, and the exploratory outcome was cannabis withdrawal severity. RESULTS: Medication adherence rates were high as assessed via self-report (100.0%) and video data capture (98.0%). Salivary progesterone levels differed between groups over time (p < 0.027) and the progesterone group achieved levels within the normal range during the luteal phase in healthy adults. All tele-drug tests were negative confirming cannabis abstinence and there was an indication (p = 0.07) of reduced cannabis craving among participants receiving progesterone. CONCLUSION: More effective and sex-based treatments for cannabis use disorder are needed. The current study provides a novel multimodal methodology with low participant burden for investigating new medications for cannabis withdrawal. Clinical trials of progesterone for cannabis withdrawal may be warranted.

Cannabis Withdrawal in Adults With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Cannabis withdrawal has not been studied in adults with attention-deficit/hyperactivity disorder (ADHD) who have high rates of cannabis use. We aimed to describe cannabis withdrawal, motivations to quit, and strategies to quit cannabis use in cannabis-dependent adults with ADHD. METHODS: Twenty-three adults with ADHD enrolled in a controlled clinical trial of pharmacotherapy (atomoxetine) for cannabis dependence (DSM-IV criteria) completed the Marijuana Quit Questionnaire (MJQQ) to provide information on their "most serious" quit attempt made without formal treatment. The study was conducted between November 2005 and June 2008. RESULTS: Participants were predominantly male (82.6%, n = 19), with a mean (SD) age of 27.4 (8.5) years (range, 18-53) at the start of their index quit attempt. The most common motive for quitting cannabis was "to save money" (87%, n = 20); the most common strategy to maintain abstinence was "stopped associating with people who smoke marijuana" (43%, n = 10). Almost all (96%, n = 22) subjects reported ≥ 1 cannabis withdrawal symptom; 7 (30%) met DSM-5 diagnostic criteria for cannabis withdrawal syndrome. CONCLUSIONS: Participants with comorbid ADHD and cannabis dependence reported withdrawal symptoms similar to other samples of non-treatment-seeking cannabis-dependent adults with no psychiatric comorbidity. These findings suggest that ADHD does not influence cannabis withdrawal in the way that it does tobacco (nicotine) withdrawal. TRIAL REGISTRATION: Data used in this secondary analysis came from ClinicalTrials.gov identifier: NCT00360269.

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 (<4ng/ml; n=16) and high (≥4ng/ml; n=9) plasma progesterone levels received either the alpha-2 adrenergic receptor antagonist yohimbine (21.6mg) 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 60min 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.

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).

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.

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.