5HT-2C agonist lorcaserin decreases cannabis self-administration in daily cannabis smokers.

There are no FDA-approved treatments for cannabis use disorder (CUD). Preclinical research has shown that the 5HT-2C agonist lorcaserin attenuates cue-induced reinstatement of THC seeking and self-administration. The goal of this placebo-controlled, counterbalanced, within-subject human laboratory study was to examine lorcaserin's effects on cannabis intoxication and self-administration. Lorcaserin (10 mg BID) was administered during one of two 13-day inpatient phases and placebo during the other; each phase was separated by ≥7 days of washout. Inpatient phases comprised (1) standardized cannabis administration (7.0% THC) at no financial cost (intoxication), counterbalanced with (2) the option to self-administer cannabis following either 0 or 3 days of abstinence. Cognitive task performance, food intake, subjective ratings of drug effects, objective/subjective sleep measures, and tobacco cigarette use were also assessed. Fifteen normal-weight, daily cannabis users (4F, 11M) not seeking treatment for CUD completed the study. Lorcaserin significantly reduced cannabis self-administration following 0 and 3 days of cannabis abstinence and also reduced craving for cannabis during abstinence. Lorcaserin produced small but significant increases in positive cannabis ratings and body weight relative to placebo. Lorcaserin also reduced tobacco cigarette smoking on days of cannabis administration relative to placebo. During abstinence, subjective but not objective measures of sleep quality worsened during lorcaserin maintenance. Overall, lorcaserin's ability to decrease drug taking and cannabis craving in nontreatment-seeking cannabis users supports further investigation of 5HT-2C agonists as potential pharmacotherapies for CUD.

Guanfacine decreases symptoms of cannabis withdrawal in daily cannabis smokers.

The α2a-adrenergic agonist, lofexidine, reduced cannabis withdrawal-related sleep disruption in the laboratory, but side effects (e.g. fatigue, hypotension) limit its utility as a treatment for cannabis use disorder. This study tested the potential efficacy and tolerability of a daily bedtime administration of the FDA-approved α2a-adrenergic agonist, guanfacine, in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (13M, 2F) completed a within-subject study comprising two 9-day inpatient study phases. Each phase tested the effects of daily placebo or immediate-release guanfacine (2 mg) on cannabis intoxication (5.6 percent THC; 2 days), withdrawal (4 days of abstinence) and subsequent 'relapse' (3 days of cannabis self-administration). Ratings of mood, sleep, cardiovascular effects, food intake, psychomotor performance and cannabis self-administration were assessed. An outpatient phase preceded each inpatient phase for medication clearance or dose induction. Under placebo medication conditions, cannabis abstinence produced significant withdrawal, including irritability, sleep disruption and anorexia. Guanfacine reduced ratings of irritability and improved objective measures of sleep during cannabis withdrawal relative to placebo but did not reduce cannabis self-administration. Guanfacine was well tolerated with little evidence of fatigue and only small decreases in blood pressure: no dose was held due to hypotension. Thus, a single daily administration of guanfacine at bedtime improved sleep and mood during cannabis withdrawal relative to placebo. This positive signal supports further studies varying the guanfacine dose, formulation or frequency of administration, or combining it with other medications to increase the likelihood of having an impact on cannabis use.

Varenicline and nabilone in tobacco and cannabis co-users: effects on tobacco abstinence, withdrawal and a laboratory model of cannabis relapse.

Tobacco and cannabis co-users (T+CUs) have poor cannabis cessation outcomes, but the mechanisms underlying this are not well understood. This laboratory study examined the effects of (1) the partial nicotinic agonist, varenicline, on tobacco cessation among T+CUs, and (2) varenicline, alone, and when combined with the cannabinoid agonist nabilone, on cannabis withdrawal and a laboratory model of cannabis relapse. Non-treatment-seeking T+CUs were randomized to active-varenicline or placebo-varenicline, and completed a 15-day outpatient phase; varenicline was titrated to 1 mg BID during days 1-8, and participants were instructed to abstain from tobacco during days 9-15. Participants then moved inpatient for 16 days, where they continued their outpatient medication and tobacco abstinence. Inpatient testing included two, 8-day medication periods, where active-nabilone and placebo-nabilone were administered in counterbalanced order, and measures of acute cannabis effects (days 1-2), withdrawal (days 4-5) and 'relapse' (days 6-8) were collected. Participants in the active-varenicline group were more likely to achieve cotinine-verified tobacco abstinence during the outpatient period versus placebo-varenicline group (46 percent versus 24 percent, respectively), and also reported less mood disturbance and cigarette craving while inpatient. Active-nabilone attenuated cannabis withdrawal in both groups but did not affect cannabis relapse. Regression analyses revealed that two tobacco-related variables, i.e. age of first cigarette use, and cigarette craving while inpatient, were independent predictors of cannabis relapse outcomes. Thus, varenicline holds promise in this population, as a tool to examine the effects of tobacco abstinence on cannabis use outcomes, and as a component of smoking cessation treatments targeting T+CUs.

Cardiovascular and subjective effects of repeated smoked cocaine administration in experienced cocaine users.

Studies using rodents have shown that behavioral responses to a stimulant are enhanced when the stimulant is given within the same context as previous stimulant administrations; this increase in effect related to context is often referred to as sensitization. We examined the role of environmental stimuli in modulating the subjective and cardiovascular effects of cocaine in humans (1) within a daily "binge" and (2) after cocaine abstinence. Ten non-treatment seeking users of smoked cocaine were admitted to the hospital for 17 consecutive days. Participants smoked cocaine (25mg/dose) under two counterbalanced conditions: paired stimuli (same stimuli presented each session) and unpaired stimuli (varied stimuli presented each session). Under each stimulus condition, participants had cocaine test sessions for three consecutive days, no sessions for the next 3 days, then another cocaine test session on the following day, for a total of eight test days. Stimulus condition had no effect on cardiovascular or subjective effects so data were analyzed as a function of repeated cocaine administration over 2 weeks. Maximal ratings on "good drug" and "drug rating" subjective effects clusters decreased over days of repeated cocaine exposure. In contrast, baseline and peak heart rate and systolic pressure increased over days of repeated cocaine administration. Thus, repeated administration of smoked cocaine to experienced cocaine users resulted in increases in baseline blood pressure and heart rate and modest decreases in positive subjective effects. These data indicate modest tolerance rather than sensitization to the positive subjective effects of cocaine with repeated exposure.

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse.

INTRODUCTION: Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence. OBJECTIVES: The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an alpha(2)-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence. MATERIALS AND METHODS: Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured. RESULTS: THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone. CONCLUSIONS: These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.