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.

Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users.

RATIONALE: Each year, over 300,000 individuals in the USA enter treatment for cannabis use disorder (CUD). The development of effective pharmacotherapy for CUD is a priority. OBJECTIVE: This placebo-controlled study examined the effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory measure of relapse. METHODS: Eleven daily, non-treatment-seeking cannabis users completed three, 8-day inpatient phases; each phase tested a different medication condition in counter-balanced order. On the first day of each phase, participants were administered placebo capsules t.i.d. and smoked experimenter-administered active cannabis (5.6 % Δ(9)-tetrahydrocannabinol (THC)). On days 2-8, the participants were administered capsules containing either placebo (0 mg at 0900, 1800, and 2300 hours), zolpidem (0 mg at 0900 and 1800, and 12.5 mg at 2300), or zolpidem (12.5 mg at 2300) and nabilone (3 mg at 0900 and 1800). Cannabis withdrawal, subjective capsule effects, and cognitive performance were examined on days 3-4, when only inactive cannabis (0.0 % THC) was available for self-administration. "Relapse" was measured on days 5-8, when participants could self-administer active cannabis. RESULTS: Both medication conditions decreased withdrawal-related disruptions in sleep, but only zolpidem in combination with nabilone decreased withdrawal-related disruptions in mood and food intake relative to placebo. Zolpidem in combination with nabilone, but not zolpidem alone, decreased self-administration of active cannabis. Zolpidem in combination with nabilone also produced small increases in certain abuse-related subjective capsule ratings, while zolpidem alone did not. Neither medication condition altered cognitive performance. CONCLUSIONS: Clinical testing of nabilone, either alone, or in combination with zolpidem is warranted.

Naltrexone Maintenance Decreases Cannabis Self-Administration and Subjective Effects in Daily Cannabis Smokers.

Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4-6 weeks, assessing cannabis' behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects ('good effect'). Participants in the placebo group had 7.6 times (95% CI: 1.1-51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of 'good effect' in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone's efficacy as a treatment for cannabis use disorder.

Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers.

Marijuana dependence is a substantial public health problem, with existing treatments showing limited efficacy. In laboratory and clinical studies, the cannabinoid receptor 1 agonist oral Δ9tetrahydrocannabinol (THC; dronabinol) has been shown to decrease marijuana withdrawal but not relapse. Dronabinol has poor bioavailability, potentially contributing to its failure to decrease relapse. The synthetic THC analogue, nabilone, has better bioavailability than dronabinol. We therefore aimed to characterize nabilone's behavioral and physiological effects across a range of acute doses in current marijuana smokers and compare these with dronabinol's effects. Participants (4 female; 10 male) smoking marijuana 6.6 (standard deviation = 0.7) days/week completed this outpatient, within-subjects, double-blind, randomized protocol. Over seven sessions, the time-dependent subjective, cognitive and cardiovascular effects of nabilone (2, 4, 6, 8 mg), dronabinol (10, 20 mg) and placebo were assessed. Nabilone (4, 6, 8 mg) and dronabinol (10, 20 mg) increased ratings of feeling a good effect, a strong effect and/or 'high' relative to placebo; nabilone had a slower onset of peak subjective effects than dronabinol. Nabilone (6, 8 mg) modestly lowered psychomotor speed relative to placebo and dronabinol. There were dose-dependent increases in heart rate after nabilone, and nabilone (2 mg) and dronabinol (10 mg) decreased systolic blood pressure. Thus, nabilone produced sustained, dose-related increases in positive mood, few cognitive decrements and lawful cardiovascular alterations. It had a longer time to peak effects than dronabinol, and effects were more dose-related, suggesting improved bioavailability. Nabilone was well tolerated by marijuana smokers, supporting further testing as a potential medication for marijuana dependence.

Efficacy and tolerability of high-dose dronabinol maintenance in HIV-positive marijuana smokers: a controlled laboratory study.

RATIONALE: Dronabinol (Δ(9)tetrahydrocannabinol) is approved for HIV-related anorexia, yet, little is known about its effects in HIV-positive marijuana smokers. HIV-negative marijuana smokers require higher than recommended dronabinol doses to experience expected effects. OBJECTIVES: Employing a within-subjects, double-blind, placebo-controlled design, we assessed the effects of repeated high-dose dronabinol in HIV-positive marijuana smokers taking antiretroviral medication. METHODS: Participants (N = 7), who smoked marijuana 4.2 ± 2.3 days/week, resided in a residential laboratory for two 16-day stays, receiving dronabinol (10 mg QID) in one stay and placebo in the other. Efficacy was assessed with objectively verified food intake and body weight. Tolerability was measured with sleep, subjective, and cognitive assessments. For analyses, each inpatient stay was divided into two phases, days 1-8 and 9-16; we compared dronabinol's effects with placebo in each 8-day phase to investigate tolerance. RESULTS: Despite sustained increases in self-reported food cravings, dronabinol only increased caloric intake in the initial 8 days of dosing. Similarly, sleep quality was improved only in the first 8 days of dosing. Dronabinol's mood-enhancing effects were sustained across the 16-day inpatient stay. Dronabinol was well tolerated, causing few negative subjective or cognitive effects. CONCLUSIONS: In HIV-positive marijuana smokers, high dronabinol doses safely and effectively increased caloric intake. However, repeated high-dose dronabinol appeared to result in selective tolerance to these effects. These findings indicate that HIV-positive individuals who smoke marijuana may require higher dronabinol doses than are recommended by the FDA. Future research to establish optimal dosing regimens, and reduce the development of tolerance, is required.

Best practices: the consultation-liaison in primary-care psychiatry program: a structured approach to long-term collaboration.

This column presents the Consultation-Liaison in Primary-Care Psychiatry model, which was developed in Australia. This model is a structured approach to collaborative care of people with mental illnesses between primary care services and specialist mental health services. The first component of the model is a consultation, liaison, and education service provided by psychiatric consultants at participating general practices. The second component involves transferring selected patients from community mental health services into general practitioner-based collaborative care. In the final component a clinical case-register and reminder system managed by the specialist services is used to actively promote follow-up for transferred clients. The column also offers some evidentiary support for this care model that suggests a best-practices model for maintaining adequacy of care for patients.