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

Abstract

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.

Keywords: cannabis; pharmacotherapy; relapse; tobacco; varenicline; withdrawal.

Figure 1.

Study design, participant randomization, and participant disposition. There were no significant differences in retention between active-varenicline vs. placebo-varenicline groups. Investigator-initiated study discharges were the result of participant noncompliance with study procedures. In instances when >4 participants in a cohort completed the outpatient phase, the investigators (blinded to medication assignment) selected n=4 for move in based on attendance reliability and adherence to outpatient study procedures, including tobacco cessation outcomes.

Figure 2.

Mean (standard error of the mean) Visual Analog Scale (‘VAS’) ratings on ‘Anxious’ (A) and ‘Miserable’ (B) clusters, ratings of tobacco craving (‘I Want Cigarettes’; C), cannabis craving (‘I Want Marijuana,’; D), and mean (± standard error of the mean) sleep onset latency (E) and sleep efficiency (F) scores during baseline experimental cannabis administration (days 1–2; ‘BL’), during cannabis withdrawal on placebo-nabilone (days 4–5; ‘PBO’), and during cannabis withdrawal on active-nabilone (days 4–5; ‘NAB’) sorted as a function of varenicline group. ‘*’ indicate significant differences between placebo-varenicline vs. active-varenicline groups during days 1–2; ‘#’ indicate differences between days 1–2 vs. days 4–5 on placebo-nabilone, and ‘Δ’ indicate differences between placebo-nabilone vs. active-nabilone during days 4–5. Results are based on repeated-measures analysis of variance, with planned contrasts, and a significance threshold of p = 0.05