Varenicline shows promise, but cannabis treatment evidence remains mixed

Cannabis use disorder (CUD) is one of the highest prevalence mental health conditions globally. Psychosocial treatments for CUD have modest efficacy. There are currently no approved adjunctive pharmacological approaches for CUD. Varenicline, a nicotinic receptor partial agonist approved for use in smoking cessation, has shown promise as a treatment for CUD. This study aims to synthesise the literature on the efficacy of varenicline in treating CUD. A secondary aim is to examine the tolerability of varenicline and its effect on concurrent tobacco use within CUD treatment. A pre-registered systematic review of records extracted from Ovid MEDLINE ALL, CINAHL Complete, APA PsycInfo, Embase, Cochrane Central Register of Controlled Trials, Web of Science Core Collection, Scopus, Clinicaltrials.gov, the WHO International Clinical Trials Registry, and Google Scholar (final extraction March 2025). Original peer-reviewed studies assessing the effect of varenicline on cannabis use or CUD in adolescents (13-18 years) or adults (18-65 years) were included. Risk of bias and study quality assessments were conducted. Five studies were identified as eligible for inclusion (total N = 299). Four studies were Randomized Controlled Trials and one was a case series. Two studies were assessed as poor quality, two as fair quality and one good quality. Narrative synthesis of studies was conducted because of lack of compatible study methodologies required for meta-analytic approaches. Mixed results were found on the efficacy of varenicline on cannabis use across studies. The single high-quality study demonstrated significant reductions in cannabis use and cannabis withdrawal symptoms. The three studies reporting on the secondary outcome of tolerability also demonstrated inconsistent findings. The high-quality study found no difference in participants experiencing at least one adverse event between the varenicline and placebo groups, however nausea was reported more frequently in the varenicline group. Inconsistent findings were observed across the four studies that measured concurrent tobacco use, with the one high-quality study reporting no differences in cigarettes per day over the treatment phase between the varenicline and placebo groups. There is currently insufficient data to draw confident conclusions about the efficacy and tolerability of varenicline as treatment for CUD in youth and adult populations.