Pharmacological Smoking Cessation Interventions in People with Cannabis, Opioid, or Stimulant Use Disorders: A Systematic Review

Introduction . Tobacco use disorder (TUD) is highly prevalent among people with cannabis use disorder (CUD), opioid use disorder (OUD), and stimulant use disorder (StUD), encompassing cocaine use disorder and methamphetamine use disorder. TUD increases the severity of other substance use disorders and leads to increased incidence of health complications, resulting in elevated mortality. We reviewed studies that examined the impact of approved pharmacological smoking cessation strategies, either alone or in combination with behavioral interventions, in people with CUD, OUD, and StUD who smoke tobacco cigarettes. Methods . We registered the systematic review on PROSPERO (CRD42023467758). We searched three databases (PubMed/Medline, Google Scholar, and EMBASE) using specific MeSH terms to identify human clinical trials published in English between January 1 ^st , 2000, and September 30th, 2024. Results . We selected 27 eligible studies, encompassing 1) CUD (n=7); 2) OUD (n=15); and 3) StUD (n=5). Approved pharmacological smoking cessation interventions, such as nicotine replacement therapy (NRT), varenicline, and bupropion, demonstrated poor efficacy in CUD, OUD, and StUD. We identified just four placebo-controlled trials for varenicline (1 in CUD, 2 in OUD, and 1 in StUD). Varenicline showed the most promise in StUD, short-term benefit in CUD, and, paradoxically, no benefit over placebo in two well-controlled OUD trials. Just four studies performed the recommended biochemical verification using both exhaled carbon monoxide (CO) and urine cotinine. Conclusions . Across the three disorders, pharmacological smoking cessation interventions demonstrated poor efficacy. More importantly, these conclusions were drawn from a sparse number of studies. Outcome measures were inconsistent across studies. Implications . This systematic review reveals a profound evidence gap in smoking cessation treatment for individuals with CUD, OUD, or StUD. Across 27 included studies, we identified only four placebo-controlled varenicline trials combined across all three disorders, in stark contrast to 33 such trials in general populations. The limited available evidence suggests approved pharmacological interventions demonstrate suboptimal and variable efficacy compared to the general population. Varenicline showed the most promise in StUD, short-term benefit in CUD, and no clear benefit in two placebo-controlled OUD trials. Bupropion demonstrated efficacy in StUD but limited evidence in other disorders. Combination pharmacotherapy remains almost completely unstudied in these populations. Most studies followed participants for 12 weeks or less, providing little information about sustained long-term abstinence. Current clinical practice guidelines offer insufficient disorder-specific guidance and do not acknowledge the apparent differential treatment responses across specific disorders. Urgent research priorities include: (1) adequately powered, placebo-controlled trials of single and combination pharmacotherapies with extended follow-up; (2) investigate novel interventions such as cytisine, digital therapeutics, and TMS; (3) and develop disorder-specific treatment approaches.