Recent Cannabis Exposure and Acute Nicotine Effects: Insights from Randomized, Double-Blind, Placebo-Controlled Intravenous Nicotine Studies

Objective Cannabis–nicotine co-use is common and may affect cessation outcomes, yet whether recent cannabis exposure alters nicotine’s acute effects in humans remains unclear. We examined whether recent, non-daily cannabis exposure modulates the acute subjective effects of intravenous nicotine. Methods We pooled data from two randomized, double-blind, placebo-controlled studies using intravenous (IV) nicotine to isolate nicotine’s pharmacodynamics in adults who smoke tobacco cigarettes (N=60). Participants completed three sessions (placebo, 0.1 mg, 0.2 mg nicotine/70 kg). Recent cannabis exposure was defined a priori (past-30-day use with positive urine THC-COOH vs no past-30-day use with negative screen). Primary outcomes were peak Drug Effects Questionnaire (DEQ) composites—stimulatory, pleasurable, aversive—within 10 minutes post-infusion. Secondary outcomes included nicotine self-administration behavior (proportion of nicotine choices) and cardiovascular responses (heart rate, blood pressure). Linear mixed-effects models included dose, cannabis exposure, sex, and FTND. Results: Nicotine increased all DEQ domains dose-dependently (p<.0001). Aversive effects showed a significant dose x cannabis exposure interaction (χ2=13.31, p=.001): participants with recent cannabis exposure reported greater aversive responses at 0.2 mg (Cohen’s d’=0.83), with minimal between-group differences at placebo/0.1 mg. Nicotine self-administration did not differ by cannabis exposure status, and no dose x cannabis exposure interactions were observed for cardiovascular responses. Conclusions Recent, non-daily cannabis exposure is thus associated with selectively greater aversive responses to a clinically relevant IV nicotine dose, without differential cardiovascular reactivity or altered nicotine choice. These findings support a shift in the aversive limb of nicotine’s dose–response and inform mechanistic and clinical studies on how cannabis exposure shapes nicotine reinforcement and cessation outcomes. Clinical trial registration: NCT01495819, https://clinicaltrials.gov/study/NCT01495819.