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 (IV) nicotine. METHODS: We pooled data from 2 randomized, double-blind, placebo-controlled studies using IV nicotine to isolate nicotine's pharmacodynamics in adults who smoke tobacco cigarettes (N = 60). Participants completed 3 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 11-nor-9-carboxy-delta-9-tetrahydrocannabinol 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.