Effect of caffeine and cannabidiol (CBD) co-administration on Δ9-tetrahydrocannabinol (Δ9-THC) subjective effects, performance impairment, and pharmacokinetics

Cannabis products premixed with caffeine are increasingly present in the United States marketplace. Despite emergence of this product class, no human laboratory data have directly evaluated the isolated impact of caffeine on Δ9-tetrahydrocannabinol (Δ9-THC) effects as well as additional impacts of other common co-administered cannabinoids. This double-blind, randomized, placebo-controlled, within-subject crossover study evaluated potential pharmacodynamic and pharmacokinetic interactions between/among Δ9-THC, caffeine, and cannabidiol (CBD). Participants (N = 20; 10 men/10 women) completed outpatient laboratory sessions in which oral Δ9-THC (7.5 mg cumulative), caffeine (180 mg cumulative), and/or CBD (105 mg cumulative) were co-administered in a cumulative dosing design. Primary outcomes included subjective effects indicative of abuse liability (e.g., drug high), performance effects that underlie safety risk (e.g., simulated driving), and plasma cannabinoid/caffeine concentrations. Caffeine co-administration produced minimal changes in Δ9-THC-induced subjective effects, performance, or metabolism, although signals for perceived driving impairment were observed. In contrast, CBD, when co-administered with Δ9-THC and caffeine increased outcomes associated with abuse liability (e.g., drug high, p = 0.002) and performance impairment versus Δ9-THC alone. CBD also increased plasma Δ9-THC (p = 0.004) and 11-OH-Δ9-THC (p < 0.001) concentrations compared with dose conditions without CBD co-administration. These data provide the first direct assessment of the pharmacodynamic and pharmacokinetic effects of Δ9-THC and caffeine when co-administered in humans. The robust alteration of Δ9-THC-induced effects and Δ9-THC pharmacokinetics by CBD further emphasizes the importance of considering full cannabinoid profiles. Broadly, these data highlight the importance of considering drug combinations and interactions in future cannabis regulatory decision-making.