Effect of caffeine and cannabidiol (CBD) co-administration on Δ9-tetrahydrocannabinol (Δ9-THC) subjective effects, performance impairment, and pharmacokinetics.
Justin C Strickland, Hayleigh E Tilton, Noah M Patton, Ryan Vandrey, C Austin Zamarripa, Tory R Spindle, Dustin C Lee, Cecilia L Bergeria, David Wolinsky, Jost Klawitter, Cristina Sempio, Jorge Campos-Palomino, Uwe Christians, Matthew T Feldner, Jessica G Irons, Marcel O Bonn-Miller
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology November 1, 2025 DOI: 10.1038/s41386-025-02232-x via PubMed
Summary
AI-generated from the abstractCaffeine co-administered with THC produced minimal changes in subjective effects, performance, or metabolism, though signals for perceived driving impairment were observed. In contrast, CBD co-administered with THC and caffeine increased outcomes associated with abuse liability and performance impairment versus THC alone. CBD also increased plasma THC and 11-OH-THC concentrations. These data provide the first direct assessment of pharmacodynamic and pharmacokinetic effects of THC and caffeine co-administered in humans, emphasizing the importance of considering full cannabinoid profiles and drug combinations in regulatory decision-making.
Study at a glance
| Characteristics | Double-blind, randomized, placebo-controlled, within-subject crossover study Peer reviewed |
|---|---|
| Sample size | 20 |
| Population | Healthy adults (10 men, 10 women) |
| Interventions | Δ9-THC caffeine CBD |
| Dose | 7.5 mg cumulative Δ9-THC, 180 mg cumulative caffeine, 105 mg cumulative CBD |
| Duration | Outpatient laboratory sessions |
| Key finding | Caffeine produced minimal changes in THC-induced effects, but CBD increased outcomes associated with abuse liability and performance impairment, and increased plasma THC and 11-OH-THC concentrations. |
Abstract
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.