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

Neuropsychopharmacology (2025)Cite this article

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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.

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Fig. 1: Timecourse and peak effects for subjective effects.
Fig. 2: Timecourse and peak effects for performance effects.
Fig. 3: Timecourse and peak effects (Cmax) for plasma Δ9-THC and metabolites.

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Data availability

Data and source code for analysis are available upon request.

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Funding

Support for this study was provided by a research contract from Canopy Growth Corporation and professional development funds from Johns Hopkins University. Canopy Growth Corporation had no direct role in data collection, analysis, or restrictions on publishing of data generated during the conduct of the study.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    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

  2. iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Jost Klawitter, Cristina Sempio, Jorge Campos-Palomino & Uwe Christians

  3. Arkansas Clinic for Stress & Anxiety, Fayetteville, AR, USA

    Matthew T. Feldner

  4. Department of Psychology, James Madison University, Harrisonburg, VA, USA

    Jessica G. Irons

  5. Charlotte’s Web, Louisville, CO, USA

    Marcel O. Bonn-Miller

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  1. Justin C. Strickland
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Contributions

JCS, RV, CAZ, TRS, DL, CLB, MTF, JGI, and MOBM contributed to study design. JCS, HET, NMP, and DW contributed to study oversight and data collection. JK, CS, JCP, and UC contributed to pharmacokinetic analysis. JCS and CAZ contributed to data analysis. JCS drafted the initial manuscript with critical feedback from all authors.

Corresponding author

Correspondence to Justin C. Strickland.

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Competing interests

JCS has received research related funding from Canopy Growth Corporation and DynamiCare Health and consulting fees from Realm of Caring Foundation and Merck Corporation in the past three years. TRS has received research funding from Cultivate Biologics and consulting fees from Canopy Growth in the past three years. MOBM is employed by Charlotte’s Web, serves as a board member of DeFloria, and is a past employee of Canopy Growth Corporation. The remaining authors have nothing to disclose.

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Strickland, J.C., Tilton, H.E., Patton, N.M. et al. Effect of caffeine and cannabidiol (CBD) co-administration on Δ9-tetrahydrocannabinol (Δ9-THC) subjective effects, performance impairment, and pharmacokinetics. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02232-x

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