Beyond Pharmacokinetics: Gaps for Rational Use of Medicinal Cannabis

A recent letter highlights important gaps in translating population pharmacokinetic (popPK) models of Δ9‐tetrahydrocannabinol (THC) into clinically appropriate dosing, raising two considerations: exposure provenance and the unclear exposure–response relationship for psychiatric outcomes.

The nominal THC dose does not necessarily reflect the actual dose received. This discrepancy can arise from the product itself, given documented discordance between labeled and measured cannabinoid content, ¹ batch‐to‐batch inconsistency, and variation in regulatory source. Most of the published THC population PK studies reported only limited information on product‐level details. ² Also, it can arise from the patient, since adherence to the intended dosing regimen is rarely assessed and is a practical challenge in real‐world settings. Both factors can contribute to the known large variability in THC pharmacokinetics, partly reflected in the wide between‐subject variability in bioavailability identified across the reviewed models. Standardized recording of product provenance in future clinical trials, through a structured reporting checklist, would help close the first gap. Confirmation of administered dose, such as biochemical verification of intake or electronic dose‐monitoring devices, would help address the second.

Although the current review focused on PK variability of THC, the deep understanding of exposure–response relationship is essential for better interpretation of exposure differences on clinical outcomes. However, such PK–PD studies remain scarce and endpoints are largely limited to acute effects such as “feeling high,” alertness, and heart rate. ³ , ⁴ , ⁵ These studies also lack heterogeneous or real patient populations, as well as evaluation under long‐term or repeated dosing. Extending PK–PD research to better reflect real‐world psychiatric outcomes will require this kind of broader, longer‐term evidence, grounded in reliable exposure characterization.

Our PopPK model repository serves as a quantitative starting point for describing THC disposition. Moving beyond pharmacokinetics, however, will require closing several gaps: verifying product provenance and patient adherence to reduce dose uncertainty, and extending PK–PD research toward heterogeneous, real patient populations with longer‐term dosing and psychiatric endpoints. Addressing these gaps will be necessary to better guide dosing in medicinal cannabis practice.