The Pharmacokinetics and Pharmacodynamics of a Hemp-Derived "Full-Spectrum" Oral Cannabinoid Product with a 1:1 Ratio of Cannabidiol to Cannabidiolic Acid and Delta-9-Tetrahydrocannabinol to Delta-9-Tetrahydrocannabinolic Acid: A Double-Blind, Placebo-Controlled, Within-Subjects Human Laboratory Study.

Aim: To examine the acute pharmacokinetics (PK) and pharmacodynamics (PD) of a patented oral cannabinoid product containing a botanical hemp-derived "full-spectrum" extract with an approximate 1:1 ratio of cannabidiol (CBD) to cannabidiolic acid (CBDA) and delta-9-tetrahydrocannabinol (THC) to delta-9-tetrahydrocannabinolic acid (THCA). Methods: Healthy adults (n = 15) ingested soft gels containing 0 (placebo), and approximately 1, 2, and 4 mg/kg of total cannabinoids (combination of CBD, CBDA, THC, THCA, and other minor cannabinoids) in an ascending-dose order in four experimental sessions separated by ≥1 week (the placebo condition occurred randomly within the dose sequence). Mean doses (mg) of primary cannabinoids in the active drug conditions were: 1 mg/kg condition (CBD = 41.1, CBDA = 43.7, THC = 2.2, THCA = 1.6), 2 mg/kg condition (CBD = 73.4, CBDA = 77.9, THC = 3.9, THCA = 2.9), and 4 mg/kg condition (CBD = 134.5, CBDA = 142.8, THC = 7.2, THCA = 5.3). PD outcomes (subjective, cognitive, and physiological effects) were measured before and repeatedly for 8 h after dosing. Plasma specimens were collected throughout the 8-h sessions and at 24- and 48-h post-dosing. PK outcomes included peak plasma concentration (C_max) and time to maximum concentration (T_max). Results: For PD outcomes, few differences were observed between 1 mg/kg and placebo. However, relative to placebo, 2 mg/kg and 4 mg/kg produced small to moderate increases in subjective drug effects, including abuse liability items (e.g., "like"), and 4 mg/kg also impaired working memory performance. Generally, PD effects peaked 3-5 h post-dosing and returned to baseline by 8 h. Dose-orderly increases in C_max were observed for CBD, CBDA, THC, THCA, and their respective metabolites (e.g., 7-COOH-CBD, THCCOOH), which were often detectable 48 h post-dosing. Across all doses, C_max for CBDA and THCA was 19-25-fold higher and T_max was up to 2-fold earlier compared with CBD and THC, respectively. Conclusions: Acute administration of a "full-spectrum" hemp-derived cannabinoid product produced dose-orderly effects; the highest dose elicited several adverse events and produced moderate cognitive impairment and subjective intoxication, despite containing a relatively low dose of THC (mean: 7.2 mg). Carboxylated cannabinoids (e.g., CBDA) exhibited substantially greater bioavailability and faster absorption compared with decarboxylated cannabinoids (e.g., CBD). Additional systematic research is needed to characterize how constituent profile impacts the effects of cannabinoid products, and more studies directly comparing carboxylated and decarboxylated compounds appear warranted.