The Individual and Interactive Effects of Alpha-Pinene and Delta-9-Tetrahydrocannabinol in Healthy Adults

Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (Δ9-THC), which is thought to be the primary driver of most of its acute pharmacodynamic effects. The entourage effect theory asserts that the pharmacological and therapeutic effects of cannabis are not solely attributable to Δ9-THC but are influenced by other constituents, such as minor cannabinoids and terpenes, through distinct pharmacological action. However, empirical studies that have systematically evaluated this theory in humans remain limited. This study tested the hypothesis that the terpene α-pinene can attenuate the acute memory-impairing effects of inhaled Δ9-THC in humans.

Participants (N = 19; last cannabis use 39 days, on average, prior to first test session [SD = 84; range = 2-365]) completed six double-blind outpatient drug administration sessions during which they inhaled, using a Mighty Medic hand-held vaporizer, α-pinene alone (15 mg), Δ9-THC alone (30 mg), Δ9-THC and α-pinene together (30 mg Δ9-THC + 0.5 mg α-pinene; 30 mg Δ9-THC + 5 mg α-pinene; 30 mg Δ9-THC + 15 mg α-pinene), or placebo (ambient air) in a randomized order. Outcomes, which were collected up to 6 h post-drug exposure, included subjective drug effects, cognitive/psychomotor performance, and vital signs.

Administration of 15 mg α-pinene alone produced no significant pharmacodynamic effects compared to placebo. Administration of 30 mg Δ9-THC alone elicited subjective, cognitive, and physiological effects consistent with acute Δ9-THC-dominant cannabis exposure, including impairment of cognitive performance and working memory ability compared to placebo. The co-administration of α-pinene with Δ9-THC did not mitigate Δ9-THC-induced memory impairment or significantly alter other acute subjective, cognitive, or physiological effects.

Inhaled α-pinene, at doses at and above those naturally found in cannabis flowers, did not mitigate Δ9-THC-induced cognitive impairments as hypothesized or influence other common acute effects of Δ9-THC in this sample of healthy adults. This result is inconsistent with some cannabis industry claims and speculation by some cannabis researchers. By systematically varying both Δ9-THC and terpene exposure and assessing their interaction across multiple pharmacodynamic domains, this work provides a model for future investigations into Δ9-THC-terpene interactions. As cannabis use continues to expand for both medicinal and non-medicinal purposes, more research is needed to better understand the acute effects of lesser studied chemical constituents of the plant and how they interact with predominant phytocannabinoids like Δ9-THC. This can inform cannabinoid drug development and product regulations.