A within-subject cross-over trial comparing the acute effects of oral delta-8-tetrahydrocannabinol and delta-9-tetrahydrocannabinol in healthy adults

Background: Oral products containing z8-tetrahydrocannabinol (z8-THC), a chemical isomer of the primary psychoactive consistent of cannabis, z9-tetrahydrocannabinol (z9-THC), have increased in popularity in recent years. The behavioral effects and pharmacokinetics of oral z8-THC remain poorly characterized. Methods: Nineteen healthy adults with no past-month cannabinoid exposure completed five randomized outpatient sessions in a within-subjects, double-blind, crossover design. Participants ingested a brownie containing z8-THC (10, 20, 40 mg), z9-THC (20 mg), or placebo. Measures included whole blood cannabinoid concentrations, subjective drug effects, cognitive/psychomotor performance, and vital signs. Results: Whole blood cannabinoid concentrations peaked between 2 and 4 h post-dose in a dose-orderly manner. The psychoactive 11-OH metabolite of z8-THC was markedly lower than that of z9-THC at the same dose. z8THC produced dose-dependent subjective effects across multiple domains, differing from placebo. Compared to 20 mg z9-THC, 20 mg z8-THC resulted in significantly lower ratings of "feel drug effect," negative subjective effects, cognitive/psychomotor impairment, and heart rate increases. No pharmacodynamic differences were observed between 40 mg z8-THC and 20 mg z9-THC. Both 20 mg and 40 mg z8-THC produced comparable positive subjective effects (e.g., drug liking) to 20 mg z9-THC, suggesting similar misuse potential. Conclusion: z8-THC demonstrated dose-dependent psychoactive effects qualitatively similar to z9-THC but with reduced potency, possibly due to lower biotransformation to its 11-OH metabolite. Importantly, higher doses of z8-THC offset reduced potency, as 40 mg z8-THC and 20 mg z9-THC produced similar effects; this is noteworthy considering people who consume cannabis products generally perceive z8-THC as less harmful or intoxicating than z9-THC. These findings inform regulatory decisions and public education, though further research on emergent cannabinoids is needed.