The 2018 Agricultural Improvement Act (or “Farm Bill”) removed hemp (cannabis with ≤0.3 % Δ9-tetrahydrocannabinol, Δ9-THC) from the United States (U.S.) controlled substances list (H.R.2, 2018). This legislation created a legal pathway for hemp-derived cannabinoid products to be sold throughout the U.S., including in states where cannabis remains illegal and in locations outside of licensed cannabis dispensaries (e.g., Internet and brick-and-mortar retail stores (Babalonis et al., 2021). Notably, the “Farm Bill” allowed for the emergence of an expansive market of products for which Δ8-tetrahydrocannabinol (Δ8-THC) is the primary constituent (Babalonis et al., 2021).

Δ8-THC is a structural isomer of Δ9-THC, the primary psychoactive constituent of cannabis (Abdel-Kader et al., 2024, Compton et al., 1991). Δ8-THC is naturally occurring in small amounts in hemp/cannabis plants, though most retail products are believed to contain Δ8-THC that was synthesized from cannabidiol (CBD; (Abdel-Kader et al., 2024, Compton et al., 1991, Tagen and Klumpers, 2022). Δ8-THC shares a similar pharmacological mechanism of action with Δ9-THC (partial agonist at cannabinoid type 1 receptors) and can produce psychoactive effects, though is considered less potent than Δ9-THC (Abdel-Kader et al., 2024, Hollister and Gillespie, 1973, Tagen and Klumpers, 2022). Importantly, an appreciable number of adolescents and adults report recently using Δ8-THC products (Harlow et al., 2024, Livne et al., 2022). Common reasons for Δ8-THC use include perceived therapeutic benefits, to experience psychoactive effects, and perceptions that it is legal and produces weaker effects than Δ9-THC (Bergeria et al., 2023, Kruger and Kruger, 2022, Livne et al., 2022).

Vaping devices are among the most popular Δ8-THC product categories (Kruger and Kruger, 2022, Livne et al., 2022). Most Δ8-THC vaping products are analogous to electronic nicotine delivery systems (ENDS) in terms of their appearance and functionality. These devices contain Δ8-THC either suspended in some type of liquid vehicle (e.g., propylene glycol or vegetable glycerin) or in a highly concentrated viscous form (or “oil”) as well as a heating element that aerosolizes Δ8-THC upon activation, allowing for inhalation (Budney et al., 2004, Morgan et al., 2022).

A few prior clinical laboratory studies, all conducted over 40 years ago, characterized the acute effects of Δ8-THC in humans. These studies administered both Δ8-THC and Δ9-THC to healthy adults either orally, intravenously, or via inhalation (by smoking; (Gong Jr et al., 1984, Hollister, 1974, Hollister and Gillespie, 1973, Karniol and Carlini, 1973). Overall, this research showed that, compared with Δ9-THC, Δ8-THC produced qualitatively similar pharmacodynamic effects (e.g., elevated heart rate (HR), subjective feelings of “high”), but was about half as potent (Gong Jr et al., 1984, Hollister, 1974, Hollister and Gillespie, 1973, Karniol and Carlini, 1973). For example, in one study, participants’ subjective ratings of intoxication were approximately 2-fold higher for Δ9-THC versus Δ8-THC at an equivalent smoked dose (i.e., 10 mg; (Karniol and Carlini, 1973).

Though these prior studies provided important initial insights into the comparative effects of Δ8-THC and Δ9-THC, they had several noteworthy limitations including very small sample sizes that precluded formal statistical analyses, inclusion of all male participants, and the use of a narrow set of pharmacodynamic outcome measures. Moreover, these studies did not characterize the pharmacokinetics of Δ8-THC or Δ9-THC, which is often crucial to interpreting the mechanism underlying observed pharmacodynamic differences in acute drug administration studies. Finally, no controlled clinical studies have characterized the effects of vaporized Δ8-THC, which is a major gap in knowledge considering the emergence of Δ8-THC vaping products and prior evidence that cannabinoid effects can differ greatly by route of administration (Spindle et al., 2018, Spindle et al., 2021, Zamarripa et al., 2022).

This study sought to advance scientific understanding of the acute comparative effects of vaporized Δ8-THC versus Δ9-THC in healthy adults who infrequently use cannabis. This is the first of two studies conducted in parallel (the second study, which will be reported separately, followed a similar protocol, except an oral route of administration was used, Zamarripa et al.). The present study is an important extension to early clinical research conducted on Δ8-THC in that it utilized modern and comprehensive pharmacodynamic assessments including an array of subjective drug effects questions and cognitive/psychomotor tasks, conducted a detailed pharmacokinetic evaluation of Δ8-THC and Δ9-THC, and examined a novel route of administration (vaping).