Cannabis containing Δ-9-tetrahydrocannabinol (referred in this manuscript as cannabis) is the most frequently used federally illicit psychoactive substance in the United States (Substance Abuse and Mental Health Services Administration, 2020). Crucially, most people who use cannabis also use tobacco (Carlini and Schauer, 2022, Chu et al., 2023). This is important because tobacco use is the leading preventable cause of disease and death in the US (U. S. Department of Health and Human Services, 2014), and co-use of cannabis and tobacco is likely more deleterious to health than use of cannabis alone (Meier and Hatsukami, 2016). Co-use of cannabis and tobacco can lead to poorer treatment outcomes for cannabis use disorder (Gray et al., 2011), and greater likelihood of recurrence after a cannabis cessation attempt (de Dios et al., 2009, Peters et al., 2012). Further, co-use of cannabis and tobacco in young adulthood has been associated with worse health outcomes (e.g., poor lung function) than smoking either substance alone (Taylor et al., 2002).

While the motivations for cannabis-tobacco co-use are most likely multifaceted, pharmacological drivers, which are still poorly understood, appear to underpin cannabis-tobacco co-use. Co-use of cannabis and tobacco may be more rewarding than use of these substances by themselves. Nicotine produces its rewarding effects by activating nicotinic acetylcholine receptors (nAChRs) on neurons in the mesolimbic dopaminergic system (Rabin and George, 2015a). Δ-9-Tetrahydrocannabinol (THC), the main psychoactive constituent in cannabis, acts as a partial agonist on cannabinoid type-1 receptors (CB1) (Rabin and George, 2015a). In preclinical studies, nicotine contributes to the reinforcing, rewarding, and physiological effects of CB1 receptor agonists. THC attenuated the anxiogenic-like effects of nicotine (Balerio et al., 2006) and nicotine potentiated pharmacological responses such as hypothermia, anti-nociception and hypolocomotion that are induced by THC, and attenuated THC tolerance in rodents (Valjent et al., 2002).

Fundamental to our understanding of the pharmacology of cannabis and tobacco co-use is knowledge of how their major psychoactive constituents, THC and nicotine, interact pharmacologically in humans. Loose-leaf vaporizers, which heat but do not combust plant materials like cannabis and tobacco, can be used to administer inhaled doses of THC and nicotine in a less chemically complex aerosol than cannabis and tobacco smoke. In this small proof-of-concept study, we examined differences in THC and nicotine intake, pharmacokinetics, subjective effects, and heart rate increase from administering cannabis only, tobacco only, and a mixture of cannabis and tobacco using a PAX-3 loose-leaf vaporizer. Findings from this study can inform future studies that seek to better understand the pharmacologic drivers and health consequences of cannabis and tobacco co-use.