Understanding the clinical pharmacology of marijuana-tobacco co-administration

ABSTRACT Marijuana, a federal illegal drug, is used by millions of people across all age groups, race, and sex. Tobacco, which causes more disease and death than any other preventable cause, is used by even more people. Importantly, most marijuana users also use tobacco. This is concerning because evidence suggests that the health risk of combined marijuana-tobacco use (also known as co-use) is greater than that caused by use of marijuana by itself. Understanding what leads to or causes sustained co-use of these two substances and the health consequences of co-use is important to preserving public health. Studies have described intake of ∆-9-tetrahydrocannabinol (THC), the primary psychoactive chemical in marijuana, and its effects from various marijuana-only products, including smoked, vaporized, and oral forms, but studies assessing the combined effects of marijuana and tobacco are scarce. To the best of our knowledge, no study has examined effects of marijuana and tobacco co-administration by systematically changing the amount of both THC and nicotine delivered to users. This has been a barrier to understanding the relationship between marijuana-tobacco co-use and health outcomes. The central aim of the project is to describe the pharmacokinetics and pharmacodynamics of THC-nicotine co-administration. In this foundational study, we will use a loose-leaf vaporizer to deliver doses of both THC and nicotine from marijuana and tobacco, respectively. We hypothesize that marijuana-tobacco co- administration will lead to larger effects than when the substances are used by themselves, particularly at lower doses of THC and nicotine. This includes higher THC and nicotine intake and systemic exposure, and more than additive cardiovascular responses. We will test these hypotheses with the following aims: (1) Describe and compare THC and nicotine pharmacokinetics and acute physiologic effects, including, heart rate changes, catecholamine release, skin blood flow, and platelet aggregation from various combinations of marijuana and tobacco; (2) Describe and compare sensory and subjective effects such as high, liking, craving reduction, and psychological reward from administration of various combinations of marijuana and tobacco; (3) Examine differences in self-administration of THC and nicotine from various combinations of marijuana and tobacco during ad libitum access. This proposal will advance the field, providing one of few experimental studies on marijuana-tobacco interaction, the first that manipulates both THC and nicotine dose. It will inform our understanding of why users co-use marijuana and tobacco and of potential health consequences related to simultaneous THC and nicotine intake.