Important research findings of three decades of controlled human cannabinoid administration studies conducted at the National Institute on Drug Abuse (NIDA), National Institutes of Health are described. Study design is critical to collecting data. Parameters to consider include dose and route of administration, controls, blinding, cross-over design, sensitivity of the pharmacodynamic measures, and selection of biological matrices and target analytes. Pharmacodynamic measures include subjective drug effects, cardiovascular effects, cognitive performance, simulated driving performance, and standardized field sobriety tests. While pharmacokinetic considerations include which biological matrices to collect, times and frequency of collection, and target analytes to quantify.
Investigations initially focused on acute cannabis or ∆9-tetrahydrocannabinol (THC) administration by the smoked route, but later also investigated the pharmacodynamics and pharmacokinetics of vaporized and oral cannabis in men and women, demonstrating the importance of self-titration of the delivered dose to achieve the desired psychological and physiological effects and the lack of linear concentration-effect curves due to counter-clockwise hysteresis. The study employed a continuous blood withdrawal pump collecting 5 mL of blood a minute during cannabis smoking to describe what occurs during inhalation, rather than after the end of inhalation that was routinely investigated. Later, the absorption, distribution, metabolism, and excretion of THC, cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), ∆9-tetrahydrocannabivarin (THCV), and their metabolites ∆9-tetrahydrocannabinol (THC)-glucuronide, 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), THCCOOH-glucuronide and 11-nor-9-carboxy-THCV (THCVCOOH) was studied following the same smoked, vaporized and oral cannabis doses in the same individuals. Other novel data were generated when the important population of chronic frequent cannabis users was investigated. The study documented extended THC presence at low concentrations in blood for as long as a month, residual psychomotor impairment for at least three weeks, and downregulation of CB1 cannabinoid receptors in the brain that normalized with sustained cannabis abstinence of one month. Rimonabant, the first specific CB1-cannabinoid receptor antagonist, was also administered to document that THC produces its effects through the CB1-cannabinoid receptor.
Controlled drug administration studies are valuable tools for acquiring a detailed understanding of the pharmacodynamic and pharmacokinetic profiles of cannabinoids. THC is the primary psychoactive cannabinoid in cannabis with the potential to negatively impact cognitive and psychomotor performance and workplace safety. These studies establish behavioral and subjective effect profiles while simultaneously collecting pharmacokinetics data. This information is important for understanding the onset, peak, and duration of effects and their corresponding concentrations in biological fluids. Results from these studies can guide regulations related to workplace drug testing, driving under the influence, post-incident workplace testing, and public health initiatives.
Many US states decriminalized medical and/or recreational cannabis use, focusing attention from establishing cannabis use to demonstrating impairment from the drug regardless of whether the test is for the purpose of driving while impaired, workplace post-incident or fitness for duty. Clinical studies are increasingly important to help inform regulators about the benefits and limitations of current laboratory tests and establishing new tests to accomplish these aims.
Detailed Learning Objectives
- Attendees will be able to describe THC and metabolite time-concentration profiles and the concentration-effect curves of inhaled cannabis, including its prominent counter-clockwise hysteresis.
- Attendees will be able to describe the pharmacokinetics of smoked, inhaled and oral cannabis.
- Attendees will be able to describe how THC effects on the brain result in cognitive and psychomotor impairment.