9-tetrahydrocannabinol (THC) is one of the major phytocannabinoids found in the cannabis plant. It is the principal constituent of the cannabis plant responsible for the euphoric effects.¹ The pharmacokinetic and pharmacodynamic properties of THC are summarized below.

Pharmacokinetics^1-3

1. Absorption: Post-inhalation, the peak plasma concentration of THC is attained rapidly within few minutes. The bioavailability of THC after inhalation ranges from 10–35%. However, post-oral ingestion, it may take up to 120 minutes to reach peak concentration and has low oral bioavailability (~6%). The oral formulations may be useful for patients requiring symptomatic relief over a longer period.
2. Distribution: Being highly lipophilic in nature, THC and its metabolites distribute rapidly to fatty tissues and the brain, causing it to accumulate and get stored in the body fat to be released slowly back into the blood for metabolism.
3. Metabolism: The metabolism of THC is predominantly hepatic via the cytochrome P450 (CYP 450) enzyme system (CYP2C9, CYP2C19, CYP3A4). It is metabolized to form 11-hydroxy-THC and 11-carboxy-THC. THC largely avoids the process of the first-pass metabolism upon inhalation (by either smoking or vaporizing) since it is absorbed from the lungs directly into the blood. Because of the differences in absorption, the THC metabolite ratios observed in the body post-administration are essentially dependent on the route of administration.
4. Elimination: THC is metabolized by the body extensively; thus, insignificant amounts of THC gets excreted in its unchanged form. Following smoking, elimination of THC and its metabolites occurs via feces (65%) and urine (20%). Following oral administration, THC and its metabolites are excreted in the feces and urine; with biliary excretion being the major route of elimination (>50%). Estimates of the elimination half-life of THC appear to vary with an estimated long terminal half-life (22 hours) and even longer time in heavy users.

Pharmacodynamics: THC acts as a partial agonist at CB1 and CB2 receptors and has activity at other non-cannabinoid receptors as well. Its psychoactive effects are mediated by agonist effects at CB1 receptors. THC results in a dose-dependent impairment in performance. Tachycardia experienced by patients after using THC is probably via direct agonism of CB1 receptors. Co-administration of CBD has been reported to reduce the side effects of THC.^1-3

References

1. Health Canada, "Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids, 2018". Available at: https://www.canada.ca/en/health-canada/services/drugsmedication/cannabis/information-medical-practitioners/information-health-care-professionalscannabis-cannabinoids.html
2. Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018;84:2477–82.
3. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 2003;42(4):327–60.