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In humans, THC is mainly metabolized (see illustration) via the cytochrome P450 (CYP) enzyme system by hydroxylation and oxidation {call-out, text:Hydroxylation and oxidation are processes by which the body converts a molecule by adding a hydroxyl or oxygen, therefore making it more water-soluble and easier to eliminate} by the enzyme CYP2C9 and CYP3A, and to a lesser extent CYP2C19 and other enzymes.1, 2 Cytochrome P450 metabolism primarily takes place in the liver.1, 2 The pathway of THC metabolism generally looks as follows: After THC has entered the body, it is converted to 11-OH-THC, after which 11-OH-THC converts to 11-COOH-THC. The first metabolite, 11-OH-THC (or 11-hydroxy-THC), is pharmacologically active, and can, just like THC, induce the effect of ‘feeling high’. It has at least as equal potency as THC, perhaps even higher.3 The reason for this is unknown, although one group reported that a potentially increased potency of 11-OH-THC may be due to its increased ease of entering into the brain. In their study, they observed that it crosses the blood-brain barrier {call-out, text:A membrane barrier that separates the circulating blood from the brain} easier.4 The subsequent metabolite 11-COOH-THC (or 11-carboxy-THC) does not give these effects. Finally, 11-COOH-THC is further converted into its glucuronide form, 11-COOH-THC glucuronide, after which it is excreted. When THC is inhaled by either smoking or vaporizing, it largely avoids the process of first-pass metabolism. First pass metabolism means that the drug is absorbed from the intestines and, from there, it is transported directly to the liver via the portal vein. When this happens, the drug is immediately metabolized by the liver before it reaches the systemic circulation (blood) and other organs. In the case of inhalation, the drug is absorbed into the systemic blood circulation directly from the lungs, thereby initially skipping the liver metabolism. Because of the differences in absorption (see illustration), the ratios at which THC metabolites are seen in the body after administration are largely dependent on the administration route. These different ratios can have implications for effect strength. Watch a brief summary video on cannabis inhalation vs. cannabis ingestion made in collaboration with Enlighten on YouTube or on the screens page. Illustration 1: Metabolic pathway with structural formulas. The first step describes the conversion from the raw plant form of THC, which is THCA (THC acid) to THC by heat, called decarboxylation. References:
  1. Dinis-Oliveira, Ricardo Jorge (2016). Metabolomics of Δ 9 -tetrahydrocannabinol: implications in toxicity. Drug Metabolism Reviews, 48(1), 80--87.
  2. Watanabe, Kazuhito; Yamaori, Satoshi; Funahashi, Tatsuya; Kimura, Toshiyuki; Yamamoto, Ikuo (2007). Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sciences
  3. Lemberger, Louis; Martz, Robert; Rodda, Bruce; Forney, Robert; Rowe, Howard (1973). Comparative pharmacology of Delta9-tetrahydrocannabinol and its metabolite, 11-OH-Delta9-tetrahydrocannabinol. The Journal of clinical investigation (2411--7).
  4. Schou, J.; Prockop, L. D.; Dahlstrom, G.; Rohde, C. (1977). Penetration of delta-9-tetrahydrocannabinol and 11-OH-delta-9-tetrahydrocannabinol through the blood-brain barrier. Acta pharmacologica et toxicologica, 41(1), 33--38.