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Cannabis is becoming a popular medicine in the United States for patients wanting to fight a wide variety of diseases and disorders. Cannabis and derived products are used to treat conditions such as multiple sclerosis (MS), cancer, inflammatory disorders, autoimmune disorders, and a wide variety of psychological disorders, ranging from depression and anxiety to schizophrenia. The majority of medical benefits cannabis consumption provides are due to the presence of cannabinoids that interact with the human endocannabinoid system.

Metabolism is the process by which a living organism converts one compound into another. OH-THC has psychoactive effects very similar to THC, with some minor distinctions that are still being explored by researchers. Scientists theorize that the differences between OH-THC and THC is the reason that edible and inhalation experiences differ. Before we delve into the effects of OH-THC versus those of THC, let's review where OH-THC comes from and where it goes in the human body.

Figure 4: The conversion of THC into OH-THC in the liver.

OH-THC is produced in the human body by an enzyme called Cytochrome P450 Oxidase 2C9 or CYP2C9 (pronounced: sip-two-cee-nine)¹. Enzymes are essentially large molecules that modify specific target molecules. CYP2C9 modifies THC by adding an OH group to it, increasing its water solubility. This change also makes THC easier to excrete from the body through urination.

Although CYP2C9 is found in small amounts in the brain, it is found in significantly higher quantities in the liver. CYP2C9 is responsible for metabolizing serotonin and over 100 pharmaceutical drugs, such as warfarin². Besides helping to excrete and breakdown, CYP2C9 also uses many of the fats and oils acquired from the diet to synthesize eicosanoids, signaling molecules the body uses for communication, often in regulating inflammation³.

Although OH-THC is psychoactive, the next metabolite down the chain, 11-nor-9-carboxytetrahydrocannabinol, or COOH-THC, is not⁴. When the body converts all available THC into COOH-THC, the “high” ends. Drug testing kits look for COOH-THC, as it builds up in the body very easily and can take up to one month to completely clear. One study found that urban sewage can have concentrations of COOH-THC as high as 10 part per trillion (ppt), due to excretion after consumption⁴.

The metabolic pathway from THC to OH-THC to COOH-THC represents the majority of human metabolism of THC, but there are minor metabolites and variants, the largest of which are the 8-OH-THC metabolites⁵. CYP3A4 metabolizes THC at the 8th carbon instead of the 11, creating 8-OH-THC. Enzymes have been observed oxidizing THC at a variety of carbon locations, creating polyhydroxylated THC derivatives (metabolites). These minor variants are seen in larger quantities in studies on non-human animals. For an overview of human metabolism of THC, see figure 5.

Figure 5: Different metabolites and pathways in the human body.

The conversion of THC to OH-THC does not reduce the THC’s psychoactivity, and some suspect that OH-THC is actually more potent than an equivalent dose of THC. This hypothesis would explain how a patient who regularly smokes approximately 200 mg of THC, can eat a 50 mg THC edible and feel overly high or overly tired. If OH-THC is more psychoactive, it could explain how 50 mg of THC orally ingested can exceed the effects experienced when 200 mg of THC is being inhaled.

The gradual conversion of THC to OH-THC is thought to be responsible for the delayed onset of some of the effects of cannabis, such as increased appetite, drowsiness and sedation. This is in contrast to the initial effects which can include heightened sensations, euphoria and mental enhancements associated with THC.

In pharmacology, there are many examples of drug metabolites gaining new biological activity after being metabolized. Chemists have discovered over 100 different metabolites of THC, and the effects of only a few are well-studied¹. We simply don’t know if other minor metabolites also have psychoactive properties. Aside from possible psychoactivity, cannabinoid metabolites may also interact with other extra-neural signaling pathways, yielding physical effects distinct from those of classical cannabinoids (IE Inflammation).

1. Mazur A, Lichti CF, et al (2009) “Characterization of Human Hepatic and Extrahepatic UDP-Glucuronosyltransferase Enzymes Involved in the Metabolism of Classic Cannabinoids”. Drug Metabolism and Disposition. DMD 37:1496–1504, 2009
2. Rettie AE, Jones JP (2005). "Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics". Annual Review of Pharmacology and Toxicology. 45: 477–94.doi:10.1146/annurev.pharmtox.45.120403.095821.PMID 15822186.
3. Spector AA, Kim HY (Apr 2015). "Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism". Biochimica et Biophysica Acta. 1851 (4): 356–65. doi:10.1016/j.bbalip.2014.07.020. PMC 4314516 . PMID 25093613
4. Ujvary I, Grotenhermen F (2014) “11-Nor-9-carboxy-delta9-tetrahydrocannabinol – a ubiquitous yet underresearched cannabinoid. A review of the literature”. Cannabinoids 2014;9(1):1-8
5. Huestis MA (June 2009) “Human Cannabinoid Pharmacokinetics”. Chem Biodivers. 2007 August ; 4(8): 1770–1804. doi:10.1002/cbdv.200790152.
6. https://www.ncbi.nlm.nih.gov/pubmed/4729039

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1. Email: marco@digammaconsulting.com