What factors influence the metabolism of cannabis, specifically tetrahydrocannabinol (THC)?

Cannabis Metabolism: Hepatic Cytochrome P450 Enzymes

The liver metabolizes cannabis through the cytochrome P450 enzyme system, primarily via CYP3A4 and CYP2C9, which convert THC into active and inactive metabolites. 1

Primary Metabolic Pathways

Hepatic First-Pass Metabolism

• When THC is absorbed from the gut (edible cannabis), it travels directly to the liver where it undergoes first-pass metabolism into 11-hydroxy-tetrahydrocannabinol (11-OH-THC), a more potent psychoactive metabolite than THC itself 1
• This hepatic conversion creates higher blood concentrations of 11-OH-THC with edible products compared to inhaled cannabis, resulting in longer latency to onset (30 minutes to 2 hours) and prolonged duration of effects (5-8 hours) 1
• The liver subsequently metabolizes THC and 11-OH-THC to 11-nor-9-carboxy-THC (THC-COOH), an inactive metabolite that is eventually glucuronidated and excreted 2

Key Cytochrome P450 Enzymes Involved

• CYP3A4 is the primary enzyme responsible for hydroxylating THC and metabolizing CBD 1, 2
• CYP2C9 plays a significant role in THC metabolism and is also involved in CBD breakdown 2, 3
• Additional enzymes including CYP1A2, CYP2B6, CYP2C8, CYP2C19, and CYP2D6 contribute to cannabinoid metabolism 1
• CBD is specifically hydroxylated to 7-OH-CBD and 7-COOH-CBD by CYP3A4 and CYP2C9 2

Route-Dependent Metabolism

Inhaled Cannabis

• Bypasses first-pass hepatic metabolism initially, with THC entering the bloodstream rapidly via the lungs and achieving peak levels within 6-10 minutes 2
• Bioavailability of inhaled THC ranges from 10% to 35%, significantly higher than oral administration 1, 2
• Effects onset within seconds to minutes and last 2-3 hours 1

Oral/Edible Cannabis

• Undergoes extensive first-pass hepatic metabolism before reaching systemic circulation 1
• Bioavailability of ingested THC is only 4% to 12% due to extensive hepatic metabolism 2
• High-fat meals significantly increase oral cannabinoid absorption, which can exacerbate effects and drug interactions 1

Distribution and Elimination

Lipid Solubility and Storage

• THC is highly lipid soluble and rapidly distributes into adipose tissue, brain, and other organs 2
• This lipophilicity results in accumulation in fat stores, leading to gradual release during periods of adipose breakdown (common in cancer patients and those losing weight) 1
• CBD also has high lipophilicity and is rapidly distributed to brain, adipose tissue, and other organs 2

Elimination Half-Life

• Plasma half-life of THC is 1 to 3 days in occasional users and 5 to 13 days in chronic users due to redistribution from adipose tissue 2
• CBD has a plasma half-life of 18 to 32 hours 2
• THC and its metabolites are excreted mainly in feces and to a lesser extent in urine 2

Clinical Implications of Cannabinoid Metabolism

Drug-Drug Interactions

• Cannabis inhibits multiple CYP450 enzymes (CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6), potentially altering metabolism of co-administered medications 1
• High-risk interactions include warfarin (very high risk), buprenorphine, and tacrolimus 1
• THC metabolites, particularly 11-OH-THC and THC-COO-glucuronide, also inhibit CYP2B6, CYP2C9, and CYP2D6, contributing to drug interactions even after THC levels decline 4
• Conversely, medications that strongly inhibit or induce CYP3A4 will affect CBD disposition and potentially alter its effects 3

Factors Affecting Metabolism

• Genetic polymorphisms in CYP2C9 can significantly affect THC metabolism rates, though this is not routinely tested clinically 3
• Chronic cannabis use may induce CYP1A2, potentially increasing metabolism of substrates for this enzyme 3
• Age-related changes in hepatic function may reduce cannabinoid clearance in elderly patients 5
• Hepatic impairment reduces cannabinoid metabolism and increases risk of adverse effects 6

Monitoring Considerations

• Patients taking medications metabolized by CYP2C9, CYP2C19, or CYP1A2 require close monitoring when using cannabis products 3
• The variable THC and CBD content in cannabis products makes drug interactions unpredictable and difficult to standardize 1, 5
• Adulteration of cannabis products with synthetic cannabinoid receptor agonists can lead to unpredictable clinical outcomes 6