Cannabis Pharmacokinetics: Absorption, Distribution, Metabolism, Elimination

Absorption: Route-Specific Pharmacokinetics

Inhalation is the most pharmacokinetically efficient cannabis delivery route, achieving peak plasma THC concentrations within 3-10 minutes with bioavailability of 10-35%. The pulmonary capillary network rapidly absorbs vaporized or combusted cannabinoids directly into systemic circulation, bypassing hepatic first-pass metabolism. This fast absorption enables precise titration and rapid dose adjustment — the pharmacokinetic basis for smoking/vaping as the preferred route for pain and nausea with immediate onset requirements.

Oral administration represents the opposite extreme: bioavailability 6-20%, peak plasma at 1-6 hours, highly variable between individuals due to GI transit variation and first-pass metabolism. The extended Tmax (time to peak plasma) explains why edible overdosing is common — consumers redose before the initial dose has reached peak effect. Combined with extensive hepatic conversion of THC to potent 11-OH-THC, oral cannabis produces delayed, intense, unpredictable effects distinctly different from inhalation at the same dose.

Sublingual administration (tinctures, Sativex) achieves intermediate pharmacokinetics: bioavailability 13-19%, peak plasma 1-2 hours, with partial bypass of hepatic first-pass via sublingual mucosal absorption into the lingual veins. This route is particularly useful for oromucosal formulations requiring patient-controlled titration with faster onset than oral ingestion. Full THC metabolism details and CBD bioavailability science expand on route-specific considerations.

Distribution: Lipophilicity and Tissue Accumulation

THC and CBD are both highly lipophilic (oil-soluble) molecules with log P values of approximately 7, making them among the most lipophilic of commonly used drugs. This extreme lipophilicity determines their distribution pharmacokinetics: rapid uptake into fat, brain, liver, and lung; high apparent volume of distribution (THC: approximately 10 L/kg, meaning extensive tissue distribution relative to blood); and 97% plasma protein binding to albumin and lipoproteins.

Tissue accumulation in adipose has profound implications. THC accumulates progressively in fat with chronic use, creating a reservoir that slowly releases back into systemic circulation over weeks. This reservoir explains: 1) extended detection windows in urine drug testing (up to 30 days in chronic heavy users); 2) the absence of clear pharmacokinetic-pharmacodynamic (PK-PD) correlation between plasma THC and degree of impairment; and 3) the slow washout of cannabinoids in fat individuals who have used cannabis heavily over extended periods.

Brain distribution follows blood-brain barrier penetration kinetics. THC crosses the BBB rapidly via passive diffusion (high lipophilicity, moderate molecular weight). CBD crosses more slowly due to active efflux transport by P-glycoprotein at the BBB. The brain concentration-time profile differs meaningfully from plasma, with brain THC persisting longer than plasma THC — explaining why behavioral effects can persist after plasma THC has declined below assay detection limits.

Metabolism: Cytochrome P450 and Active Metabolites

The liver is the primary site of cannabinoid biotransformation. THC is metabolized by CYP2C9 and CYP3A4 to 11-hydroxy-THC (11-OH-THC) — the primary active metabolite with CB1 potency estimated at 1.5-7x greater than THC itself. 11-OH-THC is further oxidized by the same enzymes to 11-nor-9-carboxy-THC (THC-COOH), an inactive glucuronide-conjugated metabolite eliminated renally.

CBD metabolism involves CYP2C19 and CYP3A4, producing 7-hydroxyCBD (active) and 6alpha-hydroxyCBD as primary metabolites. Unlike THC, CBD is not converted to psychoactive metabolites, though 7-OH-CBD has some biological activity. CBD potently inhibits its own metabolizing enzymes (auto-inhibition), contributing to non-linear pharmacokinetics at higher doses: doubling CBD dose more than doubles plasma CBD levels due to reduced clearance.

Genetic polymorphisms in CYP2C9 (poor metabolizers: 2-3% of Europeans) significantly slow THC clearance, extending psychoactive effects and detection windows. CYP2C19 poor metabolizers (2-5% of various populations) have elevated CBD and clobazam metabolite levels when both are co-administered. These pharmacogenomic considerations are directly relevant to drug interaction risk and support pharmacogenomic testing before medical cannabis initiation in complex patients.

Elimination and Detection Windows

Cannabinoid elimination follows multi-compartmental kinetics reflecting the distinct kinetics of vascular and adipose compartments. Initial rapid distribution from plasma to tissues (t1/2 approximately 4 minutes) is followed by slower redistribution from peripheral compartments back to plasma, and then terminal elimination with a half-life of 20-36 hours for THC in infrequent users extending to 13 days in chronic heavy users as fat stores release cannabinoids slowly.

Fecal excretion accounts for approximately 65% of THC and metabolites (biliary route, with partial enterohepatic recirculation), with renal excretion contributing 20-30%. Urine drug testing detects THC-COOH (the inactive glucuronide metabolite): detection windows are 3-4 days (single use), 7-10 days (occasional users), 15-30 days (chronic heavy users) at the standard 50 ng/mL cutoff. Reducing cutoff to 20 ng/mL extends these windows meaningfully.

Blood THC detection windows are much shorter than urine: active THC is detectable 1-12 hours post-inhalation in blood, with impairment correlation being poor due to the disconnect between plasma and brain THC concentrations. Oral fluid (saliva) testing detects THC at 4-24 hours post-use, making it the preferred matrix for recent-use roadside testing despite analytical challenges. Hair testing can detect cannabis use over 90-day windows per 1.5cm of hair. Understanding these matrices is critical for interpreting withdrawal research timelines and for policy applications in occupational and roadside testing.