From inhalation to 11-hydroxy-THC conversion, liver enzyme pathways, drug interactions, and why edibles produce a fundamentally different experience.
THC (delta-9-tetrahydrocannabinol) is a lipophilic (fat-soluble) molecule. This single chemical property governs almost everything about how it moves through, is transformed by, and exits the body. Its fat-solubility means it distributes rapidly into adipose tissue (body fat), brain, and other lipid-rich organs; it also means it is slowly released back from fat stores over days to weeks — which is why THC metabolites remain detectable long after psychoactive effects have ended.
The route of consumption is the most important variable in THC pharmacokinetics. Inhalation, oral consumption, and sublingual delivery produce dramatically different absorption rates, peak plasma levels, metabolite profiles, and subjective effects — even at identical THC doses.
When cannabis is smoked or vaporized, THC enters the lungs and is absorbed across the large alveolar surface area directly into pulmonary circulation — bypassing the digestive system and liver entirely. From the lungs, THC-rich blood flows to the left heart and is pumped systemically, reaching the brain within seconds.
Onset of subjective effects occurs within 5–10 minutes. Plasma THC peaks at approximately 5–10 minutes post-inhalation, then declines as THC redistributes into adipose tissue and peripheral organs. The psychoactive window for most users is 1–3 hours, though residual effects can linger up to 4–6 hours at high doses.
Bioavailability via inhalation is highly variable: 30–50% for experienced smokers. Inexperienced smokers may absorb significantly less due to less efficient breath-hold technique and smaller lung volume utilization. Vaporization at optimal temperatures (180–210°C for cannabinoids) produces similar bioavailability to smoking but with fewer combustion byproducts.
The key metabolic feature of inhalation is that minimal first-pass liver metabolism occurs. THC enters systemic circulation largely unchanged. The liver does eventually process THC, but the initial CNS dose is dominated by unmodified THC rather than its metabolites.
When THC is consumed orally (edibles, capsules, infused beverages), it must traverse the entire gastrointestinal tract before entering the bloodstream. THC is absorbed in the small intestine and carried via portal blood — which goes directly to the liver — before reaching systemic circulation. This is called first-pass metabolism.
The gastrointestinal journey is slow: onset of effects typically ranges from 45 minutes to 2 hours, with significant individual variation based on gastric emptying rate, food co-consumption, and individual gut physiology. Taking edibles on an empty stomach accelerates absorption; consuming them with a high-fat meal increases bioavailability because THC’s fat-solubility means it binds to dietary fat in the gut and is absorbed via chylomicrons (fat transport particles).
Oral bioavailability is low (10–20%) despite the significant liver conversion of THC to the more potent 11-OH-THC. Much of the consumed THC is broken down before reaching systemic circulation — but the fraction that does survive first-pass metabolism is converted to a metabolite that produces a qualitatively different and more intense psychoactive effect.
Sublingual administration involves holding a cannabis tincture, oil, or dissolvable strip under the tongue. The mucous membranes in the sublingual space are richly vascularized, and lipophilic molecules like THC readily pass through the epithelium directly into the bloodstream — avoiding first-pass liver metabolism.
Onset is intermediate between inhalation and oral: typically 15–45 minutes. Duration is generally 2–4 hours — longer than inhalation but shorter than oral. Bioavailability is estimated at 20–35%, similar to or slightly below inhalation for many users.
The practical challenge with sublingual administration is that most users inevitably swallow some of the product before it can be absorbed transmucosally. The swallowed fraction then undergoes first-pass metabolism, creating a mixed pharmacokinetic profile — some THC absorbed directly (fast onset) and some via the oral route (delayed and converted to 11-OH-THC).
11-hydroxy-THC (11-OH-THC) is the primary active metabolite of THC and is responsible for the qualitatively different and often more intense effects of edible cannabis. It is produced when the liver enzyme CYP2C9 and CYP3A4 oxidize THC at the C-11 position of the molecule.
Relative to THC, 11-OH-THC has several pharmacokinetically significant properties:
This explains the well-documented phenomenon of edibles producing unexpectedly intense effects at doses that seem equivalent to inhalation. A user who smokes 10mg THC and consumes 10mg THC via edible will receive dramatically different CNS exposures because the oral 10mg generates significant 11-OH-THC while the inhaled 10mg does not.
CYP3A4 (Cytochrome P450 3A4) is the most abundant drug-metabolizing enzyme in the human liver and small intestine, responsible for processing approximately 50% of all prescription medications. It is the primary enzyme responsible for converting THC to 11-OH-THC, though CYP2C9 also plays a significant role.
CYP3A4 also converts 11-OH-THC to 11-carboxy-THC (THC-COOH), the inactive, highly persistent metabolite that drug tests detect. THC-COOH is fat-soluble and accumulates in adipose tissue, which is why heavy cannabis users can test positive for weeks after cessation — the fat stores slowly release THC-COOH back into circulation as body fat is mobilized.
| Metabolite | Enzyme | Active? | Drug-Test Detectable? |
|---|---|---|---|
| THC (delta-9) | — | Yes | Brief window |
| 11-OH-THC | CYP3A4 / CYP2C9 | Yes (4–5× potent) | Yes (short) |
| THC-COOH | CYP3A4 | No (inactive) | Yes (days–weeks) |
| Route | Bioavailability | Onset | Peak Plasma | THC Half-Life | Duration |
|---|---|---|---|---|---|
| Inhalation (smoke) | 30–50% | 2–10 min | 5–10 min | 1.5–3 hr | 1–3 hr |
| Vaporization | 35–55% | 2–10 min | 5–15 min | 1.5–3 hr | 1–3 hr |
| Oral (edible) | 10–20% | 45–120 min | 2–4 hr | 4–6 hr | 4–8 hr |
| Sublingual | 20–35% | 15–45 min | 30–90 min | 2–3 hr | 2–4 hr |
| Transdermal patch | ~40% | 1–2 hr | 4–8 hr | 6–10 hr | 8–12 hr |
Values represent averages from pharmacokinetic literature; individual variation is substantial based on body composition, tolerance, and enzyme activity levels.
Because THC metabolism is primarily handled by CYP3A4 and CYP2C9, any substance that inhibits or induces these enzymes will alter THC’s pharmacokinetics:
CYP3A4 inhibitors (increase THC plasma levels and duration):
CYP3A4 inducers (decrease THC plasma levels and duration):
Patients on medications processed by CYP3A4 should discuss cannabis use with their prescriber. THC itself can also affect the metabolism of other CYP3A4-processed drugs by competing for the enzyme, potentially raising plasma levels of medications like warfarin, cyclosporine, and certain statins.