Cannabinoids

Pharmacokinetics

Cannabis is used primarily by the smoking route, although oral marijuana also produces both subjective effects and increases in heart rate. After inhalation, Δ9-THC is detectable in plasma within seconds, with peak concentrations 3–10 min after smoking and bioavailability that ranges from 10% to 35%, depending on the experience of the smoker (Figure 8.6). Oral administration results in low bioavailability (6–7%) because of numerous factors, but mainly extensive first-pass liver metabolism. The effects of oral Δ9-THC are significantly delayed; by up to 60–120 min compared with the smoking route. These routes of administration correlate well with their relative effectiveness in producing the subjective “high” associated with intoxication (Figure 8.7). Other potential effective, seldom used routes of administration include rectal (13.5% bioavailability), sublingual, transdermal, and opthalmic (6–40% bioavailability). The inhalation of Δ9-THC produces dose-dependent blood levels; significantly lower peak blood levels are reached after oral administration (Table 8.8).

FIGURE 8.6 Physiological and subjective effects of smoked vs. oral administration of Δ9-tetrahydrocannabinol. Smoked marijuana cigarettes contained 2.3–3.6% Δ9-THC. Oral administration was via Marinol capsules (2.5, 5, and 10 mg). (A) Heart rate before and after active drug or placebo administration. (B) End-of-session questionnaire scores after active drug or placebo administration. These data show that similar to other drugs of abuse, smoked marijuana has much faster absorption and is more effective. Notice that it took 1–2 h for significant increases in heart rate to be seen after oral administration, whereas significant increases in heart rate were observed at 5 min with smoked marijuana. [Modified with permission from Chait LD, Zacny JP. Reinforcing and subjective effects of oral Δ9-THC and smoked marijuana in humans. Psychopharmacology, 1992, (107), 255–262.]

Δ9-THC has a peculiar distribution because of its high lipophilicity compared with other drugs of abuse. As a result, it rapidly enters highly vascularized tissues. After intravenous administration, only 1% is estimated to enter the brain at the time of peak behavioral effects. The significant accumulation of cannabinoids occurs later in less vascularized tissues and body fat, which is the major long-term storage site.

Δ9-THC is broken down in the liver by enzymes of the cytochrome P450 system. In humans, hydroxylation produces 11-OH-THC, and oxidation leads to THC-COOH (Figure 8.8). The elimination half-life for Δ9-THC ranges widely, from 20 to 60 h. The half-like in chronic users is shorter (28 h) than in non-users (57 h). The elimination half-life for Δ9-THC metabolites is longer than for the parent compound, ranging from five to six days.

FIGURE 8.7 Time course of subjective high after smoked (19 mg), oral (20 mg), and intravenous (5 mg) Δ9-THC administration. These data show that the route of administration determines the profile of intoxication produced by marijuana over time. Notice that the onset of the peak levels of intoxication in the blood is delayed with oral administration compared with intravenous and smoked marijuana and that the peak levels of intoxication are higher for intravenous and smoked marijuana compared with oral administration. [Adapted from Hollister LE, Gillespie HK, Ohlsson A, Lindgren JE, Wahlen A, Agurell S. Do plasma concentrations of Δ9-tetrahydrocannabinol reflect the degree of intoxication? Journal of Clinical Pharmacology, 1981, 21(8–9 suppl): 171s–177s.]

Δ9-THC is excreted from the body as acid metabolites, and these metabolites can be detected in the urine for an average of 27 days in chronic users, and positive urine results have been detected up to 46 days after the last administration.

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