Absorption

Smoking, the principal route of cannabis administration in the United States, provides a rapid and highly efficient method of drug delivery. Approximately 30% of THC in marijuana or hashish cigarettes is destroyed by pyrolysis during smoking (23,24). Smoked drugs are highly abused in part because of the efficiency and speed of delivery of the drug from the lungs to the brain. Intensely pleasurable and strongly reinforcing effects may be produced because of the almost immediate drug exposure to the central nervous system. Drug delivery during cannabis smoking is characterized by rapid absorption of THC, with slightly lower peak concentrations than those found after intravenous administration (25). Bioavailability of smoked THC is reported to be 18-50% partly as a result of the intra- and intersubject variability in smoking dynamics that contribute to uncertainty in dose delivery (26). The number, duration, and spacing of puffs, hold time, and inhalation volume greatly influence the degree of drug exposure (27-29). THC can be measured in the plasma within seconds after inhalation of the first puff of marijuana smoke (see Fig. 1; ref. 30). Mean ± SD THC concentrations of 7.0 ± 8.1 and 18.1 ± 12.0 ng/mL were observed following the first inhalation of a low- (1.75% THC, approx 16 mg) or high-dose (3.55% THC, approx 30 mg) cigarette, respectively (30). Concentrations increased rapidly and peaked at 9.0 minutes, berfore initiation of the last puff sequence at 9.8 minutes. Figure 2 dis-

Absorption Thc

Fig. 1. Mean (N = 6) plasma concentrations of A9-tetrahydrocannabinol (THC), 11-hydroxy-A9-THC (11-OH-THC), and 11-nor-9-carboxy-A9-THC (THCCOOH) by gas chromatography/mass spectrometry during smoking of a single 3.55% THC cigarette. Each arrow represents one inhalation or puff on the cannabis cigarette. (From ref. 1 with permission.)

Fig. 1. Mean (N = 6) plasma concentrations of A9-tetrahydrocannabinol (THC), 11-hydroxy-A9-THC (11-OH-THC), and 11-nor-9-carboxy-A9-THC (THCCOOH) by gas chromatography/mass spectrometry during smoking of a single 3.55% THC cigarette. Each arrow represents one inhalation or puff on the cannabis cigarette. (From ref. 1 with permission.)

Hydroxy Thc Hplc
Fig. 2. Mean (N = 6) plasma concentrations of A9-tetrahydrocannabinol (THC), 11-hydroxy-A9-THC (11-OH-THC), and 11-nor-9-carboxy-A9-THC (THCCOOH) by gas chromatography/mass spectrometry following smoking of a single 3.55% THC cigarette. (From ref. 3 with permission.)

Smoking

Fig. 3. Individual plasma A9-tetrahydrocannabinol (THC) time course by gas chroma-tography/mass spectrometry for six subjects following smoking of a single 3.55% THC cigarette. (From ref. 3t with permission)

Smoking

Fig. 3. Individual plasma A9-tetrahydrocannabinol (THC) time course by gas chroma-tography/mass spectrometry for six subjects following smoking of a single 3.55% THC cigarette. (From ref. 3t with permission)

plays mean data for a group of six subjects after paced smoking of a single 3.55% THC cigarette. The number of puffs, length of inhalation and hold time, time between puffs, and potency of the cigarette were controlled. Figure 3 shows individual THC concentration time profiles for six subjects and demonstrates the large intersubject variability of the smoked route of drug administration. Many individuals prefer the smoked route, not only for its rapid drug delivery, but also for the ability to titrate their dose.

In some studies THC was measured in blood, and expected values were found to be about half those of plasma (31). Albumin and other proteins that bind THC and the poor penetration of THC into red blood cells contribute to these higher plasma concentrations. Postmortem blood is a common example where blood concentrations are routinely reported because of difficulty obtaining acceptable plasma samples. Significant differences in THC concentrations between the two fluids make it important to always be informed about which is being reported.

If cannabis is ingested orally, absorption is slower and peak plasma THC concentrations are lower (25,32-34). Wall et al. found peak THC concentrations approx 4-6 hours after ingestion of 15-20 mg of THC in sesame oil (34). Peak THC concentrations ranging from 4.4 to 11 ng/mL were observed 1-5 hours following ingestion of 20 mg of THC in a chocolate cookie (25). Oral bioavailability has been reported to be 4-20% (25,34), in part as a result of degradation of drug in the stomach (35). Also, there is significant first-pass metabolism to active 11-hydroxy-A9-tetrahydrocannab-inol (11-OH-THC) and inactive metabolites. Plasma 11-OH-THC concentrations range from 50 to 100% of THC concentrations following the oral route of cannabis adminis tration compared to only about 10% after smoking (34). 11-OH-THC is equipotent to THC, explaining the fact that pharmacodynamic effects after oral cannabis administration appear to be greater than those after smoking THC at the same concentrations (25).

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