The term "marijuana" refers to all parts of the plant Cannabis sativa L., whether growing or not: the seeds; resin extracted from any part of such plant; and every compound, salt, derivative or mixture, but does not include the mature stalks, fiber produced from the stalks, or oil or cake prepared from the seeds.1 Cannabis sativa L. is an annual plant that grows in all parts of the world to a height of 16 to 18 ft. Commercially, it is cultivated for hemp production, with the bulk of the plant consisting of stalks with very little foliage, except at the apex. In contrast, the wild plant and those cultivated illegally possess numerous branches as the psychoactive ingredient is concentrated in the leaves and flowering tops. There may be significant differences in the gross appearance of marijuana plants due to climatic and soil conditions, the closeness of other plants during growth, and the origin of the seed. Although the principal marijuana plant is considered to be the sativa variety, there are purported to be two other Cannabis species, namely, indica and ruderalis. The latter is not native to the West but is found in the former Soviet Union and surrounding regions.

Over 400 compounds have been identified in Cannabis sativa L. with at least 60 identified as substituted monoterpenoids known as cannabinoids. The major pyschoactive constituent of marijuana is A-9-tetrahydrocannabinol, commonly referred to as THC. Different parts of the plant contain varying concentrations of THC, with leaves containing <1% to 10% THC by weight, and hashish, a resin prepared from the flowering tops, containing approximately 15% THC. THC may be synthesized using citral and olivetol in boron trifluoride and methylene chloride.1 Pharmacology

Marijuana is typically self-administered orally or by smoking in doses of 5 to 20 mg.2 It may produce a variety of pharmacological effects including sedation, euphoria, hallucinations, and temporal distortion. In addition, THC possesses activity at benzodiazepine and opioid receptors and has effects on prostaglandin synthesis and DNA, RNA and protein metabolism.3 Due to the numerous pharmacological effects demonstrated by THC, a non-specific mechanism of action was considered likely. However, in the late 1980s a specific cannabinoid receptor was identified in the brains of rats.4 More recently an endogenous cannabinoid ligand was identified.5 This compound, arachidonylethanolamide, or anandamide, an arachidonic acid derivative, mimicked THC in binding and pharmacodynamic activity studies. Absorption

Marijuana is commonly self-administered by the smoked route by rolling dried marijuana leaves in tobacco paper and smoking as a cigarette. Smoking results in rapid drug delivery from the lungs to the brain. However, loss of drug occurs during the smoking process due to pyrolysis and side stream smoke. In an in vitro study in which loss due to side stream smoke was minimized, Davis et al.6 reported a 30% loss of THC due to pyrolysis. Sidestream THC losses of 40 to 50% have been reported. Once THC reaches the lungs, it is rapidly absorbed with peak plasma THC concentrations of 100 to 200 ng/mL occurring after 3 to 8 min.7 Huestis et al.8 demonstrated that THC is present in blood after the first puff from a marijuana cigarette. Mean +/- SD THC concentrations of 7.0 +/- 8.1 ng/mL and 18.1 +/- 12.0 ng/mL were observed after the first inhalation of low or high dose marijuana cigarettes (1.75%, 3.55%), respectively. These authors also demonstrated that peak concentrations occurred at 9 min after the first puff. Lemberger et al.9 and Huestis et al.8 demonstrated that physiological and subjective measures of drug effect occurred simultaneously with the rise in blood THC concentrations.

After oral administration, THC is also well absorbed, being 90 to 95% complete. However, the oral route results in lower peak plasma concentrations at a later time. Perez-Reyes et al.10 reported a mean peak plasma THC concentration of 6 ng/mL after ingestion of 20 mg. Wall and Perez-Reyes11 noted that peak plasma THC concentrations occurred 30 min after intravenous administration of 4 to 5 mg, with a mean concentration (N=7) of 62 ng/mL. The bioavailability of THC following smoking was reported to be 18 to 50%. This wide range reflects the large inter- and intra-subject variability that occurs in smoking dynamics. The amount of drug delivered may be varied by altering the number, duration, and spacing of puffs, the length of time the inhalation is held, and the inhalation volume or depth of puff. In addition, minimizing losses due to side and mainstream smoke and optimizing the temperature for drug volatilization will increase the amount of drug available for delivery to the lungs. One facet of smoking which cannot be controlled by the smoker is drug deposition on non- or poorly absorbing surfaces within the body. This is usually a function of drug particle or vapor size. Drug may be deposited in the nasopharyngeal region or the upper bronchial tree. This reduces the amount of drug reaching the lung alveoli where rapid absorption into the blood and subsequent transport to the brain occurs.

Ohlsson et al.12 compared the bioavailability of THC after intravenous, smoked, and oral administration. Eleven healthy subjects were administered 5 mg intravenously, 19 mg smoked, and 20 mg orally. Plasma concentrations rose rapidly after intravenous administration, reaching 161 to 316 ng/mL at 3 min and declining rapidly thereafter. Peak plasma concentrations also occurred at 3 min after smoking, with lower concentrations of THC ranging from 33 to 118 ng/mL. The plasma concentration time curve after smoking was similar to that obtained after intravenous administration but at lower concentrations. In contrast, low THC concentrations were found after oral administration, with much higher inter subject variability. The authors determined the bioavailability of THC to be 8 to 24% after smoking compared with 4 to 12% after oral ingestion. Distribution

THC is 97 to 99% plasma protein bound with little present in red blood cells. Due its lipophilicity, THC is rapidly distributed into tissues. Highly perfused organs, such as the brain, accumulate THC rapidly after administration, whereas THC distributes more slowly into poorly perfused tissues such as fat. Harvey et al.13 reported maximum THC concentrations in the brains of mice 30 min after a single intravenous dose. The distribution of THC into various tissues and organs such as brain, liver, heart, kidney, salivary glands, breast milk, fat, and lung, is reflected in the large volume of distribution (4 to 14 L/kg).2 Following an intravenous dose of THC, Hunt and Jones14 proposed a four compartment model to describe four tissue composites into which THC distributes. These investigators reported average half-lives of 1 min, 4 min, 1 h, and 19 h to describe these compartments. These authors determined that a "pseudoequilibrium" is achieved between plasma and tissues 6 h after an intravenous dose. Thereafter, THC is slowly eliminated as THC diffuses from tissue to the blood. The terminal

The Metabolite Thc
8-Hydroxy-a9-THC 8,11-Dihydroxy-a9-THC

3.7.11 Metabolic pathway of delta-9-THC.

elimination half-life is approximately 1 day but has been reported to be 3 to 13 days in frequent users.2 Metabolism and Excretion

Metabolism is the major route of elimination of THC from the body as little is excreted unchanged. In humans, over 20 metabolites have been identified in urine and feces.15 Metabolism in humans involves allylic oxidation, epoxidation, aliphatic oxidation, decarboxylation and conjugation. The two monohydroxy metabolites (Figure 3.6.11) 11-hydroxy (OH)-THC and 8-beta-hydroxy THC are active, with the former exhibiting similar activity and disposition to THC, while the latter is less potent. Plasma concentrations of 11-OH-THC are typically <10% of the THC concentration after marijuana smoking. Two additional hydroxy compounds have been identified, namely, 8-alpha-hydroxy-THC and 8,11-dihydroxy-THC and are believed to be devoid of THC-like activity. Further oxidation of 11-OH-THC produces the inactive metabolite, 11-nor-9-carboxy-THC, or THC-COOH. This metabolite may be conjugated with glucuronic acid and is excreted in substantial amounts in the urine.

The average plasma clearance is 600 to 980 mL/min with a blood clearance of 1.0 to 1.6 L/min. which is close to hepatic blood flow. This indicates that the rate of metabolism of THC is dependent on hepatic blood flow.

Approximately 70% of a dose of THC is excreted in the urine (30%) and feces (40%) within 72 h.2 Because a significant amount of the metabolites are excreted in the feces, enterohepatic recirculation of THC metabolites may occur. This would also contribute to the slow elimination and hence long plasma half-life of THC. Unchanged THC is present in low amounts in the urine and 11-OH-THC accounts for only 2% of a dose. The remainder of the urinary metabolites consist of conjugates of THC-COOH and unidentified acidic products. Following a single 10-mg dose of THC by the smoked route, urinary THC-COOH concentrations peaked within 16 h of smoking, at levels of 6 to 129 ng/mL (N=10).16 Passive exposure to marijuana smoke may also produce detectable urinary metabolite concentrations. Cone et al.17 exposed 5 volunteers to the smoke of 16 marijuana cigarettes (2.8%THC content) for 1 h each day for 6 consecutive days. After the first session, THC-COOH concentrations in urine ranged from 0 to 39 ng/mL. A maximum THC-COOH concentration of 87 ng/mL was detected in 1 subject on Day 4 of the study.

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