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National Institutes of Health -- Workshop on the Medical Utility of Marijuana
Ad Hoc Group of Experts
Feb. 19-20, 1997
Over the past 18 months there has been wide-ranging public discussion on the potential medical uses of marijuana, particularly smoked marijuana. To contribute to the resolution of the debate
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Clinical Pharmacology of Marijuana


The Pharmacology of Natural Products
It is important to keep in mind that marijuana is not a single drug. Marijuana is a mixture of the dried flowering tops and leaves from the plant cannabis sativa (Agurell et al. 1984; Graham 1976; Jones 1987; Mechoulam 1973). Like most plants, marijuana is a variable and complex mixture of biologically active compounds (Agurell et al. 1986; Graham 1976; Mechoulam 1973). Characterizing the clinical pharmacology of the constituents in any pharmacologically active plant is often complicated, particularly when the plant is smoked or eaten more or less in its natural form. Marijuana is not unusual in this respect. Cannabis sativa is a very adaptive plant, so its characteristics are even more variable than most plants (Graham 1976; Mechoulam 1973). Some of the seeming inconsistency or uncertainty in scientific reports describing the clinical pharmacology of marijuana results from the inherently variable potency of the plant material used in research studies. Inadequate control over drug dose when researching the effects of smoked and oral marijuana, together with the use of research subjects who vary greatly in their past experience with marijuana, contribute differing accounts of what marijuana does or does not do.

The Plant
Marijuana contains more than 400 chemicals. Approximately 60 are called cannabinoids; i.e., C21 terpenes found in the plant and their carboxylic acids, analogs, and transformation products (Agurell et al. 1984, 1986; Mechoulam 1973). Most of the naturally occurring cannabinoids have been identified. Cannabinoids appear in no other plant. Cannabinoids have been the subject of much research, particularly since the mid 1960s when Mechoulam and his colleagues first isolated delta-9-tetrahydrocannabinol (Delta9-THC) (Mechoulam 1973; Mechoulam et al. 1991). THC in the scientific literature is termed Delta9-THC or Delta1-THC depending on whether the pyran or monoterpinoid numbering system is used.

Cannabinoids of Importance
THC, the main psychoactive cannabinoid in marijuana, is an optically active resinous substance. THC is not soluble in water but is extremely lipid soluble (Agurell et al. 1984, 1986; Mechoulam 1973). Varying proportions of other cannabinoids, mainly cannabidiol (CBD) and cannabinol (CBN), are also present in marijuana, sometimes in quantities that might modify the pharmacology of THC or cause effects of their own. CBD is not psychoactive but has significant anticonvulsant, sedative, and other pharmacologic activity likely to interact with THC (Adams and Martin 1996; Agurell et al. 1984, 1986; Hollister 1986a).

The concentration of THC and other cannabinoids in marijuana varies greatly depending on growing conditions, plant genetics, and processing after harvest (Adams and Martin 1996; Agurell et al. 1984; Graham 1976; Mechoulam 1973). In the usual mixture of leaves and stems distributed as marijuana, concentration of THC ranges from 0.3 percent to 4 percent by weight. However, specially grown and selected marijuana can contain 15 percent or more THC. Thus, a marijuana cigarette weighing 1 gram (g) might contain as little as 3 milligrams (mg) of THC or as much as 150 mg or more.

Potency of Tetrahydrocannabinol
THC is quite potent when compared to most other psychoactive drugs. An intravenous (IV) dose of only a milligram or two can produce profound mental and physiologic effects (Agurell et al. 1984, 1986; Fehr and Kalant 1983; Jones 1987). Large doses of THC delivered by marijuana or administered in the pure form can produce mental and perceptual effects similar to drugs usually termed hallucinogens or psychomimetics. However, the way marijuana is used in the United States does not commonly lead to such profound mental effects. Despite potent psychoactivity and pharmacologic actions on multiple organ systems, cannabinoids have remarkably low lethal toxicity. Lethal doses in humans are not known. Given THC's potency on some brain functions, the clinical pharmacology of marijuana containing high concentrations of THC, for example greater than 10 percent, may well differ from plant material containing only 1 or 2 percent THC simply because of the greater dose delivered.

Some Limitations of Previous Marijuana Research
Unfortunately, much of what is known about the human pharmacology of smoked marijuana comes from experiments with plant material containing about 2 percent THC or less, or occasionally up to 4 percent THC. In addition, human experiments typically are done in laboratory settings where only one or two smoked doses were administered to relatively young, medically screened, healthy male volunteers well experienced with the effects of marijuana. Females rarely participated in past marijuana research because of prohibitions (now removed) against their inclusion. Thus the clinical pharmacology of single or repeated smoked marijuana doses given to older people or to people with serious diseases has hardly been researched at all in a controlled laboratory or clinic setting. Some of the very few reports of experiments that have included older or sicker people, particularly patients less experienced in using marijuana, suggest the profile of adverse effects may differ from healthy student volunteers smoking in a laboratory experiment (Hollister 1986a, 1988a).

THC administered alone in its pure form is the most thoroughly researched cannabinoid. Much of what is written about the clinical pharmacology of marijuana is actually inferred from the results of experiments using only pure THC. Generally, in experiments actually using marijuana, the assumed dose of marijuana was based only on the concentration of THC in the plant material. The amounts of cannabidiol and other cannabinoids in the plant also vary so that pharmacologic interactions modifying the effects THC may occur when marijuana is used instead of pure THC. Only rarely in human experiments using marijuana was the content of CBD or other cannabinoids specified or the possibility of interactive effects between THC and other cannabinoids or other marijuana constituents actually measured.

The result of this research strategy is that a good deal is known about the pharmacology of THC, but experimental confirmation that the pharmacology of a marijuana cigarette is indeed entirely or mainly determined by the amount of THC it contains remains to be completed. The scientific literature contains occasional hints that the pharmacology of pure THC, although similar, is not always the same as the clinical pharmacology of smoked marijuana containing the same amount of THC (Graham 1976; Harvey 1985; Institute of Medicine 1982). Proponents of therapeutic applications of marijuana emphasize possible but not well documented or proven differences between the effects of the crude plant and pure constituents like THC (Grinspoon and Bakalar 1993).

Route-Dependent Pharmacokinetics
Route of administration determines the pharmacokinetics of the cannabinoids in marijuana, particularly absorption and metabolism (Adams and Martin 1996; Agurell et al. 1984, 1986). Typically, marijuana is smoked as a cigarette (a joint) weighing between 0.5 and 1.0 g, or in a pipe in a way not unlike tobacco smoking. Marijuana can also be baked in foods and eaten, or ethanol or other extracts of plant material can be taken by mouth. Some users claim marijuana containing adequate THC can be heated without burning and the resulting vapor inhaled to produce the desired level of intoxication. This has not been studied under controlled conditions. Pure preparations of THC and other cannabinoids can be administered by mouth, by rectal suppository, by IV injection, or smoked. IV injection of crude extracts of marijuana plant material would be quite toxic, however.

Marijuana Smoking and Oral Administration
Smoking plant material is a special way of delivering psychoactive drugs to the brain. Smoking has different behavioral and physiologic consequences than oral or IV administration. What is well known about tobacco (nicotine) and coca (cocaine) clinical psychopharmacology and toxicity illustrates this point all too well. When marijuana is smoked, THC in the form of an aerosol in the inhaled smoke is absorbed within seconds and delivered to the brain rapidly and efficiently as would be expected of a very lipid-soluble drug. Peak venous blood levels of 75 to 150 nanograms per milliliter (ng/mL) of plasma appear about the time smoking is finished (Agurell et al. 1984, 1986; Huestis et al. 1992a, 1992b). Arterial concentrations of THC have not been measured but would be expected to be much higher initially than venous levels, as is the case with smoked nicotine or smoked cocaine.

Oral ingestion of THC or marijuana is quite different than smoking. Maximum THC and other cannabinoid blood levels are only reached 1 to 3 hours after an oral dose (Adams and Martin 1996; Agurell et al. 1984, 1986). Onset of psychoactive and other pharmacologic effects is rapid after smoking but much slower after oral doses.

Marijuana Smoking Behavior and Dose Control
As with any smoked drug (e.g., nicotine or cocaine), characterizing the pharmacokinetics of THC and other cannabinoids from smoked marijuana is a challenge (Agurell et al. 1986; Heishman et al. 1989; Herning et al. 1986; Heustis et al. 1992a). A person's smoking behavior during an experiment is difficult for a researcher to control. People differ. Smoking behavior is not easily quantified. An experienced marijuana smoker can titrate and regulate dose to obtain the desired acute psychological effects and to avoid overdose and/or minimize undesired effects. Each puff delivers a discrete dose of THC to the body. Puff and inhalation volume changes with phase of smoking, tending to be highest at the beginning and lowest at the end of smoking a cigarette. Some studies found frequent users to have higher puff volumes than did less frequent marijuana users. During smoking, as the cigarette length shortens, the concentration of THC in the remaining marijuana increases; thus, each successive puff contains an increasing concentration of THC.

One consequence of this complicated process is that an experienced marijuana smoker can regulate almost on a puff-by-puff basis the dose of THC delivered to lungs and thence to brain. A less experienced smoker is more likely to overdose or underdose. Thus a marijuana researcher attempting to control or specify dose in a pharmacologic experiment with smoked marijuana has only partial control over drug dose actually delivered. Postsmoking assay of cannabinoids in blood or urine can partially quantify dose actually absorbed after smoking, but the analytic procedures are methodologically demanding, and only in recent years have they become at all practical.

After smoking, venous blood levels of THC fall precipitously within minutes, and an hour later they are about 5 to 10 percent of the peak level (Agurell et al. 1986; Huestis et al. 1992a, 1992b). Plasma clearance of THC is quite high, 950 milliliters per minute (mL/min) or greater; thus approximating hepatic blood flow. However, the rapid disappearance of THC from blood is largely due to redistribution to other tissues in the body rather than simply because of rapid cannabinoid metabolism (Agurell et al. 1984, 1986). Metabolism in most tissues is relatively slow or absent. Slow release of THC and other cannabinoids from tissues and subsequent metabolism makes for a very long elimination half-time. The terminal half-life of THC is estimated to be from about 20 hours to as long as 10 to 13 days, though reported estimates vary as expected with any slowly cleared substance and the use of assays with varied sensitivity.

Cannabinoid metabolism is extensive with at least 80 probably biologically inactive but not completely studied metabolites formed from THC alone (Agurell et al. 1986; Hollister 1988a). 11-hydroxy-THC is the primary active THC metabolite. Some inactive carboxy metabolites have terminal half-lives of 50 hours to 6 days or more and thus serve as long persistence markers of prior marijuana use by urine tests. Most of the absorbed THC dose is eliminated in feces and about 33 percent in urine. THC enters enterohepatic circulation and undergoes hydroxylation and oxidation to 11-nor-9-carboxy-delta-9-THC (9-COOH-Delta9-THC). The glucuronide is excreted as the major urine metabolite along with about 18 nonconjugated metabolites. Frequent and infrequent marijuana users are similar in the way they metabolize THC (Agurell et al. 1986; Kelly and Jones 1992).

Route of Use Bioavailability and Dose
THC bioavailability, i.e., the actual absorbed dose as measured in blood, from smoked marijuana varies greatly among individuals. Bioavailability can range from 1 percent to 24 percent with the fraction absorbed rarely exceeding 10 percent to 20 percent of the THC in a marijuana cigarette or pipe (Agurell et al. 1986; Hollister 1988a). This relatively low and quite variable bioavailability results from significant loss of THC in sidestream smoke, from variation in individual smoking behaviors, from incomplete absorption from inhaled smoke, and from metabolism in lung and cannabinoid pyrolysis. A smoker's experience is probably an important determinant of dose actually absorbed (Herning et al. 1986; Johansson et al. 1989). Much more is known about the dynamics of tobacco (nicotine) smoking. Many of the same pharmacokinetic considerations apply to marijuana smoking.

Oral bioavailability of THC, whether given in the pure form or as THC in marijuana, also is low and extremely variable, ranging between 5 percent and 20 percent (Agurell et al. 1984, 1986). Great variation can occur even when the same individual is repeatedly dosed under controlled and ideal conditions. THC's low and variable oral bioavailability is largely a consequence of large first-pass hepatic elimination of THC from blood and due to erratic absorption from stomach and bowel. Because peak effects are slow in onset and variable in intensity, typically at least an hour or two after an oral dose, it is more difficult for a user to titrate dose than with marijuana smoking. When smoked, THC's active metabolite 11-hydroxy-THC probably contributes little to the effects since relatively little is formed, but after oral doses the amounts of 11-hydroxy-THC metabolite may exceed that of THC and thus contribute to the pharmacologic effects of oral THC or marijuana.


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