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Cannabis or THC has been administered for human research purposes via the smoked, oral, and intravenous routes of administration. Each route of administration has experimental advantages and disadvantages. The smoked route mimics the most common way that cannabis is used outside the laboratory, but it can cause pulmonary adverse effects (see Subheading and is subject to wide individual variation in effective dose and time of onset because of differences in absorption, which depend on such factors as puff frequency, depth of inhalation, and retention of inhaled smoke (8,9) (see Note 1). Smoking or ingesting the cannabis plant material administers a large number of active chemicals in addition to THC, potentially causing a different range of effects than does pure THC (3). Oral cannabis and THC also are associated with great individual variability in absorption and with reduced dose potency because of first-pass metabolism in the liver. The slower onset of effect and lower potency might be considered advantages from a safety perspective. Intravenous THC offers uniform absorption and precise investigator control of dosage and timing. Regardless of route of administration, maintenance of a double-blind design is important because significant expectancy effects are associated with cannabis administration (10,11).

The vast majority of recent US laboratory studies administering smoked cannabis have used standardized marijuana cigarettes provided by the US National Institute on Drug Abuse (NIDA) (see Note 2). These marijuana cigarettes resemble in size an unfiltered tobacco cigarette, weigh 700-1000 mg, and contain approx 1-4% of THC by weight, yielding maximum THC doses of 7-40 mg. (The actual effective dose will be up to 70% less because of pyroly-sis of THC, loss in side-stream smoke, incomplete absorption, and metabolism in the lung.) The THC concentration in NIDA cigarettes is less than the typical THC content of marijuana available in the community, which may range from 4 to 10% or higher. THC dose for research purposes can be manipulated by using cigarettes that differ in THC content and/or by varying the number of puffs administered to subjects (one cigarette is usually completely consumed with five to eight puffs). NIDA also provides placebo cigarettes from which the THC has been chemically extracted. These cigarettes burn and smell the same as active marijuana cigarettes, but the plant material may differ somewhat in color (12) (see Note 3).

Cigarettes are typically held by the subject in a clip or plastic holder in order to allow smoking of the entire cigarette without risk of burning the fingers. Plastic holders offer the advantage of hiding the end of the cigarette, minimizing the chance of subjects getting clues to dosage from the appearance of the plant material (although this appears unlikely unless subjects have prior experience with NIDA-provided cigarettes). Cigarettes are usually smoked according to a paced procedure, such that the investigator dictates the duration of an inhalation (typically 5 s), the duration of breath-holding (typically 5-10 s), and the interpuff interval (typically 40-120 s) (e.g., ref. 13). This provides greater dosing consistency across subjects and reduces the chance of subjects exceeding study dose limits by smoking more than intended. Subjects should always have the opportunity to end a smoking session at any time if they experience adverse effects.

Cannabis can also be administered orally, although this route of administration is now rarely used experimentally. Marijuana plant material is crushed into a powder, which then is baked into a brownie or similar easily consumed food (14).

Oral synthetic THC is available in the United States as dronabinol (brand name MarinolĀ®; Unimed Pharmaceuticals, Marietta, GA, a medication legally marketed as an appetite stimulant to treat weight loss due to acquired immunodeficiency syndrome (AIDS) and to treat nausea and vomiting due to cancer chemotherapy. It comes as soft gelatin capsules containing 2.5, 5, or 10 mg of dronabinol dissolved in sesame oil. The recommended doses are up to 20 mg/d for appetite stimulation and up to 15 mg/m2 (of body surface area) up to six times a day for nausea and vomiting. Use of dronabinol offers several practical advantages to investigators. First, as a legal medication classified in Schedule III of the Controlled Substances Act (whereas cannabis and THC are in Schedule I), there are fewer complicated regulatory requirements for acquiring and storing the research medication. Second, dronabinol capsules can be stored in a cool environment or refrigerator, whereas cannabis cigarettes must be stored frozen. Third, use of dronabinol within the Food and Drug Administration (FDA)-rec-ommended doses may reassure institutional review boards and potential subjects as to the safety of the study. These practical advantages must be weighed against the scientific disadvantages mentioned above.

THC has been administered intravenously in doses up to 5 mg (15). Because THC is poorly soluble in water, it must be mixed with human albumin or other solubilizing agents.

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