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Chapter: Modern Pharmacology with Clinical Applications: Contemporary Drug Abuse

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Contemporary Drug Abuse: Marijuana

The hemp plant, or cannabis (Cannabis sativa), contin-ues to be the most frequently abused illicit substance in America.

MARIJUANA

The hemp plant, or cannabis (Cannabis sativa), contin-ues to be the most frequently abused illicit substance in America. The dried leaves and flowering tops of the plant are referred to as marijuana, and it is typically smoked in pipes or rolled as cigarettes. It also may be consumed in baked goods. Hashish is a solid black resinous material obtained from the leaves of the plant and is usually smoked in a pipe.

Chemistry

The major psychoactive constituent in marijuana use is 9-tetrahydrocannabinol (THC), the prototypical can-nabinoid. Although marijuana contains a large number of cannabinoids, they lack behavioral activity with the exception of cannabinol, which is approximately one-tenth as potent as THC. The THC content in hashish is more than double that in marijuana.

Pharmacokinetic Aspects

9-THC is readily absorbed when marijuana is smoked. Pharmacological effects are produced rapidly and gener-ally peak within 30 minutes of the onset of smoking. The dynamics of smoking (number of puffs, spacing, hold time, and lung capacity) substantially influence how much drug is absorbed. Although oral ingestion of mari-juana produces similar pharmacological effects, 9-THC is absorbed more slowly than by smoking. Impairment on various performance measures related to driving skills has been demonstrated immediately following marijuana smoking and up to 24 hours thereafter. Generally, behav-ioral and physiological effects return to baseline levels 4 to 6 hours after usage. Blood concentrations of 9-THC peak prior to drug-induced effects. This time discordance between blood concentrations of 9-THC and effects has made it difficult to establish a meaningful relationship between blood concentrations and effects.

9-THC is rapidly distributed to all tissues despite being tightly bound by plasma proteins. 9-THC is a highly lipophilic substance and so accumulates in tissue high in lipid content. Traces of 9-THC have been found in adipose tissue more than 30 days after the subject smoked a single joint. The terminal half-life of  9-THC in plasma ranges from 18 hours to 4 days.

Mechanism of Action

A cannabinoid receptor identified in the brain of sev-eral species, including humans, is termed CB1. It is one of the most abundant receptors in the CNS, and its dis-tribution within the brain reflects the pharmacological effects produced by 9-THC. High receptor densities in the extrapyramidal motor system and the cerebellum are consistent with the actions of cannabinoids on many forms of movement. The effects of cannabinoids on cog-nition and memory may be due to the relatively dense receptor populations in the hippocampus and cortex. The presence of cannabinoid receptors in the ventro-medial striatum and nucleus accumbens suggests an as-sociation with dopamine neurons hypothesized to me-diate brain reward.

Pharmacological Actions

Central Nervous System

Marijuana produces a distinctive behavioral syndrome that is easily distinguished from that of most other drugs. The most prominent feature is the initial period of euphoria, or high, which has been described as a sense of well-being and happiness. Euphoria is fre-quently followed by a period of drowsiness or sedation. Perception of time is altered, along with distortions in both hearing and vision. However, illusions and halluci-nations occur infrequently. The subjective effects also include dissociation of ideas.

The subjective effects of marijuana vary from indi-vidual to individual as a function of dose, route of ad-ministration, the experience and expectation of the sub-jects, and individual vulnerability to certain psychoactive substances. Motor coordination also may decrease, espe-cially in situations requiring highly complex motor skills, such as flying an airplane and driving an automobile.

Increased appetite is frequently attributed to smok-ing marijuana. Cannabinoids are effective antiemetics, particularly in treating emesis arising during chemo-therapy. 9-THC has been reported to be as effective as codeine as an analgesic, although pronounced behav-ioral effects occur with analgesic doses.

Other Organ Systems

The most consistent pharmacological effect produced by marijuana is tachycardia, which is closely associated with the blood levels of 9-THC. There is relatively lit-tle effect on blood pressure unless large quantities of marijuana are smoked, in which case there can be marked orthostatic hypotension. Cannabinoids are also vasodilatory, which results in the characteristic conjunc-tival reddening following marijuana smoking. They also reduce intraocular pressure and are capable of produc-ing bronchodilation.

Adverse Effects

Marijuana is unique among drugs of abuse in that there have been no credible reports of fatal overdose. The most prominent effect of acute marijuana use is intoxi-cation, which can impair the cognitive and motor skills needed to complete complex tasks. Anxiety and panic reactions are occasionally reported in inexperienced users or following use of large quantities of marijuana. 9-THC causes its greatest effects on short-term mem-ory, as measured in free-recall tasks. Marijuana does not affect the retrieval of previously learned facts. In con-trast to alcohol, there is no residual hangover from a single use of high quantities of marijuana.

Heavy marijuana smoking produces bronchitis, and some individuals have evidence of precancerous lung conditions. However, definitive evidence of the rela-tionship between marijuana smoking and the incidence of lung cancer is lacking.

Tolerance develops to many of 9-THC’s effects in heavy marijuana users. Although chronic cannabis use does not result in severe withdrawal symptoms, numer-ous case reports attest to development of dependence in subjects taking high doses of THC for several weeks. The most prominent symptoms were irritability and restlessness; others included insomnia, anorexia, in-creased sweating, and mild nausea. Cessation of mild or moderate use of marijuana, however, does not produce a withdrawal syndrome.

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