Cannabis sativa contains >400 compounds in addition to the psychoactive substance, delta-9-tetrahydrocannabinol (THC). Marijuana cigarettes are prepared from the leaves and flowering tops of the plant, and a typical marijuana cigarette contains 0.5–1 g of plant material. The usual THC concentration varies between 10 and 40 mg, but concentrations <100 mg per cigarette have been detected. Hashish is prepared from concentrated resin of C. sativa and contains a THC concentration of between 8 and 12% by weight. “Hash oil,” a lipid-soluble plant extract, may contain THC between 25 and 60% and may be added to marijuana or hashish to enhance its THC concentration. Smoking is the most common mode of marijuana or hashish use. During pyrolysis, <150 compounds in addition to THC are released in the smoke. Although most of these compounds do not have psychoactive properties, they may have physiologic effects.
THC is quickly absorbed from the lungs into blood and then rapidly sequestered in tissues. THC is metabolized primarily in the liver, where it is converted to 11-hydroxy-THC, a psychoactive compound, and >20 other metabolites. Many THC metabolites are excreted through the feces at a relatively slow rate of clearance compared with most other psychoactive drugs.
Specific cannabinoid receptors (CB1 and CB2) have been identified in the central and peripheral nervous system. High densities of cannabinoid receptors have been found in the cerebral cortex, basal ganglia, and hippocampus. T and B lymphocytes also contain cannabinoid receptors, and these appear to mediate the anti-inflammatory and immunoregulatory properties of cannabinoids. A naturally occurring THC-like ligand has been identified and is widely distributed in the nervous system.
Herbal marijuana alternatives are also available. These are usually a combination of several herbs and synthetic cannabinoids. “Spice” and “K2” are among the best known, but many formulations exist, and marijuana is undetectable by the usual methods. These compounds are marketed on the Internet as containing no illegal ingredients. However a number of synthetic cannabinoids are now classified as Schedule I by the Drug Enforcement Administration due to reports of toxicity.
Marijuana is the most commonly used illegal drug in the United States. In 2012, an estimated 18.9 million people reported using marijuana within the past month. An estimated 7.2% of adolescents age 12 to 17 years reported current use of marijuana. Marijuana is relatively inexpensive and is often considered to be less hazardous than other controlled drugs and substances. Very potent forms of marijuana (sinsemilla) are widely available, and concurrent use of marijuana with other drugs such as cocaine is not uncommon. Due in part to the difficulty of detecting herbal marijuana alternatives, the prevalence of use is unknown.
ACUTE AND CHRONIC INTOXICATION
Acute intoxication from marijuana and cannabis compounds is related to both the dose of THC and the route of administration. THC is absorbed more rapidly from marijuana smoking than from orally ingested cannabis compounds. Acute marijuana intoxication may produce a perception of relaxation and mild euphoria resembling mild to moderate alcohol intoxication. This condition is usually accompanied by some impairment in thinking, concentration, and perceptual and psychomotor function. Higher doses of cannabis may produce more pronounced impairment in concentration and perception, as well as greater sedation. Although the acute effects of marijuana intoxication are relatively benign in normal users, the drug can precipitate severe emotional disorders in individuals who have antecedent psychotic or neurotic problems. Like other psychoactive compounds, both the user’s expectations and the environmental context are important determinants of the type and severity of the effects of marijuana intoxication.
As with abuse of cocaine, opioids, and alcohol, chronic marijuana abusers may lose interest in common socially desirable goals and devote progressively more time to drug acquisition and use. However, THC does not cause a specific and unique “amotivational syndrome.” The range of symptoms sometimes attributed to marijuana use is difficult to distinguish from mild to moderate depression and the maturational dysfunctions often associated with protracted adolescence. Chronic marijuana use has also been reported to increase the risk of psychotic symptoms in individuals with a past history of schizophrenia. Persons who begin marijuana smoking before the age of 17 may have more pronounced cognitive deficits and also may be at higher risk for polydrug and alcohol abuse problems in later life, but the role of marijuana in this sequence is uncertain.
The acute effects of herbal marijuana alternatives are based primarily on case reports and include anxiety, agitation, delusions, paranoia, and psychosis. The extent to which these symptoms reflect drug effects or exacerbation of an underlying psychiatric disorder is often difficult to determine.
Conjunctival injection and tachycardia are the most frequent immediate physical concomitants of smoking marijuana. Tolerance for marijuana-induced tachycardia develops rapidly among regular users. However, marijuana smoking may precipitate angina in persons with a history of coronary insufficiency. Exercise-induced angina may increase after marijuana use to a greater extent than after tobacco cigarette smoking. Patients with cardiac disease should be strongly advised not to smoke marijuana or use cannabis compounds.
Significant decrements in pulmonary vital capacity have been found in regular daily marijuana smokers. Because marijuana smoking typically involves deep inhalation and prolonged retention of marijuana smoke, chronic bronchial irritation may develop. Impairment of single-breath carbon monoxide diffusion capacity (DlCO) is greater in persons who smoke both marijuana and tobacco than in tobacco smokers.
Although marijuana has also been associated with a number of other adverse effects, many of these studies await replication and confirmation. A reported correlation between chronic marijuana use and decreased testosterone levels in males has not been confirmed. Decreased sperm count and sperm motility and morphologic abnormalities of spermatozoa following marijuana use have been reported. Prospective studies found a correlation between impaired fetal growth and development and heavy marijuana use during pregnancy. Marijuana has also been implicated in derangements of the immune system; in chromosomal abnormalities; and in inhibition of DNA, RNA, and protein synthesis; however, these findings have not been confirmed or related to any specific physiologic effect in humans. Herbal marijuana alternatives produce many of the effects of marijuana including conjunctival injection and tachycardia.
TOLERANCE AND PHYSICAL DEPENDENCE
Habitual marijuana users may develop tolerance to the psychoactive effects of marijuana, and then smoke more frequently and try to acquire more potent cannabis compounds. Tolerance for the physiologic effects of marijuana develops at different rates; e.g., tolerance develops rapidly for marijuana-induced tachycardia but more slowly for marijuana-induced conjunctival injection. Tolerance for both behavioral and physiologic effects of marijuana decreases rapidly upon cessation of marijuana use.
A distinct withdrawal syndrome has been documented in chronic cannabis users, and the severity of symptoms is related to dosage and duration of use. These symptoms typically reach their peak several days after cessation of chronic use and include irritability, anorexia, and sleep disturbances. Withdrawal signs and symptoms observed in chronic marijuana users are usually relatively mild in comparison to those observed in heavy opioid or alcohol users and rarely require medical or pharmacologic intervention. However, more severe and protracted abstinence syndromes may occur after sustained use of high-potency cannabis compounds. As yet there have been no systematic studies of tolerance and physical dependence to the herbal marijuana alternatives. The large number of synthetic cannabinoids available for combination with about 20 herbs presents a daunting challenge for analysis.
THERAPEUTIC USE OF MARIJUANA
Marijuana, administered as cigarettes or as a synthetic oral cannabinoid (dronabinol), is thought to have a number of clinically useful medicinal properties. These include antiemetic effects in chemotherapy recipients, appetite-promoting effects in AIDS patients, reduction of intraocular pressure in glaucoma, and reduction of spasticity in multiple sclerosis and other neurologic disorders. With the possible exception of AIDS-related cachexia, none of these attributes of marijuana compounds is clearly superior to other readily available therapies.