INTRODUCTION	Section 2 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Background: Cannabis shoots, leaves, and fruits unearthed in the Yanghqi Tombs, Turpan District in Xinjiang, China have been carbon dated to 2500 BC. They are believed to have been used for ritual/medicinal purposes, given the Shamanistic identity of the entombed.

Marijuana was introduced to the Western Hemisphere in the early 1500s. African slaves brought marijuana plants with them to the Portuguese colony of Brazil, while the Spaniards began growing it in Chile.

Cannabis was introduced to the Virginia colony of Jamestown in 1611 and to the Massachusetts Bay Colony in 1629. Although primarily used as a source of fiber, cannabis occasionally was smoked. Cannabis began to be used medicinally and was grown by many American planters. By 1850, it was listed in the US Pharmacopoeia. Cannabis was marketed as extract or tincture by several pharmaceutical companies and used for ailments ranging from asthma to whooping cough to anxiety.

In the United States, recreational abuse of marijuana became more common in the early 20th century. Marijuana was enjoyed with bathtub gin in the Prohibition Era (1920s). In the 1960s, marijuana use became associated with the widespread cultural changes. As a result of the Comprehensive Drug Abuse Prevention and Control Act of 1970, the penalties for marijuana use became substantially less than the penalties for other drugs such as cocaine or heroin. The medicinal use of cannabis currently is the subject of intense legal and medical debate in the United States.

Pathophysiology: Cannabis contains several pharmacologically active substances, of which the most powerful psychoactive member is delta-l-tetrahydrocannabinol (THC). Pyrolysis of marijuana releases more than 100 substances that are subsequently inhaled with the smoke. 1-trans-delta-9-THC is thought to be the ingredient most responsible for the mental effects of marijuana.

Another increasingly important constituent is cannabidiol. It is the constituent thought now to reduce many of the undesirable effects of THC; it significantly reduces the anxiety and psychoticlike symptoms that can be associated with THC. It is currently under investigation for use as an anxiolytic and antipsychotic. Double-blinded tests on volunteers have demonstrated its usefulness as an anxiolytic in anxiogenic test situations. Animal and human studies also suggest that it has a pharmacologic profile similar to atypical antipsychotics; as such, cannabis is being considered as an alternative effective treatment for schizophrenia. THC, however, has been more extensively studied; therefore, our understanding of the physiological changes induced by marijuana is based on the binding and metabolism of THC.

Smoking is the most common and efficient means of ingestion, the dose being titrated by the user through varying the depth and frequency of inhalation. THC can also be extracted by fat-containing foods or dissolved in oil for pharmaceutical purposes. Synthetic cannabinoids have existed that are more potent and somewhat more water soluble.

After intake, THC undergoes metabolism to an inactive metabolite (8-11-DiOH-THC) and also to a highly active metabolite (11-OH-delta-9-THC). The half-life of THC is approximately 4 hours. The long life of the active metabolite is explained by the incorporation of the compound in lipid storage depots and similar storage sites in muscle tissue. Thirty to 60% of THC, in all forms, is excreted in feces; the remaining amount is excreted in urine.

Delta-9-THC is believed to exert all of its effects on the brain via the cannabinoid 1 (CB1) receptor. High densities of CB1 receptors are found in the cerebral cortex (especially frontal), basal ganglia, cerebellum, anterior cingulate cortex, and hippocampus. They are relatively absent in the brainstem nuclei. Stimulation of these receptors causes monoamine and amino acid neurotransmitters to be released. Endogenous ligands for CB1 receptors include anandamide and 2-arachidonylglycerol—the endocannabinoids.

Frequency:

• In the US: Marijuana remains the most commonly used illicit drug, with 14.6 million persons reporting "past month use" (Substance Abuse and Mental Health Services Administration, 2006).
  • Reported past month rates of marijuana use have declined steadily among young Americans since 2002. For persons aged 12-17 years, reported past month rates were 6.8% Also declining were past year use (about 14%) and lifetime use (about 18%).

  • Rates of past month use by adults aged 18-25 years have increased, reported at 16.6%.

  • Among adults 26 years or older, 4.1% had used marijuana in the past month.

  In 2005, the Monitoring the Future survey, the annual survey of drug use among school-aged children, reported that marijuana has been the most widely used illicit drug throughout the 31 years of the study. Use by 8th-10th graders leveled off in 2005. Among 8th graders questioned, 16% had tried marijuana with 6% reported to be using at the time of the survey. Among 10th graders, 35% had tried marijuana and 16% were currently using. Among 12th graders, a decline has been evident, particularly since 2002. In 2005, 46% of 12th graders had tried marijuana and 20% reported using regularly (Johnston, 2006).

• Internationally: Rates of abuse vary widely. The hypothesis that cannabis is the most widely used illicit drug in most Western countries is generally accepted.

Mortality/Morbidity: While use of injected hashish oils has resulted in rare deaths from overdose, no clear evidence of deaths being caused by uncomplicated cannabis use otherwise exists. Mortality, however, may be associated with marijuana-related accidents, cancers, and comorbid substance abuse.

• Marijuana abusers account for significantly more missed work days and workman's compensation claims and higher employee turnover rates than nonusers.

• A marijuana withdrawal syndrome—increased irritability and higher scores on standardized measures of aggressiveness—has been described in chronic users, peaking about 1 week after cessation of smoking.

Race: Marijuana is abused among all racial groups, with some propensities for racial differences. Rates were lowest among Asians at a reported 3.1%, with highest rates reported for American Indians and Alaskan Natives at 12.8%. African Americans reported 9.7%, Caucasians 8.1%, and Hispanics 7.1%.

Racial differences have been found in risk of arrest. African Americans are 2.5 times more likely to be arrested for marijuana possession offenses than Caucasians. In addition to patterns of police vigilance, this has been linked to riskier patterns of purchase. African Americans are 2 times as likely to buy outdoors, 3 times as likely to buy from a stranger, and also significantly more likely to buy away from their homes.

Cannabis use is also significantly associated with low income, regardless of race.

Sex: Being male increases the odds of reporting past month cannabis use—10.2% versus 6.1% for females in 2005.

Age: Age of onset of abuse and dependence disorders tends to occur in adolescence. Adolescents and young adults are the most common group to abuse this substance; however, abuse may be observed relatively commonly in most age groups.

	CLINICAL	Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History:

• People who use marijuana may present with either acute effects of intoxication or symptoms of chronic use. The dose of marijuana ingested, the mental state of the subject, and the setting in which cannabis is taken all contribute to the influence of the drug.

• Onset of symptoms of marijuana intoxication occurs within a few minutes of smoking or within half an hour of oral ingestion. The duration of action usually is 6-12 hours; symptoms are most marked in the first 1-2 hours.

• Chronic users may also be noted to have changes in appetite, diminished drive, and lack of ambition. This "amotivational syndrome" is also characterized by lack of energy and decreased social and occupational drive.

• The following symptoms may be prominent in acute intoxication:

• Euphoria

• Relaxation

• Subjective feelings of well-being or grandiosity

• Perceptual changes (including visual distortions)

• Drowsiness and sluggishness

• Diminished coordination

• Paradoxical hyperalertness

• A subjective sense of slowing of the passage of time

• Increased appetite (the "munchies")

• Although commonly misperceived as universally resulting in a relaxed and euphoric state, cannabis intoxication can produce a dysphoric reaction. Carefully examine patients for evidence of suicidality and homicidality, document presence or absence thereof, and manage as indicated.

• Feelings of panic

• Disorientation and memory impairment (rare; usually occurs only after ingestion of high-potency cannabinoid preparations)

• Paranoia

• Mood lability

• Altered perceptions (following heavy marijuana use) manifesting as illusions or frank hallucinations, most often visual in type

• Depersonalization

• Psychotic episodes

• Recurrence of psychosis in patients with schizophrenia

Physical: Physical signs and symptoms reflect the effects of marijuana on multiple organ systems and can be classified according to the system involved.

• Effects on central and peripheral nervous systems: Cannabis-induced cerebral atrophy or neuropsychological impairment remains a controversial diagnosis. Chronic effects of long-term marijuana use may be related to marijuana's significant fat solubility resulting in high blood levels of the drug after extended use. Marijuana-induced seizures have been described.

  Studies using simulated driving and flying situations have shown that the use of cannabis has a profound effect on estimations of time and distance and causes impairment of attention and short-term memory. These effects are still discernible 24-48 hours after use of the drug. A linear relationship exists between level of impairment and serum/saliva THC in tasks necessary for driving, such as perceptual motor control, motor impulsivity, and cognitive function.

  Cannabis use is associated with an increased risk in youth for developing psychotic symptoms, even with adjustments made for age, sex, socioeconomic status, urban residence, childhood trauma, predisposition for psychosis at baseline, use of other drugs, tobacco, and alcohol.

• Effects on respiratory system: Cannabis smoke contains carcinogens similar to those found in tobacco smoke, and chronic heavy marijuana use may predispose people to chronic obstructive lung disease. Some studies indicate that pulmonary neoplasms are more common among habitual marijuana users; however, confounding by cigarette smoking limits the interpretability of some of these reports.

  Several reports of aspergillus infection resulting from inhalation have been documented among immunocompromised persons.

• Effects on cardiovascular system: Acute intoxication may induce tachycardia and orthostatic hypotension.

• Effects on reproductive system: Marijuana has been linked to infertility. In vitro studies have reported abnormal cell division and abnormal spermatogenesis resulting in decreased sperm counts; however, the effects of marijuana on human fertility remain unclear. In females, marijuana use may increase the number of anovulatory cycles. In males, marijuana use may cause a decrease in follicle-stimulating hormone, resulting in a decrease in testosterone production and, possibly, testicular atrophy.

• Effects on gastrointestinal tract: Marijuana has known antinausea properties and the use of marijuana has been permitted for the treatment of nausea in some US states for this reason. Oddly enough, a chronic nausea/vomiting syndrome has been reported in numerous habitual marijuana users. Cessation of use in these cases ends the syndrome.

  Both dronabinol, a synthetic cannabinoid, and marijuana produce significant, substantial, and comparable increases in food intake, without adverse effects in experienced marijuana smokers who have clinically significant muscle mass loss.

  Small studies have suggested that chronic marijuana use was associated with hepatic morphologic and enzymatic alterations, indicating cannabinoids as possible hepatotoxic substances.

• Ocular effects: Injected conjunctivae may occur.

Causes:

• Risk factors for use

• Peer group influences: Cannabis use is correlated with having older siblings and friends who use.

• Availability (may be affected by cultural and geographic factors, eg, urban environments)

• Comorbid alcohol abuse and/or dependence

• Comorbid drug abuse

• Genetic influences: Genetic associations have been found with respect to each stage of cannabis involvement; significant evidence exists for the heritability of use, abuse, and dependence.

• Epidemiologic reports indicate that individuals with social anxiety disorder are at increased risk for cannabis use disorders.

• Comorbidity is high between cannabis use disorders and other axis I and II disorders.