Cannabis users occasionally may experience distrust, dysphoria, fear, or panic reactions. Transient psychotic episodes are associated with cannabis use. Commonly reported adverse reactions at the prescribed dose of dronabinol or nabilone include postural hypotension, dizziness, sedation, xerostomia, abdominal discomfort, nausea, and vomiting. One case of acute pancreatitis (serum amylase concentration up to 3200 IU/mL) following a period of heavy cannabis use is reported, but the causal relationship is unclear.44
Life-threatening ventricular tachycardia (200 beats/min) has been reported.121 In six individuals with acute cardiovascular deaths, postmortem whole-blood THC concentrations ranged from 2 to 22 ng/mL (mean, 7.2 ng/mL; median, 5 ng/mL).5 While the temporal association is clear, causality is less clear because three of the six people had significant preexisting cardiac pathology. The risk of myocardial infarction is increased five times over baseline in the 60 minutes after marijuana use but subsequently declines rapidly to baseline risk levels.98 Atrial fibrillation with palpitations, nausea, and dizziness was temporally associated with smoking marijuana in four patients.38,79,138
Long-term use of cannabis is associated with a number of adverse effects.
Cannabinoids affect host resistance to infection by modulating the secondary immune response (macrophages, T and B lymphocytes, acute phase and immune cytokines). However, an immune-mediated health risk from using cannabis has not been documented.77
Chronic use of marijuana is associated with clinical findings compatible with obstructive lung disease.147 Smoking marijuana delivers more particulates to the lower respiratory tract than does smoking tobacco,155 and marijuana smoke contains carcinogens similar to tobacco smoke. Case reports and a hospital-based case-control study suggest that cancers of the respiratory tract (mouth, larynx, sinuses, lung) are associated with daily or near daily smoking of marijuana, although exposure to tobacco smoke and ethanol may be confounding factors.21,142,145 A systematic review and a cohort study with 8 years of follow-up demonstrated no association between marijuana smoking and smoking-related cancers,49,93 and a population-based case-control study found that marijuana use was not associated with an increased risk of developing oral squamous cell carcinoma.124
Marijuana use may be a risk for individuals with coronary artery disease. An exploratory prospective study of self-reported marijuana use among patients admitted for myocardial infarction found that patients who used marijuana were at significantly increased risk for cardiovascular and noncardiovascular mortality compared with nonusers.98,103
Reduced fertility in chronic users is a result of oligospermia, abnormal menstruation, and decreased ovulation.17 Cannabis is a class C drug in pregnancy16 and affects birth weight and length but does not cause fetal malformations. Statistically significant reductions in birth weight (mean, 79 g less than nonusers) and length (mean, 0.5 cm shorter than nonusers) are reported in women who had urine assays positive for cannabis during pregnancy.157 The results of three other studies are difficult to interpret because marijuana use in pregnancy was poorly documented.50,157 Epidemiologic studies based on self-reporting of cannabis use do not support an association between the use of cannabis during pregnancy and teratogenesis.78,85,157
The effect of maternal use of cannabis during pregnancy on neurobehavioral development in the offspring has been studied. No detrimental effects are reported in children born to women who smoked marijuana daily (more than 21 cigarettes per week) in rural Jamaica.34 Tremors and increased startling are reported in infants younger than 1 week of age whose mothers used cannabis during pregnancy.40 These findings, which persisted beyond 3 days, were not associated with other signs of a withdrawal syndrome. There were no abnormalities in the children of parents who used greater than five cigarettes per week in Ottawa, Canada, at 12, 24, and 36 months of age, but lower scores in verbal and memory domains at 48 months of age are reported.39,41,51 The results of studies evaluating the effect of in utero exposure to cannabis on postnatal neurobehavioral development are equivocal because of methodologic concerns regarding exposure assessment and control of covariates,31 including the continued parental use of cannabis during the postnatal and early childhood periods. The role of second hand exposure to cannabis on postnatal and early childhood development of neurobehavioral problems has not been evaluated.
In experimental animals, cannabis exposure is associated with suppression of gonadal steroids, growth hormone, prolactin, and thyroid hormone. In addition, cannabis alters the activity of the hypothalamic-pituitary-adrenal axis.17 In human studies, the results are inconsistent, long-term effects have not been convincingly demonstrated, and clinical consequences are undefined.17
There is a concern that chronic cannabis use results in deficits in cognition and learning that last well after cannabis use has stopped. Neuropsychological tests administered to 10 cannabis-dependent adolescents, eight adolescent noncannabis drug abusers, and nine nondrug users showed significant differences that persisted for the duration of the study (6 weeks of abstinence) between the cannabis group and the other groups in a visual retention test and a memory test.132 In a study of three experienced marijuana smokers, cannabis impaired arithmetic and recall tasks up to 24 hours after smoking.52 Adults who used cannabis more than seven times per week had impairments in math skills, verbal expression, and memory retrieval processes; people who used cannabis one to six times per week showed no impairments.11 After 1 day of abstinence, 65 heavy marijuana users (median, use on 29 of past 30 days) showed greater impairment on neuropsychological tests of attention and executive functions than light marijuana users (median, use on 1 day of past 30 days).116 (The authors were uncertain whether this difference was caused by residual THC in the brain, a withdrawal effect from the drug, or a direct neurotoxic effect of cannabis.)
There is little evidence that adverse cognitive effects persist after stopping the use of cannabis68 or that cannabis use causes psychosocial harm to the user.86 The hypothesis that there is a causal association between cannabis use and psychosis has not been proven unequivocally.9 An “amotivational syndrome” is attributed to cannabis use. The syndrome is a poorly defined complex of characteristics such as apathy, underachievement, and lack of energy.25,131 The association of the syndrome with cannabis use is based primarily on anecdotal, uncontrolled observations.56 Anthropologic field studies, evaluations of US college students, and controlled laboratory experiments have failed to identify a causal relationship between cannabis use and the amotivational syndrome.56 A study evaluating the role of depression in the amotivational syndrome found significantly lower scores on “need for achievement” scales in heavy users (median, daily use for 6 years) with depressive symptoms compared with heavy users without depressive symptoms and light users (median, several times per month for 4.5 years) with or without depressive symptoms.105 These data suggest that symptoms attributed to an amotivational syndrome are caused by depression, not cannabis. Another study found that behavior that could be interpreted as amotivation was inversely related to the perceived size of the reward.25
Abuse, Dependence, and Withdrawal.
The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, defines marijuana abuse as repeated instances of use under hazardous conditions; repeated, clinically meaningful impairment in social/occupational/educational functioning; or legal problems related to marijuana use. Marijuana dependence is defined as tolerance, compulsive use, impaired control, and continued use despite physical and psychological problems caused or exacerbated by use. The amount, frequency, and duration of cannabis use required to develop dependence are not well established.24,141 Much of the support for cannabis dependence is based on the existence of a withdrawal syndrome. In animals repeatedly given cannabis, the administration of a CB1 receptor antagonist produced signs of withdrawal.83,139 In humans, chronic users experience unpleasant effects when abstaining from cannabis.18 The time of onset of withdrawal symptoms is not well characterized.17 The most reliably reported effects are irritability, restlessness, and nervousness as well as appetite and sleep disturbances.139 Other reported acute withdrawal manifestations include tremor, diaphoresis, fever, and nausea. These symptoms and signs are reversed by the oral administration of THC.9,48 The duration of withdrawal manifestations, without treatment, is not clearly established.19,139
There is a single report of a withdrawal syndrome observed after heavy and prolonged nonclassical SCRA use.
Cannabinoid Hyperemesis Syndrome.
Chronic, heavy marijuana use is associated with a clinical syndrome comprised of abdominal discomfort, nausea, and hyperemesis. Symptoms are often refractory to opioids and antiemetics.151 The hallmark of the syndrome is almost immediate relief of symptoms with bathing or showering in hot water, and a major diagnostic feature is compulsive bathing. The pathophysiology of this syndrome is unclear. However, relief with hot water may indicate dysfunction of pain perception, excess substance P release, and activation of TRPV1 (a G protein receptor that has been shown to interact with the endocannabinoid system and is the only known capsaicin receptor); these may play a role in elucidating the mechanism for this syndrome as well as providing new treatment modalities. Ultimately, successful treatment of the cannabinoid hyperemesis syndrome depends on cessation of marijuana use.3,23,33,42,136,137,151