ADVERSE EFFECTS OF CANNABIS USE

ADVERSE EFFECTS OF CANNABIS USE — Cannabis use disorder constitutes a small proportion of the global burden of disease relative to other substance use disorders. Of the approximately two million total disability adjusted life-years lost to substance use disorders (not including tobacco), individual substance use disorders were [11]:

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Alcohol – 47 percent 

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Opioids – 24.3 percent

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Amphetamines – 7.0 percent

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Cannabis – 5.5 percent 

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Cocaine – 2.9 percent

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Other illicit drugs – 13.4 percent

Large-scale cross-sectional epidemiological studies and smaller prospective longitudinal studies have not found cannabis use to be significantly associated with serious or chronic medical conditions or death from medical conditions [11,27]. Cannabis use may be associated with death from motor vehicle accidents. As examples:

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A systematic review of 19 published studies found no evidence of an association between heavy cannabis use and adverse health outcomes, except for fatal motor vehicle crashes [27]. 

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A 2016 40-year longitudinal cohort study of 50,373 Swedish male military conscripts found a significant, albeit small, association between heavy cannabis use (>50 times) at baseline (age 18 to 19 years) and overall mortality (hazard ratio 1.4, 95% CI 1.1-1.8) [28]. The association was similar in those with and without a history of psychotic disorder, suggesting that schizophrenia was not a major factor driving the increased mortality. The only specific causes of death significantly associated with heavy cannabis use were infections, cardiovascular, and injuries of unknown cause, all of which showed a positive dose-response relationship with intensity of baseline cannabis use. 

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A 13-year prospective longitudinal study of 3124 randomly recruited United States young adults found no association between baseline cannabis use at least four times per month and subsequent decline in self-reported general health [29]. 

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A 20-year prospective longitudinal study of a representative birth cohort of 1037 individuals born in Dunedin, New Zealand in 1972 to 1973 and recruited at age 18 years found no significant association between cannabis use or cannabis use disorder and self-reported physical health [30].

Psychosocial functioning and health — Adolescent cannabis use is strongly associated with lower educational attainment and increased use of other drugs, but not with school performance or psychological health; even the strong associations are not clearly causal:

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A systematic review of 16 higher quality prospective longitudinal studies found consistent associations for cannabis use with lower educational attainment, and with increased use of other illegal drugs [31]. Inconsistent associations were found for cannabis use with poor psychological health, and with problematic or criminal behavior. None of the associations was definitely causal, with the possibilities of reverse causation, potential bias, or confounding factors. 

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Two 2015 prospective longitudinal studies found no association for adolescent cannabis use with high school academic performance or mental health problems, after controlling for concurrent alcohol and tobacco use [6,32].

Neuropsychological effects — Cannabis acutely impairs a variety of neuropsychological functions in a dose-dependent manner, especially attention, concentration, episodic memory, and associative learning [33,34]. However, evidence of an association between cannabis use and long-term neurocognitive deficits is mixed [34,35].

While meta-analyses and systematic reviews of studies on cannabis-associated neuropsychological function in cannabis users generally show impairment [33-35], a meta-analysis of 13 studies including cannabis users with at least one month of abstinence found no differences from nonusers on neuropsychological test performance [36]. This finding suggests that cannabis-associated impairment resolves over the time period needed to eliminate body stores of lipid-soluble cannabinoids.

A review of three long-term prospective longitudinal studies suggested that greater cumulative intensity of cannabis exposure and earlier age of onset of cannabis use were associated with greater persistence of cannabis-associated impairment [37]. A more recent prospective longitudinal study of 5115 adults (aged 18 to 30 years at baseline) found that 84.3 percent were life-time cannabis users at 25-year follow-up, while only 11.6 percent were current users [38]. Current cannabis use was associated with impaired verbal memory and slower cognitive processing speed. A linear regression analysis that excluded current cannabis users and controlled for age, use of tobacco, alcohol, and other illegal drugs, and baseline cognitive function found cumulative lifetime cannabis use significantly associated with impaired verbal memory, but not with processing speed or executive function. 

Psychotic disorders — There is substantial evidence that chronic cannabis use, especially during adolescence, is associated with later development of schizophrenia. The mechanisms responsible for the association between cannabis use and schizophrenia remain unclear. Some experts believe that early cannabis use is a causal factor in developing schizophrenia. 

A systematic review of 35 longitudinal studies found an increased risk of psychosis for those who ever used cannabis compared with those who did not (adjusted odds ratio 1.41, 95% CI 1.20-1.65) [39]. There was a significant dose-response relationship, with a twofold increase in risk among those who used cannabis most frequently (odds ratio 2.09, 95% CI 1.54-2.84). The review adjusted for several known confounding factors and excluded cohorts with identified mental illness or substance use problems at baseline.

Cannabis use causes transient acute psychosis in some users. It is not known whether this acute effect is related to the development of schizophrenia associated with chronic cannabis use. (See "Cannabis (marijuana): Acute intoxication", section on 'Toxic effects'.) 

Cannabis use exacerbates symptoms in patients with established psychotic disorders such as schizophrenia. A systematic review and meta-analysis of 24 published longitudinal studies (involving 16,565 participants) found that cannabis use was associated with increased relapse, rehospitalization, and positive symptoms (but not negative symptoms), and poorer level of functioning [40]. A two-year, prospective longitudinal study of 220 adults with first-episode psychosis found a significantly increased risk of relapse with hospitalization during periods of cannabis use (odds ratio 1.13; 95% CI 1.02-1.24) [41]. (See "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis".)

Mood disorders — Most, but not all, prospective longitudinal studies have found that cannabis use or cannabis use disorder is associated with subsequent development of depression or bipolar disorder:

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Depression – A 2014 meta-analysis of 14 prospective longitudinal studies that controlled for depression at baseline found that heavy cannabis users had a 1.62 odds ratio (95% CI 1.21-2.16) for developing clinically diagnosed major depression or depressive symptoms, compared with light or nonusers [42]. As an example, a three-year prospective longitudinal study of a representative sample of almost 35,000 community-living United States adults found a bidirectional comorbidity between cannabis use disorder and major depressive disorder [43]. Individuals with cannabis use disorder at baseline had an adjusted odds ratio = 6.61 (95% CI 1.67-26.21) for major depressive disorder at follow-up, after controlling for likely confounding sociodemographic variables. However, a prospective longitudinal community-based study of 34,653 adults found cannabis users at no increased risk of developing a mood disorder (odds ratio 1.2, 95% CI 0.8-1.6) [12].

A twin study concluded that comorbidity of cannabis dependence and major depressive disorder is probably due to genetic and environmental factors that predispose to both outcomes, rather than a direct causal relationship between cannabis use and depression [44].

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Bipolar disorder – A meta-analysis of two studies of individuals with bipolar disorder found cannabis use associated with a threefold increased risk (odds ratio = 2.97, 95% CI 1.80-4.90) for new onset of manic symptoms [45]. As an example, a three-year prospective longitudinal study of community-living United States individuals found that initiation of weekly to almost daily cannabis use was associated with increased incidence of bipolar disorder (adjusted odds ratio = 2.47 [1.03-5.92 95% CI]), while daily use was not associated with increased incidence (0.61 [0.36-1.04]) [46].

Cannabis use has been found to be associated with earlier age of onset of first manic episode and more frequent mood episodes [19].

Anxiety disorders — Cannabis intake causes transient acute anxiety in many users. Two prospective longitudinal studies had conflicting findings regarding the association between long-term cannabis use and anxiety disorders: 

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A prospective longitudinal community-based study of 34,653 United States adults found cannabis users at no increased risk of developing an anxiety disorder (odds ratio 1.0, 95% CI 0.8-1.3) [12]. 

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A 15-year prospective longitudinal study of 1943 Australian adolescents found daily cannabis use during adolescence associated with a 2.5-fold increased risk of anxiety disorder at age 29 years [47].

Pulmonary — Cannabis smoke contains many of the same respiratory irritants and carcinogens as tobacco smoke [48], although their effects may be moderated by the absence of nicotine [49]. Cannabis smoking acutely irritates the airways and is associated with transient cough, sputum production, wheezing, chest tightness, and airway inflammation, as well as bronchodilatation, which may account for past use of cannabis to treat asthma [48,50]. 

Cannabis smoking produces acute, transitory respiratory symptoms, but chronic cannabis use is not associated with impaired pulmonary function:

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A systematic review of 12 studies that evaluated the effect of a smoked cannabis challenge on lung function found an 8 to 48 percent decrease in airway resistance lasting up to one hour (eight studies), a 0.15 to 0.25 L increase in forced expiratory volume one (FEV1) (five studies), a 10 percent increase in peak airflow (one study), and immediate reversal of methacholine-induced or exercise-induced bronchospasm in asthma patients (one study) [50].

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A subacute study in which 28 healthy, young adult male cannabis users smoked cannabis cigarettes (2.2 percent delta-9-tetrahydrocannabinol) ad lib for 47 to 59 days (mean of 5.2 cigarettes/day) found significant decreases, compared with baseline, in FEV1 (3±1 percent), maximal mid-expiratory flow rate (11±2 percent), plethysmographic specific airway conductance (16±2 percent), and diffusing capacity (8±2 percent) [51]. These findings suggest that regular cannabis smoking for six to eight weeks causes mild airway obstruction.

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A systematic review of 14 studies (9 cross-sectional, 4 longitudinal, 1 case-control) comparing long-term cannabis smokers with nonsmokers found increases in chronic cough, sputum production, wheezing, dyspnea, bronchitis, and pharyngitis, but no significant abnormalities in pulmonary function [50]. 

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A cross-sectional survey (2007 to 2010) of 6723 United States community-living adults (18 to 59 years old) found no significant association between cumulative cannabis use up to 20 joint-years and performance on standard spirometry tests (forced vital capacity [FVC], forced expiratory volume [FEV], or FEV/FVC) [52]. Greater cumulative use was associated with an odds ratio of 2.1 (95% CI 1.1, 3.9) for an abnormally low (<70 percent) FEV/FVC, which was due to increased FVC, rather than decreased FEV (unlike obstructive lung disease, which is typically associated with decreased FEV). 

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A prospective longitudinal study of 5115 United States adults followed for 20 years found a nonlinear association between cannabis use and performance on standard spirometry tests [53]. Occasional and low-intensity cumulative cannabis use (<7 joint-years) was associated with no change from baseline or even improvement in FVC and FEV; greater cumulative cannabis use was linearly associated with worse lung function. 

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A 20-year prospective longitudinal study of a representative birth cohort of 1037 individuals born in Dunedin, New Zealand in 1972 to 1973 and recruited at age 18 years found no significant association between cannabis use or cannabis use disorder and impaired lung function [30].

Limited evidence from small case series and case-control studies suggests that inhalation of cannabis vapor generated by electronic devices may be less irritating to the lungs than inhalation of cannabis smoke [54-56]. This suggestion has some biological plausibility, in that cannabis vapor has less hot gases and less toxic pyrolytic breakdown products, but remains to be confirmed by larger systematic studies.  

Cancer — Molecular, cellular, and histopathological evidence, both in vivo and in vitro, plausibly suggests that cannabis smoking may cause cancer [57,58]; however, epidemiologic studies do not consistently show a significant association. The failure to observe a significant association may be due, in part, to substantial methodologic limitations in many studies, such as the difficulty controlling for important confounding factors, especially cigarette smoking, the assessment of cannabis use by retrospective self-report, and the small sample sizes for heavy cannabis users.

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Lung cancer – A 2006 systematic review of 19 studies evaluating the association between cannabis smoking and lung cancer found associations with alveolar macrophage dysfunction, oxidative stress, and bronchial mucosal abnormalities, but no association with lung cancer after adjusting for tobacco use [58]. A more recent review of six epidemiologic studies also found no significant association [57]. (See "Cigarette smoking and other possible risk factors for lung cancer", section on 'Marijuana and cocaine'.)

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Head and neck cancer – A review of 11 studies found some increased risk and some decreased risk associated with cannabis smoking, possibly due in part to differences in human papillomavirus status (a known causal factor in such cancers) [57]. A pooled analysis of five case control studies including 4029 cases and 5015 controls did not find an association between cannabis use and cancer of the head and neck [59]. (See "Epidemiology and risk factors for head and neck cancer", section on 'Tobacco products'.)

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Testicular cancer – A meta-analysis of three case-control studies found cannabis use at least weekly associated with an increased risk (odds ratio of 2.59 [95% CI 1.60, 4.19]) for non-seminoma testicular cancer compared with never users [60]. There was inconsistent evidence regarding an association with seminoma tumors.  

Cardiovascular — Cannabis intake acutely increases sympathetic activity and decreases parasympathetic activity, resulting in release of catecholamines, tachycardia, vasodilation, and an increase in cardiac output and myocardial oxygen demand with little or no increase in blood pressure [61,62]. These acute changes probably account for the orthostatic hypotension associated with cannabis use [63] and the association between cannabis smoking and acute myocardial infarction (although the absolute risk appears to be small). Further information approximately associations between cannabis use and cardiovascular disease is as follows:

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Myocardial infarction – Cannabis smoking may be associated with a modest, short-lived increase in risk of acute myocardial infarction, even in individuals without a history of angina or hypertension. A prospective study followed 3886 adult inpatients with an acute myocardial infarction, 3.2 percent of whom had smoked cannabis within the prior year [64]. Cannabis smokers were less likely than nonsmokers to have a history of angina (12 versus 25 percent) or hypertension (30 versus 44 percent) at their index hospitalization. A case-crossover analysis found a 4.8-fold (95% CI 2.4, 9.5) increased risk of myocardial infarction in the first 60 minutes after cannabis use, which became nonsignificant by the second hour [64]. After a median 3.8 years of follow-up (1913 subjects), weekly cannabis users had a hazard ratio of 4.2 (95% CI 1.2-14.3) for subsequent mortality, compared with nonusers [65]. After up to 18 years of follow-up of the entire cohort, there was no longer any significant difference in mortality rate between cannabis smokers and nonsmokers (29 percent higher rate, 95% CI 0.81, 2.05) [66].

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Stroke – Cannabis use has been associated with stroke, although the absolute risk appears to be small. A review of 64 published cases of stroke associated with cannabis use found that the majority had characteristics suggesting causality, ie, a close temporal relationship, exclusion of other likely causes, and another stroke after reuse of cannabis [67]. A cross-sectional national survey of patients hospitalized for acute ischemic stroke found that cannabis users had a 17 percent increased likelihood of acute ischemic stroke compared with nonusers (odds ratio 1.17, 95% CI 1.15, 1.20) [68]. 

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Atrial fibrillation – Cannabis use has been associated with atrial fibrillation in a growing number of case reports, although the absolute risk appears to be small [69,70].

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Arteritis – A 2013 review identified 80 published cases (91 percent men, mean age 28.4 years) of cannabis-associated limb arteritis, the majority affecting the lower limbs [61]. 

Hyperemesis syndrome — Cannabinoid hyperemesis syndrome is a well-defined but apparently relatively rare syndrome involving episodic severe nausea and vomiting and abdominal pain which is relieved by exposure to hot water (shower or bath) [71]. The pathophysiology remains unknown, but patients are almost always daily cannabis users for at least one year and symptoms resolve within one to two days of cessation of cannabis use. (See "Cyclic vomiting syndrome", section on 'Chronic cannabis use'.)

Reproductive — Cannabis use has been found to be associated with several reproductive processes:

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Spermatogenesis – The endocannabinoid system is involved in regulation of the male reproductive system. In vitro and in vivo studies suggest that cannabis disrupts the hypothalamic-pituitary-adrenal axis, reduces spermatogenesis, and impairs several sperm functions, including motility, capacitation, and the acrosome reaction [72]. A cross-sectional study of 1215 Danish male military recruits who had smoked cannabis within the prior three months found that weekly or more frequent users had a 28 percent (95% CI -48, -1) lower sperm concentration and a 29 percent (95% CI -46, -1) lower total sperm count compared with less frequent users [73]. 

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Prolactin – Acute cannabis use probably has no significant effect on plasma prolactin levels, although some earlier, small studies showed either increases or decreases [74]. Chronic cannabis users have approximately 20 percent lower plasma prolactin levels than healthy nonusers [74].

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Neonatal outcomes – Cannabis use by pregnant women does not appear to significantly affect fetal health or neonatal outcome [75]. Almost all studies are limited by relying on self-report to assess cannabis use. A meta-analysis of 10 studies of the association between cannabis use during pregnancy and birthweight found a pooled odds ratio of 1.09 (95% CI 0.94-1.27) for low birthweight with any cannabis use [76]. Women who used cannabis more than four times a week had babies with birthweights a mean of 131 g lighter than women who did not use any cannabis. 

Two retrospective cohort studies from 2015 and 2016, one including 8138 women, 680 (8.4 percent) of whom used cannabis during pregnancy [77], and one including 12,069 women, 106 (0.88 percent) of whom reported cannabis use during pregnancy [78], found no significant adverse neonatal outcomes associated with cannabis use, after controlling for known confounders such as cigarette smoking and other drug use. The latter study found that concurrent use of cannabis and tobacco was associated with significantly increased risks over tobacco use alone: preterm birth (adjusted odds ratio 2.6, 95% CI 1.3, 4.9), low birth weight (adjusted odds ratio 2.8, 95% CI 1.6, 5.0), and increased rates of pre-eclampsia (adjusted odds ratio 2.5, 95% CI 1.4, 5.0) [78]. (See "Substance misuse in pregnant women", section on 'Marijuana'.)

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Breast milk – Cannabinoids appear in breast milk, at levels estimated at 0.8 percent of those ingested by the mother [75]. Limited preclinical evidence suggests that cannabis use may reduce lactation by inhibiting prolactin secretion [79]. 

Liver — Cannabis use is not associated with acute hepatotoxicity [80]. Daily cannabis use worsens the progression of chronic viral hepatitis C infection. Two cross-sectional studies with a combined 585 consecutive patients with chronic hepatitis C infection undergoing liver biopsy (approximately half cannabis users) found daily cannabis smoking associated with more severe fibrosis (odds ratio 3.4, 95% CI 1.5-7.4) [81] and more severe steatosis (odds ratio 2.1, 95% CI 1.01-4.5) [82].

Dental — Cannabis smoking is associated acutely with dry mouth and irritated oral mucosa, chronically with leukoplakia, inflamed oral mucosa (cannabis stomatitis), increased risk of periodontal disease (gingivitis), and oral candidiasis [83]. A 20-year prospective longitudinal study of a representative birth cohort of 1037 individuals born in Dunedin, New Zealand in 1972 to 1973 and recruited at age 18 years found that cannabis use was associated with significantly poorer periodontal health (beta = 0.10, 95% CI 0.05-0.16) [30].

Ophthalmologic — Cannabis causes conjunctival vasodilation (red eyes) and reduces intraocular pressure [84]. Effects of cannabis on vision are poorly understood, but may include increased photosensitivity and decreased visual acuity

MEDICO-LEGAL CONTEXT — Under the United Nations international Single Convention on Narcotic Drugs (as amended in 1972), the cannabis plant, cannabis resin and its extracts and tinctures are classified under Schedule I, meaning use should be allowed only for “medical and scientific purposes”; cannabis and cannabis resin are also in Schedule IV, meaning use should be limited to “medical and scientific research” [85]. In practice, the legal status of cannabis and its use in health care varies widely internationally [86]. Possession of small amounts is legal in all or parts of several countries (Australia, Colombia, India, Spain, Uruguay) and decriminalized in more than two dozen, chiefly in Europe and Latin America. Medical use is legal in about a dozen countries, including Canada and parts of Australia. In the United States, cannabis is subject to contradictory legal regulation under state and federal law. 

Cannabis and all phytocannabinoids (ie, compounds found in the Cannabis sativa plant) are classified as schedule I compounds under the United States Controlled Substances Act [87]. Schedule I compounds, which are considered to have “high potential for abuse” and “no currently accepted medical use in the United States,” are illegal to possess or use under federal law.

Medical use — As of September 2016, twenty-five US states, the District of Columbia, Puerto Rico, and Guam authorize medical use of cannabis, although not all programs are operational [88]. An additional 17 states have limited programs that authorize use of high cannabidiol/low delta-9-tetrahydrocannabinol (THC) cannabis formulations for treatment of childhood epilepsy, especially refractory seizures. Cannabidiol is a phytocannabinoid without psychoactive effects, so has little or no abuse liability. (See "Seizures and epilepsy in children: Refractory seizures and prognosis", section on 'Cannabinoids'.)

In these states, licensed clinicians can recommend or certify patients with certain specified conditions (which vary by state) to obtain medical cannabis from state-licensed dispensaries (or, in a few states, grow their own) [89]. Federal courts have ruled that such recommendations to patients are free speech protected under the First Amendment and do not violate federal laws regulating “prescribing” of controlled substances. Several states, including Alaska, Colorado, Oregon, and Washington, as well as the District of Columbia have legalized recreational use of cannabis.

There are a handful of approved medical uses in numerous countries for cannabis, cannabis-derived products, or synthetic cannabinoids. (See 'Synthetic cannabinoids' below.)

A cannabis extract with equal proportions of THC and cannabidiol (nabiximols, Sativex) is approved for medical use in 27 countries (including Canada), but not in the United States, for treatment of pain and muscle spasticity due to multiple sclerosis. (See "Symptom management of multiple sclerosis in adults", section on 'Cannabinoids'.)