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Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects

Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects
Literature review current through: Sep 2023.
This topic last updated: Dec 21, 2022.

INTRODUCTION — Cannabis (also called marijuana) is the third most commonly used psychoactive substance worldwide, after alcohol and tobacco [1]. Its euphorigenic (“high”), sedative, and analgesic properties are primarily due to one cannabinoid: delta-9-tetrahydrocannabinol (THC); THC concentration is commonly used as a measure of cannabis potency [2].

The legal status of cannabis use, for medical as well as recreational purposes, varies internationally as well as across the United States. The potency of cannabis has increased around the world in recent decades [2], which may have contributed to increased rates of cannabis-related adverse effects.

The epidemiology, pharmacology, comorbidity, and adverse effects of cannabis use and disorder in adults are reviewed here. Effects of acute intoxication, and treatment of cannabis use disorder and cannabis withdrawal are reviewed separately. (See "Cannabis use disorder: Clinical features, screening, diagnosis, and treatment" and "Cannabis (marijuana): Acute intoxication" and "Cannabis withdrawal: Epidemiology, clinical features, diagnosis, and treatment".)

EPIDEMIOLOGY

Cannabis use

Incidence and prevalence — Cannabis was used by an estimated 200.4 million people (95% CI 141.4 to 256.4 million) worldwide in 2019, approximately 4 percent (95% CI 2.8 to 5.1 percent) of the global population age 15 to 64 years [1].

Cannabis use is most prevalent the following geographic locations:

North America (14.5 percent [95% CI 14.5-14.6], 47.1 million users)

Australia and New Zealand (12.1 percent [95% CI 12.1-12.1], 2.4 million users)

West and Central Africa (9.4 percent [95% CI 5.1-12.7], 27.8 million users)

Cannabis use is least prevalent in the following geographic locations:

East and Southeast Asia (1.2 percent [95% CI 0.5-1.5], 19.3 million users)

Eastern and Southeastern Europe (2.1 percent [95% CI 1.5-2.9], 4.6 million users)

Central Asia and Transcaucasia (2.6 percent [95% CI 0.8-4.3], 1.5 million users) [1]

A large, nationally representative, community-based, epidemiologic survey (the National Survey on Drug Use and Health [NSDUH]) estimated the following prevalence rates of cannabis use in the community-dwelling United States population (12 years or older) in 2019 [3]:

Lifetime use of 46 percent (standard error 0.35, 127.1 million users [standard error 0.96]).

Past-year use of 18 percent (standard error 0.24, 48.2 million users [standard error 0.67]).

Past-month use of 12 percent (standard error 0.19, 31.6 million users [standard error 0.52]). This was almost a doubling of the prevalence rate of 6 percent in 2002.

Cannabis use was initiated by 3.5 million individuals in 2019, 38.9 percent of them between ages 12 and 17 years [3]. Cannabis use during the past month more than doubled (116.7 percent increase) over the past two decades (2002 to 2019). This increase in cannabis use over the past two decades (2002 to 2019) occurred in adults, rather than adolescents [3]. Past-month use by adolescents actually decreased by 9.2 percent.

Sociodemographic groups — Cannabis use is present in all sociodemographic groups, but some groups show greater prevalence than others [1,3-5].

Age – Young adults between the ages of 18 and 25 years have the highest past-year prevalence (35.4 percent) of cannabis use, followed by those 26 to 49 years old (21.7 percent) [3]. Cannabis use is less common among early adolescents (12 to 17 years old, 13.2 percent) and individuals age 65 and over (5.1 percent).

Gender – Males age 18 years and over are more likely than females age 18 years and over to have used cannabis over the past month (14.6 versus 9.4 percent) [3].

Pregnancy – Pregnant women are approximately one-third as likely as nonpregnant women to have used cannabis in the past month (5.4 versus 14.7 percent), with lower rates during the third trimester than the first trimester (3.3 versus 9.1 percent) [3].

Other demographic characteristics – College graduates (9.2 percent), those not in the labor force (8.8 percent), and those living in rural areas (7.9 percent) are less likely to have used cannabis in the past month than the contrasting demographic groups [3].

Cannabis use disorder — Cannabis use disorder refers to problematic cannabis use (table 1).

An estimated 22.1 million (95% CI 19-25.6) individuals worldwide had a cannabis use disorder in 2016, an age-standardized prevalence of 289.7 per 100,000 (95% CI 248.9-339.1), a 7.1 percent decrease from the age-standardized prevalence in 1990 [3,6,7].

A meta-analysis of 10 published international studies (Australia, Europe, United States) found the median age of onset for cannabis use disorder as 22 years. Only 3.2 percent of cases appeared by age 14 years; 75 percent appeared by age 29 years [8]. The prevalence of past-year cannabis use disorder is highest among young adults age 18 to 25 years old (5.8 percent) and lowest among adults age 65 or older (<0.4 percent) [3,6,7]. Approximately 10 percent of current cannabis users had a cannabis use disorder.

Risk factors for cannabis use and disorder

Frequency of use — The primary risk factor for developing cannabis use disorder is the frequency of cannabis use [9,10]. A nationally representative survey of 43,093 community-dwelling United States adults (National Epidemiologic Survey of Alcohol and Related Conditions wave I) found higher rates of past-year moderate-severe cannabis use disorder among respondents with more frequent cannabis use: 9 percent among those using at least once, 22 percent among those using weekly, and 30 percent among those using daily [9].

Duration of use — Duration of cannabis use is also a risk factor for developing cannabis use disorder [11-13]. For example, a secondary analysis of the 2015 to 2018 NSDUH surveys found a significant positive association between lifetime duration of cannabis use and prevalence of past-year cannabis use disorder among respondents 12 to 17 or 18 to 25 years old [13]. Among 12- to 17-year-olds, prevalence of past-year cannabis use disorder increased from 11 percent (95% CI 9.3-12.3 percent) among those using up to one year to 15 percent (95% CI 13.2-16.2 percent) among those using one to two years, 17 percent (95% CI 15-18.8 percent) using two to three years, and 20 percent (95% CI 18-22.3 percent) among those using more than three years [13].

Genetic factors — Family and twin studies suggest that there is a substantial degree of heritability for certain patterns of cannabis use and development of cannabis use disorder. No single gene or single nucleotide polymorphism has been robustly associated with these traits in replicated studies [14,15]. A substantial proportion of genetic influence on cannabis use and use disorder is shared with other psychoactive substances, rather than being specific to cannabis [14-16].

Twin and population-based studies suggest that genetic factors account for one-quarter to one-third of the variability in initiation of cannabis use [17,18] and age at first use [19] and two-thirds to three-quarters of the variability in frequency of cannabis use [20] and development of cannabis use disorder [17,20,21]. There is limited evidence of genetic influence on the acute subjective effects of cannabis, such as cannabis craving [22,23].

Psychosocial factors — Large, population-based observational studies and smaller longitudinal studies suggest several risk and protective factors associated with cannabis use and the development of cannabis use disorder during adolescence and young adulthood, after controlling for sociodemographic characteristics and other substance use [24-28]. However, study results are not always consistent and many studies are of low quality [29].

Psychological factors – Depressed mood, anxiety, abnormal negative mood regulation, persisting conduct problems as a child or adolescent [30], or a pre-existing psychiatric disorder are associated with increased risk of initiating cannabis use among adolescents and young adults and of developing cannabis use disorder. In many instances, this appears to be a bidirectional comorbidity as discussed in detail below. (See 'Comorbidities' below.)

Other substance use – Use of alcohol and tobacco and other substances is associated with greater risk of cannabis use, daily use of cannabis, and of developing cannabis use disorder. This association appears to be bidirectional as discussed below. (See 'Comorbidities' below.)

The evidence is more consistent with this association being due to common pre-existing environmental and genetic factors that contribute to all substance use and substance use disorders (so-called “common liability” model), rather than to cannabis use at a specific time contributing to subsequent use of other substances (so-called “sequential gateway” model) [31-34].

Education – More years of education are associated with lower prevalence of cannabis use [24], but not with the development of cannabis use disorder [26].

Others – Other factors associated with cannabis use and development of cannabis use disorder include parental cannabis use [35,36], adverse childhood experiences (eg, physical, emotional, or sexual abuse) [37], and stressful life events (such as unemployment, financial difficulties) [26,37,38].

Protective factors – Protective factors against initiating cannabis use or developing cannabis use disorder include close parental monitoring and opposition to cannabis use [39], and attendance at religious services [40].

PHARMACOLOGY OF CANNABINOIDS

Naturally occurring cannabinoids — The cannabis plant contains a mixture of more than 400 identified phytocannabinoids, terpenoids, and flavonoids, few of which have been fully characterized pharmacologically [41-43].

Pharmacokinetics, site of action, and cannabis formulations are discussed in detail separately. (See "Cannabis (marijuana): Acute intoxication", section on 'Pharmacology and toxicity'.)

Synthetic cannabinoids — Synthetic compounds with cannabinoid-like action, but not necessarily a phytocannabinoid chemical structure, are known as synthetic cannabinoids. Many physiologic effects of synthetic cannabinoids are similar to the effects of cannabis; however, the effects of non-US Food and Drug Administration (FDA)-approved, illicit synthetic cannabinoids are more intense or longer lasting (sometimes for days) and have greater potential for life threatening toxicity [44,45].

Synthetic cannabinoids include illicit, misused substances (so-called “spice” and “K2”) as well as FDA-approved medications that can be legally prescribed (such as dronabinol [synthetic delta-9-tetrahydrocannabinol]).

The clinical presentation and management of acute intoxication and withdrawal from synthetic cannabinoids are reviewed separately. (See "Synthetic cannabinoids: Acute intoxication" and "Cannabis withdrawal: Epidemiology, clinical features, diagnosis, and treatment", section on 'Synthetic cannabinoids' and "Cannabis withdrawal: Epidemiology, clinical features, diagnosis, and treatment", section on 'Synthetic cannabinoid withdrawal'.)

Use of synthetic cannabinoids in the treatment of cannabis withdrawal and other medical conditions is discussed elsewhere.

(See "Management of cancer anorexia/cachexia", section on 'Not recommended'.)

(See "Management of poorly controlled or breakthrough chemotherapy-induced nausea and vomiting in adults", section on 'Cannabinoids and medical marijuana'.)

(See "Assessment and management of anorexia and cachexia in palliative care".)

(See "Cannabis withdrawal: Epidemiology, clinical features, diagnosis, and treatment", section on 'Delta-9-tetrahydrocannabinol: Dronabinol, nabiximols'.)

COMORBIDITIES — There is substantial bidirectional comorbidity between cannabis use or cannabis use disorder and psychiatric disorders including several substance use disorders. It is often unclear to what extent this is due to a direct causal relationship, the chance co-occurrence of two common conditions, or the presence of risk factors common to both conditions. Regardless of etiology, the presence of comorbid cannabis use or use disorder often worsens the clinical course of the psychiatric disorder [46,47]. (See "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis", section on 'Etiologic theories'.)

Substance use disorders — Large, community-based surveys have established the following comorbidities associated with cannabis use disorder [10,24-26,48-56]:

Alcohol – Adults with current (past 12 months) alcohol use disorder are six times more likely than adults without alcohol use disorder to have current cannabis use disorder (adjusted odds ratio 6, 95% CI 5.10-6.97) [51].

Adults with current cannabis use disorder are nearly three to four times more likely than adults without cannabis use disorder to have current alcohol use disorder (adjusted odds ratio 2.8, 95% CI 2.19-3.60 for men; adjusted odds ratio 3.8, 95% CI 2.33-6.48 for women) [51].

The mechanisms of these associations are unclear. Two large-scale cross-sectional studies using Mendelian randomization to control for potential confounding variables found no significant association between genetic liability to cannabis use and alcohol use [34,57].

Use of cannabis and alcohol within several hours of each other may result in more intense intoxication than use of either substance alone [58].

Tobacco – Adults with current (past 12 months) tobacco (nicotine) use disorder are more than six times more likely than those without tobacco use disorder to have current cannabis use disorder (adjusted odds ratio 6.2, 95% CI 5.24-7.34) [52]. Cigarette smoking is significantly associated with eventual development of cannabis use disorder among those without cannabis use (adjusted odds ratio 1.62, 95% CI 1.35-1.94), persistence of cannabis use disorder in those who have it (adjusted odds ratio 1.63, 95% CI 1.30-2.00), and relapse to cannabis use disorder in those in remission (adjusted odds ratio 1.23, 95% CI 1.09-1.45) [59].

Adults with current cannabis use disorder are three times more likely than adults without cannabis use disorder to have current tobacco use disorder (adjusted odds ratio 3, 95% CI 2.43-3.66 for men; adjusted odds ratio 3.7, 95% CI 2.61-5.26 for women) [51].

A bidirectional Mendelian randomization study found a significant positive association between genetic liability to lifetime cannabis use and risk of lifetime cigarette smoking and intensity (pack-years) of lifetime cigarette use but no significant association between genetic liability to lifetime cigarette smoking and risk of lifetime cannabis use [57].

Cannabis is often smoked simultaneously with tobacco in the form of “blunts” (cannabis within hollowed-out cigar wrappings) or “spliffs” (cannabis and tobacco mixed within a joint) [60]. Such co-use of cannabis and tobacco is associated with less likelihood of cessation of use of either substance [61,62].

Opioids – Individuals with opioid use disorder appear to have a high prevalence of cannabis use. A systematic review of 41 studies of adults receiving medication treatment for opioid use disorder (majority receiving methadone) found that the median prevalence of cannabis use at treatment baseline was 23 percent (range 12 to 67 percent) and of frequent use (five to seven days/week) was 18.5 percent (range 16 to 33 percent) [63]. Cannabis use did not significantly influence treatment outcome.

Individuals with current cannabis use disorder are nearly five times more likely than those without cannabis use disorder to have current opioid use disorder (adjusted odds ratio 4.6, 95% CI 3.0-6.8) [54].

Stimulants – Individuals with current cannabis use disorder are more likely than those without cannabis use disorder to have current cocaine use disorder (adjusted odds ratio 9.3, 95% CI 5.6-15.5) or prescription stimulant use disorder (adjusted odds ratio 4.3, 95% CI 2.3-7.9) [54].

Other psychoactive drugs – Individuals with current cannabis use disorder are more likely than those without cannabis use disorder to have current sedative/hypnotic use disorder (adjusted odds ratio 5.1, 95% CI 2.9-9) or “club drug” (eg, MDMA, methamphetamine) use disorder (adjusted odds ratio 16.1, 95% CI 6.3-40.8) [54].

Individuals with current cannabis use disorder have a higher prevalence of current hallucinogen use disorder and current inhalant/solvent use disorder than those without cannabis use disorder. However, adjusted odd ratios were not reported [54].

Psychiatric disorders — Large, community-based surveys suggest that after, controlling for potentially confounding sociodemographic factors, a variety of psychiatric disorders are comorbid with cannabis use and cannabis use disorder [46].

Depressive disorders – While the bidirectional relationship between cannabis use and depressive disorders is demonstrated in prospective surveys and meta-analysis, not all data support this relationship.

Individuals with depression and other mood disorders appear to be more likely to use cannabis according to some studies:

In large prospective surveys of community living adults in the United states, a bidirectional comorbidity between cannabis use and major depression has been reported [64].

Individuals with depression are found to have nearly twice the odds of past month cannabis use compared with those without depression (odds ratio 1.9, 95% CI 1.62-2.24) [65]. Additionally, individuals with a lifetime mood disorder are more likely to develop cannabis use disorder after starting cannabis use as compared with those without any psychiatric disorder [66,67].

Individuals who use cannabis appear to be at risk of developing a mood disorder in some studies:

In a meta-analysis of 14 prospective longitudinal studies, heavy cannabis users were more likely than light or nonusers to develop clinically diagnosed major depression or depressive symptoms (odds ratio 1.62, 95% CI 1.21-2.16) [68].

A meta-analysis of seven prospective longitudinal studies found that adolescents who used cannabis were more likely those that did not use cannabis to develop depression (clinically significant symptoms or major depressive episode; odds ratio 1.37, 95% CI 1.16-1.63), suicidal ideation (three studies; odds ratio 1.5, 95% CI 1.11-2.03), or suicide attempt (three studies; odds ratio 3.46, 95% CI 1.53-7.84) during young adulthood [69].

In contrast, a prospective, community-based longitudinal study of 34,653 adults found users of cannabis at no increased risk of developing a mood disorder (odds ratio 1.1, 95% CI 0.8-1.4) [50].

Bipolar disorders – While large, cross-sectional surveys support the bidirectional relationship between cannabis use and disorder and bipolar disorders, not all data support this relationship.

Individuals with bipolar disorder appear to be at risk of cannabis use and disorder and for worsening symptoms of disease:

A meta-analysis including 36 published studies found that among adults with bipolar disorder, the prevalence of lifetime cannabis use was 24 percent (95% CI 18-29 percent) and of lifetime cannabis use disorder 20 percent (95% CI 14-29 percent) [70].

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 [71]. Additionally, cannabis use has been found to be associated with earlier age of onset of first manic symptom and more frequent mood episodes [72].

Individuals who use cannabis appear to be at risk for developing bipolar disorders:

A large, cross-sectional study of a representative sample of community-living adults found that adults with lifetime cannabis use disorder had almost four times the odds of having bipolar I disorder (adjusted odds ratio 3.8, 95% CI 3.1-4.59) and almost three times the odds of having bipolar II disorder (adjusted odds ratio 2.8, 95% CI 1.51-5.23), compared with those without lifetime cannabis use disorder [46].

In contrast, in a three-year longitudinal study of community living adults in the United States, the association between cannabis use and bipolar disorder was unclear [73].

A bidirectional Mendelian randomization study found a significant association between genetic liability to bipolar disorder and risk of lifetime cannabis, but no significant association between genetic liability to lifetime cannabis use and risk of developing bipolar disorder [74].

Nonaffective psychosis and schizophrenia – Individuals with schizophrenia are reported to be two to three times more likely to have cannabis use and develop cannabis use disorder than those without any psychiatric disorder [66,67].

Additionally, cannabis use may also be a risk factor for schizophrenia and other psychotic disorders. This is discussed below. (See 'Psychiatric effects' below.)

Anxiety disorders Prospective longitudinal studies have conflicting results regarding the association between long-term cannabis use and anxiety disorders [46,50,75,76].

Individuals with a lifetime anxiety disorder are two to three times more likely to have lifetime cannabis use than those without any psychiatric disorder [66] and to develop a cannabis use disorder after starting cannabis use [66,67].

However, a meta-analysis of three prospective longitudinal studies found that adolescents who used cannabis during adolescence were no more likely than nonusers to develop anxiety (clinically significant symptoms or anxiety disorder) during young adulthood (18 to 32 years; odds ratio 1.18, 95% CI 0.84-167) [69].

Posttraumatic stress disorder (PTSD) – Several community-based national epidemiologic studies found comorbidity rates of around 10 percent for current PTSD among adults with current cannabis use disorder and for current cannabis use disorder among those with current PTSD [51,52]. The prevalence of cannabis use disorder among United States veterans with PTSD is substantially higher, almost three-quarters in some studies [77]. Cannabis use by adults with PTSD is associated with more severe PTSD symptoms [78], especially intrusive symptoms among veterans [79].

Attention-deficit hyperactivity disorder (ADHD) – Studies of large, unselected adult populations suggest a 10 to 30 percent prevalence of cannabis use disorder among adults with ADHD [80,81].

Childhood/adolescent ADHD, especially if untreated, is a risk factor for later development of cannabis use disorder [82,83].

Conversely, a cross-sectional survey of a convenience sample of 341 United States veterans with lifetime cannabis use found a 29 percent prevalence of lifetime adult ADHD (based on self-report using a validated screening instrument) [84].

A bidirectional Mendelian randomization study found a significant association between genetic liability to ADHD and risk of lifetime cannabis use, but no significant association between genetic liability to cannabis use and risk of lifetime ADHD [85].

Other psychiatric disorders – More limited evidence suggests that there is comorbidity between obsessive-compulsive disorder [86] and cannabis use and use disorder. Additionally, there is evidence for comorbidity between lifetime or current cannabis use disorder and several personality disorders, especially antisocial, dependent, and borderline personality disorders [46,51,86,87].

ADVERSE EFFECTS OF CANNABIS USE

Disability and all-cause mortality — Much of the morbidity associated with cannabis use disorder may be due to comorbid psychiatric and substance use disorders, rather than to cannabis use disorder itself [88]. Cannabis use disorder constitutes a very small proportion of the global burden of disease relative to other substance use disorders. The Global Burden of Disease Project, using data from 195 countries, estimated that cannabis use disorder was associated with only 6.4 percent of the more than 6.1 million disability-adjusted life years attributed to substance use disorders (excluding tobacco) in the United States and Canada [6].

There is insufficient evidence to assess whether cannabis use is associated with an increased all-cause mortality [89]. However, a population-based, longitudinal cohort study of all individuals born in Sweden 1955 to 1980 found that those identified as having cannabis use disorder had a higher mortality than the general population (hazard ratio 10.93, 95% CI 11.36-12.03) [90].

The most common causes of death associated with cannabis are accidents (primarily motor vehicle), suicide, and medical conditions (primarily cardiovascular and pulmonary disease) [89,91,92]. Other psychoactive substances are found in the majority of cases (most commonly alcohol).

Medical and systemic effects

Pulmonary – Smoking marijuana may contribute to respiratory symptoms and possibly respiratory disease.

Individual studies [93-95] and a meta-analysis [96] with low-quality evidence suggest that smoking marijuana is associated with cough (relative risk 2.04, 95% CI 1.02-4.06), sputum production (relative risk 3.84, CI 1.62-9.07), wheezing (relative risk 2.83, CI 1.89-4.23), and dyspnea (relative risk 1.56, CI 1.33-1.83) [96].

In addition, cannabis inhalation can acutely exacerbate asthma; however, the association between chronic cannabis use and asthma remains unclear [97]. A retrospective review of electronic health records from a large metropolitan health system found that adults who were regular cannabis users, compared with nonusers, had a greater risk for asthma (adjusted odds ratio 2.13, 95% CI 1.75-2.59) whether they had a diagnosis of tobacco use disorder [98]. Evidence on the association between marijuana use and chronic obstructive lung disease and pulmonary function was inconclusive due to methodologic issues [96]. A large Mendelian randomization study including 79,055 participants found no significant association between genetic liability to cannabis use or use disorder and impaired pulmonary function [99].

Cannabis smoke and vapor acutely irritate the airways. However, chronic cannabis use is not clearly associated with impaired pulmonary functioning. A prospective longitudinal study of 1037 individuals born in Dunedin, New Zealand and followed through age 45 years found that cumulative cannabis use, in individuals with no tobacco use, was significantly associated with increased lung volumes (total lung capacity, forced vital capacity) but not with measures of airway resistance, airway conductance, or diffusion capacity [100]. While cannabis smoke contains many of the same respiratory irritants and carcinogens as tobacco smoke, the effects of cannabis smoke may be moderated by the absence of nicotine and the presence of cannabinoids with anti-inflammatory action [93,94]. Cannabis vapor contains fewer toxic compounds than cannabis smoke [101], however, use of electronic drug delivery devices (so-called “e-cigarettes”) containing cannabis or pure delta-9-tetrahydrocannabinol (THC) is associated with acute lung injury (e-cigarette or vaping-associated lung injury [102]. (See "E-cigarette or vaping product use-associated lung injury (EVALI)".)

Cancer – Molecular, cellular, and histopathological evidence plausibly suggests that cannabis smoking may cause cancer; however, epidemiologic studies do not consistently show an association [103]. This may be due, in part, to the fact that smokers of cannabis have less exposure to inhaled carcinogens than do smokers of tobacco or both cannabis and tobacco [104,105].

Lung cancer – Case-control, cohort, and cross-sectional studies have inconsistent results regarding an association between cannabis smoking and lung cancer. Most studies had high risk of bias [103]. A pooled analysis including 5144 participants from six large, good-quality case control studies found no association between “habitual” cannabis use (at least one joint-year) and lung cancer when compared with nonhabitual or never use (odds ratio 0.96, 95% CI 0.66-1.38) [106]. However, a large Mendelian randomization study including 85,716 individuals found a significant association between genetic liability for lifetime cannabis use (but not for cannabis use disorder) and squamous cell carcinoma of lung (odds ratio 1.22, 95% CI 1.07-1.39) [99]. There was no such significant association with other forms of lung cancer. (See "Cigarette smoking and other possible risk factors for lung cancer", section on 'Marijuana and cocaine'.)

Head and neck and oral cancer – Meta-analyses have found no association between ever using cannabis and head and neck [103] or oral cancer [103]. (See "Epidemiology and risk factors for head and neck cancer", section on 'Tobacco products'.)

Testicular cancer – Cannabis use is associated with one form of testicular cancer. A meta-analysis of three case-control studies found that cannabis use for more than 10 years is to be associated with an increased risk for nonseminoma testicular cancer compared with never users (odds ratio 1.85, 95% CI 1.1-3.11) [103].

Cardiovascular – Cannabis smoking has a possible association with the following conditions [107-109]:

Myocardial infarction (MI) – A cross-sectional survey of a nationally representative sample of 133,706 United States adults (18 to 74 years old) who were lifetime never cigarette smokers found significant associations between frequent cannabis use (at least 10 days per month) and risk of lifetime MI or coronary artery disease among the entire sample (adjusted odds ratio 1.88, 95% CI 1.15-3.08) and among a younger subsample (men <55 years old, women <65 years old; adjusted odds ratio 2.3, 95% CI 1.2-4.3) [110].

Additionally, other data suggest that the risk of acute MI is significantly elevated in the 60 minutes after smoking cannabis (relative risk 4.8, 95% CI 2.4-9.5) [111].

Stroke – A retrospective medical record review of 3,307,310 United States hospitalizations (2007 to 2014) among young adults (18 to 49 years old) found an association between lifetime cannabis use and any stroke (adjusted odds ratio 1.16, 95% CI 1.14-1.19) or acute ischemic stroke (adjusted odds ratio 1.41, 95% CI 1.31-1.51) [112].

Arrhythmias – Cardiac arrhythmias of any type (except sinus tachycardia) are rare among adolescent and young adult cannabis users [112,113]. Low-quality case-control studies and case series suggest a possible association between cannabis use and atrial fibrillation and ventricular tachycardia [114]. A medical record review of 67.7 million United States inpatients hospitalized between 2010 to 2014 (Nationwide Inpatient Sample) found current cannabis use disorder associated with increased risk of cardiac arrhythmia among younger patients, after adjusting for race, sex, alcohol and tobacco use disorders, obesity, and medical comorbidities: relative risk 1.28 (95% CI 1.23-1.35) among 15- to 24-year-olds and 1.52 (95% CI 1.47-1.58) among 25- to 34-year-olds [115]. The most common arrhythmia among patients with cannabis use disorder was atrial fibrillation (42 percent).

Due to methodologic issues in most studies, including recall bias, inadequate assessment of cannabis exposure, and failure to control for all potential confounding factors (such as other substance use), the evidence is insufficient to conclusively establish the association between cannabis use and these cardiovascular outcomes [107]. However, the known acute cardiovascular effects of cannabis smoking, such as tachycardia, vasodilation, increased myocardial oxygen demand, and reduced myocardial oxygen supply, provide plausible pathophysiological mechanisms for producing these outcomes [108,109,111,116-122].

Hyperemesis syndrome – Cannabinoid hyperemesis syndrome is a well-defined but relatively rare syndrome involving episodic severe nausea and vomiting and abdominal pain which is relieved by exposure to hot water (shower or bath). The pathophysiology remains unknown, but patients are almost always daily cannabis users for at least one year. Symptoms typically resolve within one to two days of cessation of cannabis use. This syndrome is described in detail separately. (See "Cyclic vomiting syndrome", section on 'Chronic cannabis use' and "Cannabis (marijuana): Acute intoxication", section on 'Cannabis hyperemesis syndrome'.)

Sexual function, reproductive system, and neonatal outcomes

Sexual function – Several large, cross-sectional surveys suggest that cannabis use does not impair male or female sexual function in healthy individuals [123-125] nor delay the time to pregnancy in healthy couples trying to conceive [126]. There is no good-quality evidence associating cannabis use with erectile dysfunction. A meta-analysis of case-control studies involving 3395 healthy men found a significant difference in prevalence of erectile dysfunction between cannabis smokers and nonusers in one of three statistical metrics [127]. There was substantial heterogeneity across studies and only one study controlled for potential confounds such as other substance use and depression. That study found no significant difference in prevalence.

Spermatogenesis – Cannabis use is associated with reduced spermatogenesis and impaired sperm function in most [128,129], but not all [130] studies. (See "Causes of male infertility", section on 'Drugs and radiation'.)

Breast milk THC, cannabidiol, and perhaps other cannabinoids appear in the breast milk of lactating women who use cannabis [131,132]. THC concentration in breast milk is two- to sixfold higher than its concentration in plasma. THC is detectable in breast milk for several weeks after the mother stops cannabis use. The effects on the infant of cannabinoids in breast milk are uncertain. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Cannabis' and "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Cannabis'.)

Pregnancy and neonatal outcomes – Cannabis use by the mother during pregnancy (ie, prenatal cannabis exposure) is associated with increased risk of low birth weight, small for gestational age, and neonatal intensive care admission in most, but not all studies [133-135]. Cannabis use during pregnancy is not generally associated with adverse outcomes for the mother, such as gestational diabetes or pre-eclampsia [133,135].

Cognitive effects and neuroimaging changes

Cognitive effects – Cannabis (primarily THC) use acutely impairs cognitive functions including attention, concentration, episodic memory, and associative learning in a dose-dependent fashion [136-138]. These effects are time limited, with the duration of impairment dependent on dose taken, route of administration, and degree of tolerance. (See "Cannabis (marijuana): Acute intoxication", section on 'Clinical manifestations'.)

The association of long-term cannabis use with long-term cognitive impairment is supported by some, but not all, studies [138-140]. As examples:

-In a prospective longitudinal study involving a representative cohort of individuals born in Dunedin, New Zealand (n = 1037; 91 percent of eligible births over a one-year period), subjects were periodically assessed from birth through age 45 years for cognitive function and cannabis use and dependence [141]. Long-term cannabis use was defined at age 45 as at least weekly cannabis use or a diagnosis of cannabis dependence in the prior year and at least weekly cannabis use at one or more previous assessments. Among long-term users of cannabis, the mean decline in intelligence quotient (IQ) was greater (n = 86; -5.5 points) than among lifetime nonusers of cannabis (n = 196; -0.7 points), long-term users of tobacco (n = 75; -1.5 points), and long-term users of alcohol (n = 57; -0.5 points). Long-term users of cannabis showed declines in tests of learning and processing speed and self-reported memory and attention, after controlling for other substance use, family history, and other factors. Similar cognitive decline was not seen in those who used cannabis less than weekly during mid-life (32 to 45 years) and were never diagnosed with cannabis dependence (n = 65), those who were not using cannabis at age 45 years but had previously used at least four times per week or been diagnosed with cannabis dependence (n = 60), and long-term users of tobacco or alcohol.

-Longitudinal studies have suggested an association with long-term cognitive impairment, especially in the domain of episodic memory; however, effect sizes are small and group differences are often attenuated or eliminated after controlling for potential confounds such as other substance use and psychiatric comorbidity [142]. One longitudinal study of 804 European teenagers followed over five years did not find evidence to support the presumption that cannabis consumption leads to a decline in neurocognitive ability [143].

-In a systematic review and meta-analysis of 69 cross-sectional studies of adolescents and young adults (2152 cannabis users [in most studies, at least weekly users or with cannabis use disorder] and 6575 comparison participants with no or “minimal” cannabis use) found small but significant impairment in neurocognitive domains of learning, processing speed, delayed memory, executive functioning, and attention [144]. Nevertheless, the 15 studies that conducted cognitive testing more than 72 hours after last cannabis use found no significant cognitive impairment. Additionally, a meta-analysis of 13 studies examining neurocognitive performance in users of cannabis with at least 25 days of abstinence versus nonusers of cannabis found similar global performance on neuropsychological testing [145].

Neuroimaging changes – Neuroimaging studies show associations between cannabis use, reduced hippocampal volume [141] and gray matter density, thinning orbitofrontal cortex, and smaller cerebellar white matter volume in cannabis users compared with cannabis nonusers. As examples:

-A systematic review of 56 published neuroimaging studies of brain structure and function in adult cannabis users found consistent evidence of reduced hippocampal volume and lower hippocampal gray matter density in cannabis users relative to controls [139]. No evidence for changes in whole brain volume was noted. Evidence for changes in other brain regions was inconsistent or inconclusive.

-A cross-sectional study comparing 129 European adults who were regular cannabis users (mean 349 doses/month for men, 264 doses/month for women) with 114 healthy nonusers found that the regular cannabis users had significantly smaller volume of the orbitofrontal cortex and cerebellar white matter, after controlling for age, intelligence quotient, intracranial volume, and alcohol and tobacco use [146].

-A prospective longitudinal study of 799 European adolescents followed from age 14 years (prior to any cannabis use) to 19 years found a significant dose-dependent association between frequency of cannabis use and thinning of the frontal cortex bilaterally, after controlling for age, sex, handedness, total brain volume, and alcohol intake [147].

Functional neuroimaging studies (chiefly functional magnetic resonance imaging) suggested that adult cannabis users have decreased neuronal activity in anterior cingulate cortex and right dorsolateral prefrontal cortex relative to controls [139]. In addition, increased functional connectivity across brain regions relative to controls has been noted. Abnormalities of neuronal activity were observed even when cognitive task performance was normal, suggesting that cannabis users may need to engage different levels of neuronal activation to achieve normal performance.

Other systemic effects

Hepatic – Cannabis use is not associated with acute hepatotoxicity [148] or with worsening progression of hepatic fibrosis in patients with chronic viral hepatitis C [149]. Cannabis use disorder is associated with increased risk of hepatic encephalopathy among inpatients hospitalized with chronic viral hepatitis C, after controlling for age, race, sex, alcohol use disorder, HIV/AIDS, viral hepatitis B, diabetes, and obesity (odds ratio 2.2, 95% CI 1.48-3.35) [150].

Renal Cannabis use (recreational or medical) is not associated with nephrotoxicity in healthy individuals [151,152], or with adverse outcomes after kidney transplantation [151]. Cannabis use may accelerate the decline in kidney function among men with hypertensive kidney disease [153].

Endocrine – Cannabis use is not associated with the development of type II diabetes (and is protective in some studies) [154-156], but is associated with poorer glycemic control and increased risk of diabetic ketoacidosis in adults with type I or type II diabetes [157,158]. Cannabis use is not associated with obesity [159].

Ophthalmologic Cannabis use causes acute and transient ophthalmologic effects (ie, decreased intraocular pressure, increased photosensitivity, reduced tear production [“dry eyes”], conjunctival injection [“red eye”], but is not associated with chronic ophthalmologic dysfunction) [160,161].

Oral – Chronic cannabis use is associated with a variety of adverse oral health effects, including xerostomia (“dry mouth”), leukoplakia, and periodontitis [162].

Psychiatric effects

Psychosis and psychotic disorders – Individuals who use cannabis appear to be at greater risk of psychosis than those who do not use cannabis:

Cannabis-associated psychosis – Cannabis use causes transient acute psychosis (cannabis-induced psychosis) in some users (see "Cannabis (marijuana): Acute intoxication"). 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) [163]. 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).

In a subsequently published prospective longitudinal study, 6534 individuals born in northern Finland were evaluated at age 15 to 16 years and again at age 30 years. Those individuals who used cannabis at least five times by age 15 to 16 years of age were found to have an increased risk of psychosis compared with those who had never used cannabis (adjusted hazard ratio 3.02, 95% CI 1.14-7.98) [164]. There was no increased risk for those who used cannabis one to four times.

Cannabis use as a risk factor for schizophrenia – Some experts believe that early cannabis use is a causal factor in developing schizophrenia.

-There is substantial evidence that chronic cannabis use, especially during adolescence, is associated with later development of schizophrenia. For example, cross-sectional studies indicate that cannabis users have two- to threefold increased prevalence of schizophrenia and schizophrenia spectrum disorders compared with nonusers [165]. This association is stronger with earlier age of onset of use (eg, early adolescence), more intense cannabis use, and use of cannabis with high THC content and THC:cannabidiol ratio [166,167].

For example, a Danish national registry-based prospective study of 7,186,834 individuals who were 16 years or older between 1972 and 2016 found that the adjusted hazard ratio for schizophrenia among those with cannabis use disorder, compared with those without cannabis use disorder, was approximately 4 (95% CI 3-6) throughout the time period, after adjusting for age, sex, birth outside of Denmark, other psychiatric diagnoses (including other substance use disorders), parents’ education level, and parents’ psychiatric history [168]. The population-attributable risk fraction of schizophrenia attributable to cannabis use disorder increased from two in 1992 to six to eight in 2010 to 2016, paralleling the increasing incidence of cannabis use disorder (0.02 percent in 1992 to 0.18 percent in 2016).

Genetic liability to cannabis use disorder is strongly associated with schizophrenia, but evidence for a causal association is mixed [169].

Individuals who have had an episode of cannabis-induced psychosis may be at particularly high risk. As examples:

-A systematic review and meta-analysis of six studies involving 3040 participants with cannabis-induced psychosis found a transition rate to schizophrenia of 34 percent (95% CI 25-46 percent) [170].

-A Danish national registry study followed 1492 individuals with a diagnosis of cannabis-induced psychosis for up to 20 years [171]. Forty-one percent (95% CI 36.6-46.2) of these individuals converted to a diagnosis of schizophrenia, with 50 percent of men converting within 2 years and 50 percent of women within 4.4 years. The hazard ratio for conversion to schizophrenia, compared with matched comparison subjects without a history of substance-induced psychosis, was 101.7 (95% CI 74.1-139.7).

Cannabis use in patients with established psychotic disorder Cannabis use exacerbates symptoms in individuals 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, more severe positive symptoms (but not negative symptoms), and poorer level of functioning and treatment adherence than nonusers or those who discontinued cannabis use [172]. Additionally, in individuals with first episode of psychosis, cannabis use is associated with an increased risk of psychotic experiences [173] and of relapse and re-hospitalization [174]. (See "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis".)

Mood and anxiety disorders – Studies provide mixed evidence as to the association between cannabis use and mood or anxiety disorders. (See 'Psychiatric disorders' above.)

Other effects

Education – Systematic reviews and prospective longitudinal studies have found consistent associations for cannabis use with lower educational attainment. However, none of the associations was clearly causal and potential bias and confounding factors were noted [175,176]. Adolescent cannabis use was not found to be associated with high school academic performance or mental health problems in prospective longitudinal studies [177,178].

Motor vehicle accidents – Cannabis use is associated with injury and death from motor vehicle accidents. Ingested or inhaled doses of THC acutely impair attention, concentration, short-term memory, executive functioning, and visuo-motor coordination, while the cannabinoid, cannabidiol has little acute psychoactive effect [136]. Meta-analyses have found that recent cannabis use increased the risk of injury from motor vehicle accident from between 32 and 97 percent [89,179-182].

Emergency department visits and hospitalizations – A retrospective cohort study of electronic health records of a 4 million-member integrated health system found that individuals with cannabis use disorder are more likely than individuals without cannabis use disorder to visit the emergency department or have an inpatient hospitalization [183]. A study of all emergency department visits at 49 United States hospitals found that cannabis-related visits represented 18 percent of all psychoactive drug-related (ie, excluding alcohol) visits, most in combination with other psychoactive drugs and/or alcohol [184].

MEDICO-LEGAL CONTEXT — The legal status of cannabis and its use in health care varies internationally.

Classification – 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” [185].

Under the United States Controlled Substances Act, cannabis and all phytocannabinoids (ie, compounds found in the Cannabis sativa plant) are classified as schedule I compounds, with the exception of hemp (legally defined as a cannabis plant containing no more than 0.3 percent delta-9-tetrahydrocannabinol) [186]. 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 – Medical use is legal in more than two dozen countries, including Canada. In the United States, medical cannabis is legal at the state level in 37 states, the District of Columbia, Puerto Rico, the United States Virgin Islands, and Guam, but remains illegal at the federal level [187]. An observational study utilizing state medical cannabis patient registries from 26 states and the District of Columbia found that nearly 3 million individuals were enrolled in medical cannabis programs in 2020, a 4.5-fold increase since 2016 [188]. The proportion of patients with conditions or symptoms for which there is conclusive or substantial evidence of medical cannabis efficacy (based on a review by the United States National Academy of Sciences, Engineering, and Medicine) [189] decreased from 84.6 percent to 68.2 percent over the same four-year period (based on data from 19 states). Medical use of cannabis and cannabinoids is discussed elsewhere. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Cannabinoids'.)

Recreational use – Possession of small amounts for adult recreational use is legal at the state level in 19 states, the District of Columbia, and two territories in the United States [187] and in five countries worldwide (Canada, Mexico, Uruguay, South Africa, Georgia).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cannabis use disorder and withdrawal".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Cannabis use disorder (The Basics)" and "Patient education: Cannabis hyperemesis syndrome (The Basics)")

SUMMARY

Epidemiology – Cannabis is the third most commonly used psychoactive substance worldwide after alcohol and tobacco. Young adults age 18 to 25 years have the highest rates of cannabis use and disorder. (See 'Incidence and prevalence' above.)

Risk factors

Frequency and duration of use – The primary risk factors for developing cannabis use disorder are frequency and duration of cannabis use. (See 'Risk factors for cannabis use and disorder' above.)

Genetic factors – Family and twin studies suggest that there is substantial heritability for initiation of cannabis use and development of cannabis use disorder. However, no single gene nor nucleotide polymorphism is robustly associated with these traits. (See 'Risk factors for cannabis use and disorder' above.)

Psychosocial factors

-Other substance use – The use of alcohol, tobacco and other substances is associated with greater risk of cannabis use, daily use of cannabis, and of developing cannabis use disorder. (See 'Psychosocial factors' above.)

-Psychological factors Other factors associated with increased risk of cannabis use include pre-existing psychiatric disorders, persisting conduct problems, education level, adverse childhood experiences and stressful life events. (See 'Psychosocial factors' above.)

Comorbidities – Much of the morbidity associated with cannabis use disorder may be due to comorbidities:

Individuals with cannabis use or cannabis use disorder often use other psychoactive substances. Bidirectional comorbidity with alcohol, tobacco, opioids, stimulants, sedative/hypnotics and hallucinogen use disorder is reported. (See 'Substance use disorders' above.)

Substantial bidirectional comorbidity is seen between cannabis use disorder, mood disorders, schizophrenia, anxiety disorders, posttraumatic stress disorder, and antisocial personality disorder. (See 'Comorbidities' above.)

Adverse effects

Disability and all-cause mortality – Cannabis use disorder may be associated with higher a long-term mortality rate than the general population. This is largely associated with accidents (especially motor vehicle), suicide, and cardiopulmonary conditions. Much of the morbidity may be due to comorbid psychiatric (including substance use) disorders. (See 'Disability and all-cause mortality' above.)

Medical and systemic effects – Adverse systemic and medical effects of cannabis use may include pulmonary effects, cardiovascular effects, hyperemesis syndrome, and nonseminoma testicular cancer. The association between cannabis smoking and lung cancer is unclear due to high risk of bias in most studies. (See 'Medical and systemic effects' above.)

-Cannabis acutely impairs attention, concentration, and coordination in a dose-dependent manner. While effects typically resolve after a month of abstinence, impairments may contribute to cannabis-related injury and death from motor vehicle accidents. (See 'Medical and systemic effects' above.)

-Neuroimaging studies show associations between cannabis use, reduced hippocampal volume, thinning orbitofrontal cortex, and smaller cerebellar white matter volume in cannabis users versus cannabis nonusers. (See 'Medical and systemic effects' above.)

Psychiatric effects – Chronic cannabis use, especially during adolescence, is associated with later development of schizophrenia. Some experts believe that early cannabis use is a causal factor in developing schizophrenia. There is mixed evidence as to the association between cannabis use and mood or anxiety disorders. (See 'Psychiatric effects' above.)

Medico-legal context – Medical use is legal in more than two dozen countries worldwide. In the United States, medical cannabis is legal in 37 states, the District of Columbia, Puerto Rico, the United States Virgin Islands, and Guam. Possession of small amounts for adult recreational use is legal in five countries worldwide and in 19 states and the District of Columbia in the United States. (See 'Medico-legal context' above.)

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Topic 7797 Version 39.0

References

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