Cannabis use and disorder: Epidemiology, comorbidity, health consequences, and medico-legal status
INTRODUCTION — Cannabis (also called marijuana) is the most commonly used illegal psychoactive substance worldwide [1]. Its psychoactive 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 significantly around the world in recent decades, which may have contributed to increased rates of cannabis-related adverse effects. Cannabis use disorder develops in approximately 10 percent of regular cannabis users, and may be associated with cognitive impairment, poor school or work performance, and psychiatric comorbidity such as mood disorders and psychosis.
The medico-legal context, epidemiology, comorbidity, and health consequences of cannabis use and cannabis use disorder in adults are reviewed here. The pathogenesis, pharmacology, clinical manifestations, course, assessment, diagnosis, and treatment of cannabis use disorder are reviewed separately. Acute cannabis intoxication is also reviewed separately.
EPIDEMIOLOGY — Cannabis grows in nearly every country in the world.
Cannabis use — Cannabis was used by an estimated 182 million people (range 128 to 234 million) worldwide in 2014, approximately 3.8 percent (range 2.7 to 4.9 percent) of the global population age 15 to 64 years [1]. Cannabis use is most prevalent in West and Central Africa (12.4 percent, 30.6 million users), North America (12.1 percent, 38.5 million users), and Oceania (10.2 percent, 2.6 million users), and least prevalent in East and South-East Asia (0.6 percent, 10.2 million users), Eastern and South-Eastern Europe (2.4 percent, 5.5 million users), the Caribbean (2.5 percent, 700 thousand users), and Central America (2.9 percent, 810 thousand users) [1].
A large, nationally representative, community-based, epidemiologic survey estimated the 2015 prevalence rate of past-year cannabis use in the general United States population (12 years or older) at 13.5 percent (estimated 36 million users) and past-month use of 8.3 percent (estimated 22.2 million users) [3]. Cannabis use during the past month increased from 6.2 percent (estimated 14.5 million users) in 2003. Two point six million individuals initiated cannabis use in 2015, almost half (45 percent) 12 to 17 years old [3].
Risk and protective factors for cannabis use include:
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Age – Cannabis use varies with age. The highest past-year prevalence is among young adults (18 to 25 years old) (32.2 percent); the lowest prevalence is among early adolescents (0.8 percent among 12 year olds and 2.6 percent among 13 year olds); past year prevalence is 10.4 percent among those 26 years or older (6.5 percent) [3]. Cannabis use is rare in those 65 years or older (2.4 percent). In 2015, the mean age of first-time cannabis users was 21.1 years [3].
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Sex – Men are almost twice as likely as women to have used cannabis over the past month, 10.6 versus 6.2 percent, respectively [3]. Men and women initiate cannabis use in roughly comparable numbers and at roughly comparable mean ages [3], suggesting that women may stop cannabis use at higher rates. Pregnant women are one-third as likely as nonpregnant women to have used cannabis in the past month, with rates somewhat lower during the third trimester (2.7 percent) than the first trimester (4.0 percent) [3].
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Race and ethnicity – Cannabis use over the past month is more prevalent among those of mixed race (13.4 percent), Pacific Islanders (9.2 percent), blacks or African Americans (10.7 percent), and Native Americans (11.2 percent) compared with among the general non-Hispanic United States population (8.5 percent), and less prevalent among Asians (3.0 percent) [3]. Cannabis use among whites (8.4 percent) and Hispanics (7.2 percent) is comparable to that of the general population.
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Education – College graduates have a lower prevalence of cannabis use during the past month (5.9 percent) than do those with less education (8.2 to 10.5 percent) [3]. Full-time college students have the same rate of current use as do their non-student peers.
The school experience strongly influences risk of cannabis use. Among adolescents enrolled in school, two- threefold greater prevalence of cannabis use during the past month is seen among adolescents with (compared with without) the following characteristics [4]:
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Failing grades
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Nonparticipation in extracurricular activities
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Dislike of school
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Others in grade who use cannabis, alcohol, or cigarettes
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Employment status – Those employed full-time or not in the labor force (eg, students, retired, disabled) have lower prevalence of cannabis use during the past month than do those working part-time (11.6 percent) or unemployed (7.5 and 4.8 versus 15 percent) [4].
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Income – Adults with income less than $20,000 USD annually have 2.5-times higher rates of cannabis use during the past year than adults with income of at least $70,000 USD annually (15.6 versus 5.9 percent) [5].
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Marital status – Unmarried adults are more likely to have used cannabis during the past year than are married adults or those widowed/separated (21.0 versus 5.5 versus 8.3 percent) [5].
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Legal status – Adults on parole, probation, or supervised release status are approximately three times more likely to have used cannabis in the past month than are individuals not in such legal status [4]. Adolescents with violent or illegal behavior in the past year are at least twice as likely as those without such behavior [4].
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Social network – Among adolescents, a positive relationship with parents and having parents, friends, or peers who disapprove of cannabis use are all associated with at least twofold lower prevalence of cannabis use over the past month [4].
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Religion – Adolescents with frequent attendance at religious services or strong religious beliefs are two to three times less likely to have used cannabis over the past month than those without such protective factors [4].
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Other substance use – Cigarette smokers and alcohol drinkers are each five to six times more likely than nonsmokers and nondrinkers to use cannabis [4].
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Geography – Prevalence of cannabis use over the past month in the United States varies somewhat by geographic characteristics [3]. Highest rates are found in New England (11.0 percent) and the West (10.3 percent) and in large (>1 million population) metropolitan areas (8.7 percent). Lowest rates are found in the South Central region (5.9 percent) and in rural areas (4.5 percent).
Patterns of use — Frequency of cannabis use varies widely among those not in treatment [4]. Approximately a quarter of current users use only one to two days per month, while approximately two-fifths use at least 20 days monthly. Prospective longitudinal studies suggest several distinct patterns of use over time [6]:
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Early onset with persisting chronic use
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Late onset with increasing use over time
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Use limited to adolescence
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Occasional use which never increases
Two models have been proposed to explain the sequence of cannabis use in relationship to other psychoactive substance use: the sequential gateway model and the common liability model:
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Sequential gateway model – The classical “gateway” model holds that there is a typical sequence of initiation of use of psychoactive substances: first use (usually in adolescence) of legal substances (alcohol, tobacco), followed by cannabis use, and then use of more harmful illegal drugs such as stimulants, opiates, or hallucinogens. The model assumes a causal relationship across the sequence, so that prevention of cannabis use would likely prevent later use of other illegal drugs [7,8].
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Common liability model – Pre-existing environmental and genetic factors contribute to all substance use and substance use disorders, so that use of a specific substance at one time is not a major factor in determining what substance is used at a later time [8].
Data from large, well-controlled, community-based epidemiologic studies and twin studies are generally not consistent with the sequential gateway model, but are often suggestive of the common liability model [8,9]. Cross-national studies suggest that the underlying prevalence of substance use in the population also influences the sequence of substance use [10].
Cannabis use disorder — An estimated 13.1 million individuals world-wide had moderate-severe cannabis use disorder in 2010, a point-prevalence of 0.19 percent [11]. Prevalence was greatest in young adult (20 to 24 years old) males living in high-income regions.
An estimated 4.0 million community-dwelling residents had current (use during past year) cannabis use disorder in the United States in 2015, a prevalence rate of 1.5 percent [3], which had not changed substantially over the previous decade (1.8 percent in 2002) [4]. Approximately one in eight cannabis users had a cannabis use disorder (12.7 percent). A smaller, more detailed community-based epidemiologic survey found a doubling of the cannabis use disorder rate among adults over a comparable period, from 1.5 percent (standard error 0.08) in 2001 to 2002 to 2.9 percent (standard error 0.13) in 2012 to 2013 [5].
Users of cannabis over the past year are 7.6 (95% CI 4.8-12.0) times more likely than nonusers to develop cannabis use disorder over the next three years, after controlling for potential confounders [12]. Risk of developing cannabis use disorder increases significantly with greater intensity of cannabis use.
There are substantial differences in population rates of cannabis use disorder over the past year among different sociodemographic groups. The risk of cannabis use disorder over the past year among cannabis users (so-called “conditional” cannabis use disorder) varies much less, suggesting that much of the variation in cannabis use disorder rates is more due to differences in rates of cannabis use than to differences in development of cannabis use disorder.
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Age – Prevalence of cannabis use disorder declines substantially with age in adults: 7.5 percent among young adults (18 to 29 years old), 1.3 percent among the middle-aged (45 to 64 years old), and 0.3 percent among older adults 65 years or older [5]. Adolescents (12 to 17 years old) have an intermediate prevalence (2.9 percent) [4].
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Sex – Adult men are more than twice as likely as adult women to have cannabis use disorder over the past year (4.2 versus 1.7 percent, respectively) [5].
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Education – Adults with at least some college education are less likely to have cannabis use disorder over the past year (2.5 percent) than are high school dropouts (3.3 percent) and high school graduates (3.7 percent) [5].
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Race and ethnicity – Native Americans (5.5 percent) and blacks (4.6 percent) have higher cannabis use disorder rates over the past year than whites (2.7 percent) and Asians (1.3 percent) [5]. Hispanics have a rate (2.8 percent) comparable to the general population (2.9 percent).
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Income – Cannabis use disorder rates decline significantly with increasing income from less than $20,000 USD annually to at least $70,000 USD annually [5].
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Urban residence – The cannabis use disorder rate over the past year is greater in urban (3.1 percent) than in rural (2.3 percent) areas [5].
PSYCHIATRIC COMORBIDITY — Cannabis use and use disorder have high rates of comorbidity, in both directions, with several psychiatric disorders, including other 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.
The most rigorous information comes from large, representative community-based studies, preferably prospective longitudinal studies, rather than cross-sectional. Case series of patients in treatment are less informative, and subject to selection bias.
Alcohol — There is substantial bidirectional comorbidity between cannabis use or cannabis use disorder and alcohol use or alcohol use disorder. A cross-sectional survey of 36,309 community-living adults in the United States found those with current (past 12 months) alcohol use disorder were six times more likely compared with those without alcohol use disorder to have current cannabis use disorder (prevalence rate 10.9 percent [standard error 0.55], adjusted odds ratio 6.0, 95% CI 5.10-6.97). Those with current cannabis use disorder were three to four times more likely to have current alcohol use disorder (prevalence rate 59.4 percent [standard error 2.46], adjusted odds ratio 2.8, 95% CI 2.19-3.60 for men; 59.5 percent [standard error 3.52], adjusted odds ratio 3.8, 95% CI 2.33-6.48 for women) [13]. Prospective longitudinal surveys suggest that cannabis users are 2.0 (95% CI 1.4-2.7) [12] to 5.43 (95% CI 4.54-6.49) [14] times more likely to develop alcohol use disorder over the next three years than are nonusers. Among adults with a history of alcohol use disorder, cannabis use is associated with increased likelihood of persistent alcohol use disorder over the next three years compared with those without cannabis use (odds ratio 1.74, 95% CI 1.56-1.95) [14]. A majority of daily recreational cannabis users also binge drink alcohol [15].
Tobacco — There is substantial bidirectional comorbidity between cannabis use or cannabis use disorder and cigarette smoking [16]. A cross-sectional survey of 36,309 community-living adults in the United States found those with current (past 12 months) tobacco (nicotine) use disorder about six times more likely than those without tobacco use disorder to have current cannabis use disorder (prevalence rate 8.1 percent [standard error 0.43], adjusted odds ratio 6.2, 95% CI 5.24-7.34) [17] and those with current cannabis use disorder about three times more likely to have current tobacco use disorder (prevalence rate 63.4 percent [standard error 2.31], adjusted odds ratio 3.0, 95% CI 2.43-3.66 for men; 64.8 percent [standard error 3.24], adjusted odds ratio 3.7, 95% CI 2.61-5.26 for women) [13]. A prospective longitudinal study of 34,653 United States adults found that cannabis users were 1.8 (95% CI 1.2-2.7) times as likely to develop a moderate to severe tobacco use disorder over the next three years as were nonusers, after controlling for potential confounders [12].
Opiates — A cross-sectional, nationally representative survey of community-living United States adults identified 10,943 respondents with current cannabis use disorder, of whom 2.26 percent (standard error 0.24) also had current heroin use disorder and 9.67 percent (standard error 0.48) another current opioid use disorder [18]. Individuals with current cannabis use disorder are 2.6 times more likely to have a current heroin use disorder compared with those without a substance use disorder [19].
Stimulants — A cross-sectional, nationally representative survey of community-living United States adults identified 10,943 respondents with current cannabis use disorder, of whom 8.19 percent (standard error 0.39) also had current cocaine use disorder and 2.92 percent (standard error 0.29) another current stimulant use disorder [18].
Mood disorders — There is substantial comorbidity between cannabis use/cannabis use disorder and mood disorders (depression, bipolar disorder). Secondary analyses of data from a representative sample of 43,093 community-based adults in the United States found that individuals with a lifetime mood disorder were two to three times more likely to have used cannabis during their lifetime compared with those without any psychiatric disorder [20] and to develop a cannabis use disorder after starting cannabis use [20,21]. Cross-sectional studies have found lifetime rates of cannabis use of approximately 70 percent and cannabis use disorder of approximately 30 percent among patients with bipolar disorder [22].
A systematic review of nine published community-based national epidemiologic surveys found a mean prevalence of 17 percent (range 10 to 30 percent) for current cannabis use disorder among respondents with bipolar disorder and a prevalence of 10 to 25 percent for bipolar disorder among respondents with current cannabis use disorder [23]. A systematic review by the same research group that included 78 published studies of inpatient and outpatient clinical populations found a 20 percent prevalence rate for cannabis use disorder among patients with bipolar disorder [24].
Schizophrenia (nonaffective psychosis) — There is substantial comorbidity between cannabis use and schizophrenia; some experts believe that early cannabis use is a causal factor in developing schizophrenia. (See 'Psychotic disorders' below.)
Cross-sectional studies indicate that cannabis users have two- to threefold increased prevalence of schizophrenia compared with nonusers [25]. This association is stronger with earlier age of onset of use (eg, early adolescence), more intense cannabis use, and use of cannabis with high delta-9-tetrahydrocannabinol (THC) content and THC:cannabidiol ratio [26]. Secondary analyses of data from a representative sample of 43,093 community-living adults in the United States found that individuals with lifetime schizophrenia were two to three times more likely to have lifetime cannabis use than those without any psychiatric disorder [20] and to develop cannabis use disorder [20,21].
A systematic review of 53 published studies found that patients with schizophrenia-spectrum disorders had a 23.1 percent prevalence (range 4.5 to 81.1 percent) of cannabis use over the past 6 months and a 42.2 percent (range 19.2 to 89.1 percent) prevalence of lifetime use [27]. A systematic review of 35 published studies found that patients with schizophrenia-spectrum disorders had a 16.0 percent (8.6 to 28.6 percent interquartile range) prevalence of current cannabis use disorder and a 27.1 percent (12.2 to 38.5 percent interquartile range) prevalence of lifetime cannabis use disorder [28].
A prospective, national, register-based, birth cohort study in Denmark that followed 41,470 people with schizophrenia born in 1955 or later found an increased risk of all-cause mortality in those with cannabis use disorder (hazard ratio 1.24, 95% CI 1.04-1.48, p = 0.0174) [29].
Anxiety disorders — There is substantial comorbidity between anxiety disorders and cannabis use. A meta-analysis of 31 studies involving 112,000 individuals in 10 countries found associations between anxiety disorder and cannabis use (odds ratio = 1.24, 95% CI 1.06-1.45) or cannabis use disorder (odds ratio = 1.68, 95% CI 1.23-2.31) [30].
Secondary analyses of a representative survey of 43,093 community-based adults in the United States found that individuals with a lifetime anxiety disorder were two to three times more likely to have lifetime cannabis use than those without any psychiatric disorder [20] and to develop a cannabis use disorder after starting cannabis use [20,21].
A community-based, nationally representative survey of 36,309 adults in the United States found that one-quarter or more (23.4 percent, standard error 2.30 among men; 36.1 percent, standard error 3.74 among women) of respondents with current cannabis use disorder had a current anxiety disorder, although the adjusted odds ratios were not significant (1.2, 95% CI 0.88-1.56 for men; 0.8, 95% CI 0.58-1.23) [13]. Current prevalence rates for individual anxiety disorders among men and women were specific phobia 8.6 (standard error 1.50) and 9.9 (standard error 1.93) percent, respectively; generalized anxiety disorder 12.2 (standard error 1.88) and 19.9 (3.19) percent, respectively; social phobia 7.1 (standard error 1.42) and 7.2 (standard error 1.76) percent, respectively; and panic disorder 7.4 (standard error 1.20) and 15.2 (standard error 2.81) percent, respectively. None of the adjusted odds ratios were significant.
Posttraumatic stress disorder — Several community-based national epidemiologic studies found comorbidity rates of around 10 percent for current cannabis use disorder and posttraumatic stress disorder (PTSD). For example, a cross-sectional, nationally representative survey of 36,309 community-living United States adults found the prevalence of current cannabis use disorder among those with current PTSD to be 9.4 percent (standard error 0.94) (adjusted odds ratio 4.3, 95% CI 3.15-4.67) [17] and the prevalence of current PTSD among those with current cannabis use disorder to be 12.3 percent (standard error 1.66) (adjusted odds ratio 1.7, 95% CI 1.12-2.57) for men and 26.9 percent (standard error 3.37) (adjusted odds ratio 1.6, 95% CI 1.01-2.48) for women [13].
Obsessive-compulsive disorder — A cross-sectional, nationally representative, household survey of 8841 adult Australians found a 19.9 percent (standard error 7.4) prevalence of obsessive-compulsive disorder among respondents with current cannabis use disorder, compared with 4.6 percent (standard 1.2) among current cannabis users without cannabis use disorder and 2.4 percent (standard error 0.2) among current nonusers [31]. However, the odds ratios for having obsessive-compulsive disorder were not significantly different from one for current cannabis users with cannabis use disorder versus current users without cannabis use disorder (odds ratio 2.3, 95% CI 0.6-8.7) or for current nonusers versus current users without cannabis use disorder (odds ratio 0.8, 95% CI 0.4-1.6).
Attention deficit hyperactivity disorder — Two studies of large, unselected populations suggest a 20 to 30 percent comorbidity rate between attention deficit hyperactivity disorder (ADHD) and cannabis use disorder. A nationally representative survey of 33,488 community-living United States adults found about a 30 percent prevalence of lifetime cannabis use disorder (varying by ADHD subtype: inattentive, hyperactive-impulsive, or combined) among the 965 respondents with ADHD, compared with 5 percent among the 15,614 respondents without ADHD or ADHD-type symptoms (adjusted odds ratio 2.14 [adjusted for socioeconomic characteristics, conduct disorder, major depression, and anxiety disorder], 95% CI 1.58-2.90) [32]. The 17,009 respondents with ADHD-type symptoms (but not meeting full DSM-IV diagnostic criteria for ADHD) also had significantly greater prevalence of lifetime cannabis use disorder (10 percent; adjusted odds ratio 1.29, 95% CI 1.20-1.38). A 2010 to 2011 study of 5103 male Swiss Army conscripts found a 21.9 percent prevalence of current cannabis use disorder among the 215 conscripts with current ADHD, compared with an 8.0 percent prevalence among conscripts without current ADHD (chi-square 48.43, p <0.001) [33].
Personality disorders — There is substantial comorbidity between cannabis use disorder and several personality disorders, especially antisocial and obsessive-compulsive personality disorders. A community-based, nationally representative study of 36,309 adults in the United States found high rates of current personality disorder in men and women with current cannabis use disorder: 48.2 (standard error 2.51) and 58.6 (standard error 3.17), respectively, two to three times the rate of those without cannabis use disorder (adjusted odds ratios 2.0, 95% CI 1.56-2.65 for men; 3.1, 95% CI 2.14-4.35 for women) [13]. Current prevalence of specific personality disorders included:
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Antisocial personality disorder: 21.8 (standard error 2.12) percent (adjusted odds ratio 1.5, 95% CI 1.08-2.02) for men; 16.1 (standard error 1.95) percent (adjusted odds ratio 1.7, 95% CI 1.13-2.58) for women.
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Borderline personality disorder: 39.1 (standard error 2.32) percent (adjusted odds ratio 2.0, 95% CI 1.46-2.67) for men.
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Schizotypal personality disorder: 24.9 (standard error 2.17) percent (adjusted odds ratio 1.3, 95% CI 0.98-1.85) for men; 33.5 (standard error 3.21) percent (adjusted odds ratio 2.0, 95% CI 1.26-3.18) for women.
Secondary analysis of an earlier community-based, nationally representative study of 43,093 adults in the United States found that cannabis users with any lifetime personality disorder were more than twice as likely to develop cannabis use disorder than those without any disorder (adjusted odds ratio 2.36, 95% CI 2.05-2.71) [21].
Respondents with lifetime cannabis use disorder were 10-fold more likely (odds ratio 10.2, 95% CI 8.77-11.88) to have lifetime antisocial personality disorder than those without cannabis use disorder [34]. Respondents with lifetime cannabis use disorder were also twice as likely to have lifetime childhood conduct disorder (2.2, 95% CI 1.65-3.03) and seven times more likely to have lifetime adult antisocial behavior (7.1, 95% CI 6.47-7.88). Women show this increased prevalence of personality disorders two-three times more than men.
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” [97]. In practice, the legal status of cannabis and its use in health care varies widely internationally [98]. 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 [99]. 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 November 2017, twenty-nine US states, the District of Columbia, Puerto Rico, and Guam authorize medical use of cannabis, although not all programs are operational [100]. 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.
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) [101]. 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.
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.
Clinicians recommending cannabis for medical treatment should consider:
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Prior experience with cannabis – Patients with no prior experience with cannabis are more likely to experience the psychoactive effects as dysphoric rather than pleasurable. Patients who are regular cannabis users are more likely to be tolerant to some of the adverse effects, eg, cognitive and psychomotor impairment.
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Cannabinoid content – “Dosing” of cannabis is determined by the means of administration, frequency, and amount used as well as the cannabinoid content of the recommended strain (especially in terms of THC and THC:cannabidiol ratio). Some states require labeling of medical cannabis strains or dosing units with their content of major cannabinoids such as THC and cannabidiol. States that have legalized only low THC:high cannabidiol medical cannabis typically have a maximum permitted THC content.
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Route of administration:
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Smoked and inhaled cannabis have a rapid onset of effect (typically minutes) and relatively short duration of action (typically two to four hours). These routes are preferred by some patients because they allow frequent and precise titration of dose to effect (eg, analgesia).
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Oral cannabis has a slow onset of effect (typically half to one hour) and long duration of action (typically 4 to 12 hours). This may lead to inadvertent overdosing; when patients don’t experience effects as soon as they expect, they may take another dose, resulting in a cumulative overdose. This is especially likely by patients familiar with the rapid onset of smoked or inhaled cannabis.
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Drug interactions – THC has potential drug-drug interactions with other medications [102]. THC is a substrate for the CYP2C9 and CYP3A4 drug-metabolizing enzymes, so may interact pharmacokinetically with other substances metabolized by these enzymes, such as tricyclic antidepressants (2C9), protease inhibitors (3A4), or sildenafil (2C9, 3A4) [103]. The clinical significance of these interactions has not been established.
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Sedative effect – As a central nervous system (although not respiratory) depressant, THC potentiates the sedative effects of other central nervous system depressants such as alcohol and benzodiazepines. This additive interaction is especially relevant when driving or operating heavy machinery. As an example, a 2015 blinded controlled study of the effects of inhaled (vaporized) cannabis and oral alcohol on simulated driving performance found that a 5 mcg/L blood THC concentration combined with a 0.05 g/210 L breath alcohol concentration produced the same impairment as a 0.08 g/210 L alcohol concentration [104].
There is little information from controlled clinical trials regarding contraindications to use of medical cannabis. Based on known adverse effects of recreational cannabis use, it seems prudent to avoid recommending medical cannabis to individuals with a history of schizophrenia, a recent acute myocardial infarction or episode of cardiac tachyarrhythmia, or who must drive or operate heavy machinery.
Recreational use — Several counties and states in the United States have considered or enacted legislation allowing recreational use of cannabis. As of January 2019, nine states and the District of Columbia will have authorized cannabis for recreational (as well as medicinal) use under state law. Not all the state programs were operational as of February 2018 [100].
Synthetic cannabinoids — Synthetic cannabinoids have been approved in some countries for specific clinical indications.
Dronabinol (Marinol synthetic THC) and nabilone (a THC analogue, eg, Cesamet) are classified under schedule III of the Controlled Substances Act in the United States (and similar schedules in other countries) and approved by the US Food and Drug Administration for oral administration in the treatment of:
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Anorexia associated with weight loss in patients with AIDS.
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Nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
Dronabinol and nabilone are psychoactive, which is often experienced as an adverse effect by cannabis-naïve patients. They appear to have little abuse or diversion liability [105], perhaps because the oral route of administration does not provide the rapid onset and intense euphoria desired by the typical recreational drug user.
Synthetic cannabinoids are discussed further separately.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.
SUMMARY
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Cannabis is the most commonly used illegal psychoactive substance, used by an estimated 182 million individuals worldwide (3.8 percent of the 15- to 64-year-old population in 2014 and an estimated 36 million community-living individuals (13.5 percent of those 12 years and older) in the United States in 2015. (See 'Cannabis use' above.)
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Rates of cannabis use in the United States are higher in young adult men with low incomes and no college education than among other population groups. Approximately one in eight current regular cannabis users develops a cannabis use disorder. (See 'Cannabis use'above and 'Cannabis use disorder' above.)
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Cannabis use before age 17 years is strongly associated with lower educational attainment and increased use of other drugs, but these associations are not clearly causal. (See 'Psychosocial functioning and health' above.)
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Individuals with cannabis use or cannabis use disorder often use other psychoactive substances, especially alcohol and tobacco. Substantial bidirectional comorbidity is seen between cannabis use disorder, schizophrenia, and several other psychiatric disorders, including depression, bipolar disorder (mania), anxiety disorders, and antisocial personality disorder. (See 'Psychiatric comorbidity'above.)
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Cannabis acutely impairs attention, concentration, episodic memory, associative learning, and motor coordination in a dose-dependent manner. Long-term cannabis use is associated with impairment of verbal memory and cognitive processing speed, which resolves after at least a month of abstinence. (See 'Neuropsychological effects' above.)
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Substantial evidence suggests 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. (See 'Psychotic disorders' above.)
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Chronic cannabis use has not been found to be associated with serious or chronic medical conditions or death from medical conditions. Cannabis use may be associated with death from motor vehicle accidents. (See 'Adverse effects of cannabis use' above.)
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Cannabis smoking is associated with acute, transient respiratory symptoms, but chronic use is not associated with impaired lung function. (See 'Pulmonary' above.)
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Cannabis smoking acutely increases sympathetic activity and myocardial oxygen demand, and is associated with a small increased risk of myocardial infarction and stroke. (See 'Cardiovascular' above.)
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Cannabis use is also associated with periodontal disease, hyperemesis syndrome, and a lower sperm count. Hyperemesis syndrome is a relatively rare condition involving episodic severe nausea and vomiting and abdominal pain. Frequent cannabis smoking has been associated with a lower sperm count; the clinical significance of this finding is unknown. (See 'Dental' above and 'Hyperemesis syndrome' above and 'Reproductive' above.)
ACKNOWLEDGMENTS — The editorial staff at UpToDate would like to acknowledge John Bailey, MD, Robert DuPont, MD, and Scott Teitelbaum, MD, who contributed to an earlier version of this topic review.