**4. Prevalence of cannabis use and cannabis use disorder (CUD)**

Cannabis remains the most commonly used illicit\* (\*state/country-dependent) psychoactive drug. Large epidemiological studies show that ~43% of individuals in the US and Canada report having tried cannabis, with ~35% having tried it more than once [18–20]. Cannabis use is highest in adults (ages 18–44), with just over half reporting using cannabis [18]. Past-year cannabis use in emerging adult populations (18–24 years-olds) is around 33.3%, with daily use almost 4% in this age group [18, 19].

drawing on large-scale NESARC data, 7.96% of cannabis users met criteria for cannabis dependence, which was higher than alcohol (5.82%) but substantially lower than tobacco (46.13%), heroin (26.96%), and cocaine (23.91%) [32]. In an interesting study of addiction experts using a multi-criteria decision analysis to judge substance use harms, cannabis was ranked 8th out of 20, behind alcohol, heroin, crack cocaine, methamphetamine, cocaine, tobacco, and amphetamine (in that order). Collectively, these findings suggest that although cannabis is far from without risk, it can also be thought of as lower risk than a number of

Cannabis Use Disorder

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Other comorbid conditions are common in CUD; in particular, high rates of depression, anxiety, substance use and personality disorders are consistently associated with CUD [5, 9]. Understanding associations between CUD and other disorders is important as it provides

Other substance use disorders (SUDs) are most commonly associated with CUD, with greater lifetime use of illicit drugs, including sedative/tranquilizers, painkillers, cocaine stimulants, club-drugs, hallucinogens, inhalant/solvents, heroin and other prescription drugs [33]. Recent epidemiological studies suggest increasing links with stimulant-based substances including MDMA, methamphetamine and prescription stimulants such as Ritalin [33]. It is possible that cannabis and stimulant co-abuse patterns represent individuals counterbalancing each drug's pharmacokinetic effects; for example applying sedative effects of cannabis following stimulant use [33]. Individuals with CUD are also more likely to also be current smokers and report high rates of alcohol use [9, 33]. Longitudinal studies are now providing more support for a causal relationship between early cannabis use and CUD as well as substance use and other psychiatric disorders. One large study demonstrated consistent, dose-response characteristics between early cannabis use and the development of CUD, other illicit substance use, depression and suicide attempts [34]. Altogether consistent data show polydrug use with CUD even when controlling for other health and psychiatric factors present before or during

In terms of other conditions, personality disorders are highly comorbid, in particular increased rates of antisocial and borderline personality disorder are noted [9]. Anxiety disorders are also linked to CUD, with Post Traumatic Stress Disorder (PTSD) most highly associated, followed by general anxiety and panic disorder [9, 21]. Applying the CUD severity specifiers (mild, moderate, severe) shows that increasing CUD severity is associated with the increasing strength of associations with these psychiatric conditions [21]—similar to CUD, clinical

Converging lines of preclinical, epidemiological and experimental studies demonstrate strong links between cannabinoids and psychosis. The exogenous cannabinoid hypothesis posits that cannabinoid exposure is linked to the development of psychosis [35]. In controlled human laboratory settings, THC and cannabis extract administration produces increased positive symptoms, (including delusions, suspiciousness and perceptual alterations), negative

other psychoactive drugs, both legal and illegal.

more information on course and progression of the disorder.

**5. Common comorbidities**

adolescence [33, 34].

problems also exist on a severity continuum [5].

Cannabis use prevalence rates from 2002 to 2012 show overall increases across North America [5, 18, 19, 21] and, increases in use and frequency of use coincide with declining risk perceptions of the drug [5]. Nevertheless, cannabis use trends differ longitudinally across specific age groups. For example, since 2002, prevalence rates appear to have increased in adults aged 25–44 (from 14 to 15.6%), remained stable in 18–24 year olds (around 33%) and decreased in the 15–17 age range (from 28.5 to 20%) [18, 19].

Prevalence rates for cannabis use disorder (CUD) range from 2.9% up to 19%—with approximately 13 million individuals worldwide meeting criteria [9, 22, 23]. Severe lifetime CUD rates are around 2%, with rates peaking during the emerging adulthood period (~21 years of age) [9]. There are also sociodemographic differences in prevalence rates—lifetime CUD rates are almost twice as high in males versus females, in adults 18–29, with a mean age of onset in the early twenties [9]. Unmarried individuals and those with lower socio-economic status report higher CUD prevalence rates; however, education appears largely unrelated [9].

One large epidemiological study in the United States also suggests that CUDs doubled between 2002 and 2012 [21], but not all longitudinal studies report the same prevalence trends in CUD [5, 20, 21, 24]. Discrepant prevalence rates may relate to underreporting in earlier studies as social acceptance of cannabis use increases [25]. Indeed, there are notable sociocultural influences on harm perception and willingness to acknowledge CUD symptoms varies between legal cultures [26]. Endorsement of CUD criteria can differ between countries and may relate to legalization status. For example, reports of failed quit attempts and withdrawal symptoms differ between the US and Netherlands [26, 27].

Importantly, CUD is associated with high levels of disability, including social and emotional functioning and greater CUD severity is associated with increasing levels of disability [9]. Information on cannabis-related disability is fairly new, as many previous studies did not include cannabis when studying disease burdens, but newer studies demonstrating that CUD can produce more years with disability [28]. Disability can persist even after CUD remission, although the reason for this is not yet clear [29]. It is also important to note that cannabis use and misuse (more broadly than just CUD) are associated with significant economic costs. In Canada, the estimated economic burden of cannabis use was 2.8Bn in 2014 and cannabis costs exhibited the largest increase among substances from 2007 to 2014, a 19.1% increase [30].

Finally, it is important to contextualize cannabis with other psychoactive drugs. One way to quantify addiction liability across substances is to examine the proportion of individuals who develop a substance use disorder, such as CUD, relative to the number of individuals who have at least tried a given substance. Using this metric in the large National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) cohort, fewer than one in ten (8.9%) individuals transitioned from any cannabis use to cannabis dependence (pre-DSM-5), which was lower than tobacco, alcohol, and cocaine [31]. Another way to contextualize relative risk is to consider the conditional probability between use and misuse (i.e., the proportion of active users of a given drug that have a diagnosable problem). Again, drawing on large-scale NESARC data, 7.96% of cannabis users met criteria for cannabis dependence, which was higher than alcohol (5.82%) but substantially lower than tobacco (46.13%), heroin (26.96%), and cocaine (23.91%) [32]. In an interesting study of addiction experts using a multi-criteria decision analysis to judge substance use harms, cannabis was ranked 8th out of 20, behind alcohol, heroin, crack cocaine, methamphetamine, cocaine, tobacco, and amphetamine (in that order). Collectively, these findings suggest that although cannabis is far from without risk, it can also be thought of as lower risk than a number of other psychoactive drugs, both legal and illegal.
