**5. Common comorbidities**

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

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

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

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,

use almost 4% in this age group [18, 19].

140 Recent Advances in Cannabinoid Research

the 15–17 age range (from 28.5 to 20%) [18, 19].

symptoms differ between the US and Netherlands [26, 27].

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 more information on course and progression of the disorder.

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 adolescence [33, 34].

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 problems also exist on a severity continuum [5].

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 symptoms (including blunted affect, psychomotor retardation, reduced rapport), cognitive deficits (including learning, memory and attention),—some of which are related to schizophrenia including verbal recall impairment with increased "false positives" and "intrusions" [36]. In healthy individuals, these acute laboratory effects of cannabis are time-locked to drug administration, dose-related and transient [36].

downregulating CB1 receptors [43]; full recovery of CB1 receptor density has been detected after one-month abstinence and substantial recovery has been detected as soon as 72-hours

Cannabis Use Disorder

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Both the acute and chronic effects of cannabis on the central nervous system are not wellunderstood in humans. CB1 receptors are heavily expressed in the striatum, hippocampus, amygdala and prefrontal cortex (PFC) and it is mostly in these regions that regular cannabis users show altered neuroanatomy [45]. Understanding neuroanatomic alterations with cannabis use is complicated by this drug's composition changes in recent years including different cannabinoid compounds with unique neural effects [45]. Since the 1990s, THC potency has increased from 4 to 12%; simultaneously, the average concentration of THC to cannabidiol has increased almost 80 times, suggesting plants are now bred with much higher THC concentrations (based on confiscated cannabis materials) [46]. These compound alterations are important as preclinical evidence suggests neurotoxic effects of THC on CB1 rich areas [45]. In humans, volumetric reductions and gray matter density alterations are consistently noted in the hippocampus, which relate to duration of use and cannabis dosage [45, 47, 48]. There are also links with compound composition; THC levels are inversely related to volumetric reductions while higher THC/cannabidiol ratios are associated with reduced volume and gray matter [45]. There is some evidence for neuroprotective cannabidiol effects as individuals with high cannabidiol levels do not show hippocampal volume reductions, however the mechanisms by which cannabidiol might offset THC effects are currently unknown [45]. Outside of the hippocampus, neuroanatomic alterations are additionally noted in high-density CB1 areas including the amygdala and striatum, PFC, parietal cortex, insula and cerebellum [45]. Altogether, these neuroanatomic alterations may result from THC metabolites accumulating and producing neurotoxic effects, cannabinoid receptor adaptations and/or changes in cells or vascularity [45]. All of these CB1-rich areas serve core functions in memory, attention, learning and reward and cognitive control. The hippocampus, PFC and amygdala are central in cognitive processing, indeed behavioral/functional impairments are noted in memory,

Although the findings are mixed, overall subtle neurocognitive deficits in executive function, memory and learning are found with cannabis exposure, however, long term cannabis effects, and whether they are reversible, are still unclear [49, 50]. The ability to hold and manipulate information is consistently impaired with acute cannabis administration, although few studies report long-term working memory problems [50–53]. Diminished prefrontal cortex and

Of particular relevance to cannabis is the role of impulsivity—a systematic review provides

There are mixed behavioral findings when examining attention and concentration in CUD as well as impulsive behaviors following acute administration, short-term and long-term abstinence [50]. Nevertheless several neuroimaging studies demonstrate reduced prefrontal,

hippocampal activity are noted during memory tasks in heavy cannabis users [54].

support for alterations in inhibitory control in heavy cannabis users [55].

[43, 44].

attention and learning in CUD [49].

**6.2. Cognitive functioning**

Consistent with acute intoxication experiments, epidemiological studies also provide strong evidence for cannabis use increasing the risk for psychosis, even after adjusting for covariates [37]. While these studies have difficulty demonstrating a causal relationship with psychotic disorders, a growing number of longitudinal prospective studies are beginning to demonstrate these links [37]. There is still more research needed integrating neurobiology, epidemiology and psychopharmacology with particular compounds and potencies (including synthetic cannabinoids) to determine the magnitude and mechanisms of a causal effect [37]. Nevertheless, many individuals who use cannabis regularly do not develop psychotic disorders, therefore understanding those subgroups most at risk to propsychotic effects still needs to be clarified [35].

These findings have significant implications for treatment; high comorbidity rates underscore the fact that clinicians should screen for other conditions as these are likely present. Additionally, treatment approaches may need to target concurrent conditions. The co-relationship between CUD and other conditions is also important if CUD prevalence increases with legislative changes. While the causal relationship between these co-occurrences is not yet definitive, the close association nonetheless highlights important vulnerabilities and speaks to the importance of prevention and early intervention efforts.
