Managing the hazards of cannabis use

The increasing use of cannabis and the extent of possible harmful mental health effects is a growing global concern. Cannabis ranks first (after alcohol and tobacco) for used substances worldwide with an estimated 22 million people meeting the criteria for cannabis use disorder and 200 million people using cannabis at least once per year.1 Cannabis use disorder (CUD) is defined by the DSM-5 as continued use of cannabis despite clinically significant impairment and distress and combines what was previously grouped and termed as abuse and dependence. At least two of eleven listed criteria (eg social/interpersonal problems, withdrawal) need to be present during the last 12 months to qualify for a diagnosis of CUD. The overall number of annual cannabis users is estimated to have increased by nearly 18 per cent during the period 2010–2019.1 The lifetime risk of developing CUD in cannabis users is 9% but rises to 16% with early-onset cannabis use, that is during adolescence, and to 25–50% when cannabis is used daily.2 Globally, there is a trend towards legalization with several US states, Canada and Uruguay permitting the sale and recreational use of cannabis.1 The cannabis plant, Cannabis Sativa L., contains more than 70 unique compounds (phytocannabinoids) with Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being the two most abundant constituents. THC is responsible for the psychotogenic and euphoric effects of cannabis via partial agonist effect on cannabinoid receptors, whereas CBD has been associated with potentially therapeutic properties.3, 4 Marked increases in THC concentration in various cannabis products have been observed within the last couple of decades in international cannabis markets with observed increases in THC being larger in cannabis resin than in herbal cannabis.5 Especially in Denmark, a recent study found markedly increased THC concentration in cannabis resin from 8% in 2000 to 25% in 2017.6 The addiction potential of cannabis is believed to increase with the content of THC, that is high-potency cannabis. Other cannabis products such as cannabis concentrates and edibles may have an even higher potency and thus increased risk of adverse health consequences.1 Acute administration studies in healthy individuals have documented that a single THC administration induces psychotic and general psychiatric symptoms with large effect sizes.7 Increasing frequency of use and high-potency cannabis has been shown to be associated with increased risk of psychosis. A recent case-control study found that daily consumption of cannabis was associated with increased odds of developing psychosis (odds ratio (OR) 3.2), and that the risk was further increased (OR 4.8) in high-potency cannabis users.8 This increased risk of psychosis has been considered the core mental health risk of cannabis use both as an acute psychotic effect7 and as the development of more long-lasting or chronic psychotic conditions like schizophrenia.9 Compared with the established association between cannabis and psychosis much less is known about a possible connection between cannabis use and depression. A recent review reported a bidirectional relationship between cannabis and depression including higher risk for depression in people with heavy use of cannabis and when cannabis consumption was initiated in early adolescence.10 Furthermore, clinical evidence suggested that cannabis use concomitant with depression was associated with a worse prognosis than depression in individuals with no cannabis use.10 Data investigating the association between cannabis use and anxiety are mixed.2 Cannabis use in youth may pose an even more pronounced risk because of potentially more detrimental effects of THC on the maturing brain. Another important area where regular cannabis use exerts a negative effect is neurocognitive performance where particularly adolescent cannabis use is associated with impairment in several domains including attention, processing speed, verbal learning and memory, and executive functioning. Early age of onset of cannabis use and heavy use have been found to be associated with increased likelihood of cognitive impairment in adulthood and decreased likelihood of returning to previous intellectual level and development possibilities after abstinence.11 Clinically, this is reflected in increased risk of adverse mental health effects with frequent cannabis use in youth including poor psychosocial outcomes like dropping out of school, lower than expected academic and occupational achievements, and behavioural and legal conflicts.12 The nationwide registries of the Nordic countries comprise a valuable source of information on various long-term risks of exposure to a given substance. Such risks cannot, by definition, be examined in clinical studies that measure acute exposure to cannabis constituents. Data from the Danish nationwide registries have recently been used to examine this question in more detail focusing on the possible causality between cannabis use and psychosis. The results show 1) a more than 2-fold increase in incidence rate of cannabis-induced psychosis in Denmark from 2.8 per 100 000 person years in 2006 to 6.1 per 100 000 person years in 2016,13 2) that 47.7% of persons with cannabis-induced psychosis in Denmark from 1994–2014 converted to either schizophrenia or bipolar disorder,9 and 3) that the fraction of new schizophrenia cases being attributable to CUD increased from 2% in 1995 to reach stability at 6–8% in 2010, thus increasing 3- to 4-fold during the past two decades coincident with increased use and potency of cannabis.14 Additionally, Swedish register-based data suggest that apart from increasing the risk of schizophrenia, cannabis use significantly worsens the prognosis of schizophrenia being associated with a higher burden of lifetime inpatient care compared with non-cannabis using patients with schizophrenia.15 In the present issue of Acta Psychiatrica Scandinavica, Denissoff et al.16 report the results from a Finnish register-based study documenting that cannabis use in adolescence (15–16 years of age) is a predictor of severe self-harm during 18 years of follow-up (until the age of 33) with hazard ratio (HR) 2.06 (95% confidence interval (CI) 1.07–3.95). The absolute number of suicides in the cohort was low (n=22) and the estimate for the association of cannabis use with death by suicide did not reach statistical significance (HR 2.60; 95% CI 0.77–8.78). The authors linked the Northern Finland Birth Cohort 1986 (including 99% of all births in two provinces in Finland) with nationwide registries to evaluate if self-reported use of cannabis at 15–16 years of age was associated with certain harmful effects including self-harm requiring medical attention or death by suicide. Subjects were only included if they did not have a history of self-harm at baseline, that is 15–16 years. The regression analysis was controlled for sex, psychiatric disorders before age 16, parental psychiatric disorders, frequent alcohol intoxications and other illicit substance use. Cannabis exposure was evaluated as lifetime cannabis use at 15–16 years and in this study operationalized as yes or no. The size of the final sample was 6,582 individuals. Denissoff et al.’s paper16 presents an important contribution to our understanding of long-term risks of cannabis use in adolescence, which is a particularly vulnerable period for potential neurotoxic exposure because of the neural maturation that occurs during this period. The association between adolescent cannabis use and subsequent self-harm (crude analysis HR 3.93; 95% CI 2.24–6.90) was markedly attenuated and thus confounded by frequent alcohol intoxications and other illicit substance use (adjusted HR 2.04; 95% CI 1.07–3.90) in the report by Denissoff et al.16 This raises an awareness of the possibility of residual confounding, that is that the current results might be confounded by unmeasured or unavailable variables associated with both cannabis use and severe self-harm. To examine the question of causality in more detail, a Mendelian randomization study tested the genetic relationships between cannabis use, depression and self-harm. Cannabis use was found to be genetically associated with depression and self-harm, but the study was not powered to confirm the direction of causality.17 The current data from Denissoff et al.16 point to the importance of meticulously collecting data on multiple substance use disorders both in clinical practice and in research settings. A recent systematic review found that heavy alcohol use during adolescence resulted in decreases in cortical thickness, disrupted network efficiency and poorer impulse and attentional control, and that heavy cannabis use was related to decreased subcortical volumes, disrupted functional development and decreased executive functioning in studies with a few years of follow-up.18 Notably, the added effect of co-use of alcohol and cannabis use has not been sufficiently examined yet to provide comprehensive results on the neuropsychiatric effects of concomitant use of cannabis and alcohol.18 Currently, no established consensus on cannabis assessment and classification of use exists, but it has been suggested that good clinical practice should include, at least, assessment of the quantity, frequency and mode of administration, and—if the information is available—an estimate of the content of THC and CBD in the cannabis products being used.19 When considering the legalization of cannabis use it is important to distinguish between recreational and medical use because pros and cons may be differently weighted. Cannabis-based medicines are being investigated for potential therapeutic effects in numerous medical and psychiatric conditions – and may eventually play a role in the treatment of adolescent CUD.12 A new treatment modality to supplement evidence-based psychosocial interventions (ie cognitive behavioural therapy, motivational enhancement therapy, and contingency management) will have significant clinical implications if CUD-associated conditions and consequences (including psychosis) could be prevented. Thus, it is important that local jurisdictions allow clinical research into THC- and CBD-based medicines to continue. On the other hand, legalizing recreational use of cannabis is a more complex issue where the increasing knowledge of short- and long-term mental health risks seems not in favour of such an approach. This viewpoint is emphasized by available evidence suggesting that legalization of previous illicit substances increases the availability; and therefore, the numbers of regular users and people with a use turning into a substance use disorder.19 It has been argued that the legalization of recreational use of cannabis has caused adolescents to perceive cannabis as a less harmful substance and as a consequence increase their use.1 To conclude, the sum of emerging hazards of cannabis use makes it increasingly important that this evidence is acknowledged when planning initiatives to minimize public health harms. Dr. Baandrup has no conflicts of interest. The peer review history for this article is available at https://publons.com/publon/10.1111/acps.13395. Data sharing is not applicable as no datasets were generated or analysed as preparation or part of this article.

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