In persons <25 years old, greater cannabis use is associated with more psychological symptoms, especially among those with a predisposition or existing vulnerability to such outcomes (Oxford Centre for Evidence-Based Medicine level 3 or 4). Policy makers need to consider the adverse effects of cannabis use in youth when planning a public health approach to cannabis legalization.

Of the 534 citations identified through the literature search, 23 met the eligibility criteria and were included in this review. With psychosis as the outcome, all except one study found that earlier cannabis use was generally associated with higher risks. With depression/anxiety as the outcome, 6 of the 11 included studies reported findings indicating that earlier use of cannabis was linked to higher symptom levels.

We conducted a systematic review of articles published prior to March 2018 by searching OVID MEDLINE, PsycINFO, EMBASE, and the references of included studies. We included comparative studies (cohort, case-control, cross-sectional) that reported on cannabis use in persons <25 years of age (exposure) and symptoms of psychosis, depression, or anxiety (outcome). We narratively synthesized the studies according to design (cohort, etc.) and psychiatric outcome. We used the Newcastle-Ottawa Scale to assess risk of bias.

This study was conducted to review the current state of evidence on the association between age of initiation of cannabis use and symptoms of psychosis, depression, or anxiety among youth under 25 years of age.

Cannabis is the most commonly used drug in the world following tobacco and alcohol.1 Among Canadians aged 15 years and older, an estimated 43% have used cannabis in their lifetime.2 According to the United Nations Office on Drugs and Crime,3 the number of people using cannabis is rising and is estimated to be between 142.6 to 190.3 million globally. Furthermore, the prevalence of its use is very high among youth aged 25 years or younger.4

The prevalence of cannabis use among adolescents has caused concerns regarding its potential effects on mental health and psychiatric morbidity. Some studies have suggested that adolescent cannabis use might have long-term impacts on various neurotransmitter systems,5 possibly leading to psychotic,6 depressive, and anxiety symptoms.6,7

Canada has undertaken a policy process to legalize and regulate cannabis nationally, beginning October 17, 2018. Different jurisdictions have recommended different minimum ages for cannabis use. Considerations for establishing a minimum age include health protection; the age should be set above the exposure threshold that is associated with higher than average risks of disease.

To our knowledge, no previous study has synthesized the literature on the association between cannabis use among youth and mental health outcomes to inform policy on the minimum age for cannabis use. To address these gaps and inform health policy, this study was conducted to review the published literature on cannabis use and psychosis, depression, and anxiety outcomes among youth younger than 25 years.

Methods Study Objective This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines8 and included studies meeting the following eligibility criteria (see online appendix). Types of studies: Cohort, cross-sectional, and case-control.

Length of follow-up: No restriction.

Types of participants: Cannabis-using adolescents (aged 12-17 years) and young adults (aged 18-25 years) or studies that dichotomized age of initiation of cannabis use (i.e., <18 years vs. ≥18 years [no upper age limit]) to compare early versus late initiation regardless of the source population.

Types of exposure: Cannabis use of any frequency, potency, amount, and duration during adolescence or young adulthood (<25 years).

Types of outcome: Psychosis, depression, or anxiety symptoms or disorders, using any method of diagnosis.

Timing: No restriction on length of follow-up.

Setting: No restriction on the setting of the study (e.g., community based, school based, hospital based).

Language: Restricted to English-language studies. Search Strategy We searched the following databases from inception to March 2018: MEDLINE (OVID interface, 1946 onwards), EMBASE (OVID interface, 1974 onwards), and PsycINFO (OVID interface, 1806 onwards). Search Our literature search criteria were developed with the help of a medical librarian. The following search terms were used to search the databases: cannabis, marijuana abuse, marijuana smoking, depression, depressive disorders, anxiety, anxiety disorders, psychosis, psychotic disorders, schizophrenia, age and initiation, and age at onset (see online appendix). Study Selection Two independent raters used the eligibility criteria to screen the retrieved citations at 1) title/abstract and 2) full text. The following information was extracted from each included study: details (i.e., author, year), sample characteristics (i.e., age, sex), design, exposures, outcomes, and covariates included in analyses. Any disagreements were resolved by a third rater, who brought the original raters together to discuss discrepancies and reach consensus. Risk of bias was assessed by one rater using the Newcastle-Ottawa Scale9 (see online appendix). In this review, the beta coefficients are from linear regression models, and as such, they represent differences in means, whereas in log-transformed models, the exponentiated coefficients (e.g., hazard ratio [HR], odds ratio [OR], adjusted OR [aOR]) have been reported.

Discussion Many of the included studies provided evidence of an association between cannabis use prior to age 25 years and psychotic outcomes, especially among youth with preexisting vulnerabilities. The subset of studies comparing different ages of initiation of cannabis use27,29 did not show that early onset cannabis use by itself is sufficient to precipitate psychotic illness. Rather, early onset use is one component of an interrelated system wherein a combination of different genetic dispositions and environmental factors coalesces to produce psychotic symptoms.33 Following the Oxford Centre for Evidence-Based Medicine Levels of Evidence,34 the level of evidence from the included studies falls between levels 3 and 4, which corresponds to low evidence for using the findings to suggest a minimum age for cannabis use. Our results indicated a less clear link between adolescent cannabis use and depression. Cannabis use may adversely influence educational attainment, employment status, and relationships, as well as indirectly affect depressive symptoms through changes in these factors. The relationship between cannabis use and anxiety symptoms appears more complex, with some findings suggesting that cannabis use may be associated primarily with acute and short-term anxiety symptoms.35 However, in the long run, some individuals may use cannabis to cope with anxiety. The level of evidence from the included studies regarding the depression/anxiety as the study outcome also falls between levels 3 and 4 corresponding to a low evidence level for using the results to recommend a minimum age for cannabis use. Limitations of Existing Studies The included studies demonstrated heterogeneity in methods and recruitment that limited our ability to draw an overall set of clear conclusions. Few studies measured cannabis exposure among early users in great detail (i.e., onset, type, frequency, potency, amount, duration), which is crucial to understanding whether and how cannabis use influences mental health symptoms. The included studies occasionally omitted important confounding factors such as concomitant tobacco, alcohol, or other drug use; medical or mental health comorbidities; and other psychosocial factors (e.g., substance-using peers).21,23,24,29 The retrospective measures employed by many of the studies prevented one from teasing apart the effect of cannabis use at an early age from cumulative exposure to cannabis over time. All of the included studies used self-report measures of cannabis use, which could lead to underestimates of true effects due to social desirability and recall bias (particularly in studies with military conscripts with more severe recall bias). Last, the cross-sectional nature and lack of adequate follow-up periods of 10 (7 cross-sectional and 3 case-control) of the studies prevented us from accurately assessing the temporal relationship between early onset cannabis use and psychiatric outcomes. Finally, we did not perform a meta-analysis because the included studies were heterogeneous in terms of source populations and samples, lengths of follow-up, and measures of exposure and outcome. A meta-analysis was further precluded because many studies did not report between-group data regarding the mean scores of outcome measures (psychosis, depression, anxiety) across different exposure groups (i.e., young cannabis users and nonusers). Future Directions To improve our understanding of the relation between onset of cannabis use prior to age 25 years and psychiatric outcomes, future research needs to use rigorous and prospective methodological designs. These designs need to control for confounding elements (e.g., psychiatric comorbidities; family history of psychiatric disorders; type, quantity, duration, and frequency of cannabis use; multisubstance use) to further assist our understanding of various aspects of cannabis use that may or may not be related to each of these mental health effects. Furthermore, more specific prospective clinical studies, such as the Saguenay Youth Study (SYS) in Canada36 and the Adolescent Brain and Cognitive Development (ABCD) study in the United States,37 can be used to study the specific elements of cannabis use that may be associated with psychiatric conditions among youth. Cohort studies that actively recruit youth at the start of their teenage years and follow them over time would be ideal. These participants would have to have no known psychiatric illness at the time of recruitment. Follow-up could persist for at least a decade and exposure assessment would involve a combination of tetra-hydro-cannabinol (THC) measures and self-report. These studies would be quite expensive and time-consuming, though, and the data would not be available to inform clinical practice and health policy for some time. In the absence of existing studies with such an optimal design, clinicians and policy makers should be aware of the limitations of current research. From a policy perspective, more work needs to be done to recognise the predisposing risk factors related to illicit cannabis use, reasons for the induction of cannabis use, and the directness of a link between cannabis use and psychiatric symptomatology.

Acknowledgement We thank Jackie Stapleton for devising the literature search strategy and assisting with the literature search itself. We also thank Advina Kamaric and Bradley Bonitatibus for assisting with article screening. The data used in the review can be found in the evidence table in the online appendix.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD

Mark Oremus, PhD https://orcid.org/0000-0001-8190-253X Supplemental Material

Supplemental material for this article is available online.