Major depressive disorder (MDD) is a psychiatric condition characterized by continuous low mood and loss of interest or pleasure in enjoyable activities. The past-year prevalence of MDD has been estimated to be 4.7% globally and it is considered as one of the most severe mood disorders (Ferrari et al. 2013), associated with high mortality due to suicide and a major func- tional impairment caused directly and indirectly. In 2010, MDD was the most disabling mental disorder worldwide, accounting for more than 40% of the disability-adjusted life years (a combination of premature mortality and dis- ability) caused by mental illness (Whiteford et al. 2013). Therefore, extensive effort has been made throughout the years in order to identify risk factors associated with the onset of MDD and its clinical course, including the literature published concerning the effect of substance use and sub- stance use disorders (Moore et al. 2007; Whiteford et al. 2013).
Following tobacco and alcohol, cannabis is the most commonly used addictive substance, with the estimated worldwide past-year prevalence rate of 3–4.5% (Degenhardt et al. 2011; United Nations Office on Drugs and Crime 2012). The number of cannabis users continues to increase globally by roughly 16% between 2006–2016, currently estimated at around 190 million world- wide (WHO 2016). In accordance with an incline in the number of cannabis users, the prevalence of the past-year diagnostic and statistical manual of mental disorders (DSM)-IV cannabis use disorder (i.e. cannabis abuse or cannabis dependence) was 1.4% and 8.5% in 2005 (Stinson et al. 2006), while in 2013, the prevalence of DSM-5 cannabis use disorder (CUD) was 2.54% (Hasin et al. 2016).In this chapter, we will first review evidence on the co-occurrence of depression and cannabis use reported in cross-sectional studies. We will then present data on the longitudinal association between cannabis use and depression, exploring two inverse causal pathways. We will then review the possible contribution of age and gender to the association between cannabis use and depression, as well as newly emerging evidence on possible genetic and neurological factors that may under- line this association. Finally, we will review the preclinical and clinical evidence for the use of cannabis as an antidepressant, and pharmacologi- cal treatment for comorbid cannabis use disorder and depression.
5.2 Co-Occurrence of Cannabis Use and Depression
5.2.1 Cannabis Use among Individuals with Depression
With a growing number of studies reporting on the co-occurrence of cannabis use and depression, Degenhardt et al. (2003) concluded in an early review that “there is increasing evidence that regular cannabis use and depression occur together more often than we might expect by chance” (p. 1497). Results from the United States National Comorbidity Survey have indicated that more than half of the individuals with MDD reported lifetime use of cannabis (Chen et al. 2002). Data from the national epidemiological survey on alcohol and related conditions (NESARC) focusing on adults with past-year MDD or dysthymia (N 1⁄4 6534) have indicated that the past-year prevalence of cannabis use among these individuals was 10%, with nearly equally distributed between regular users (those using cannabis at least once a week; 4.5%) and occasional users (using less than weekly; 5.4%) (Aspis et al. 2015). According to data from the National Survey on Drug Use and Health, the past-year prevalence of cannabis use among adolescents with depression was substantially higher compared to adult population, estimated at 25%, compared to only 12% among those without depression (SAMHSA 2007).
Concerning the co-occurrence of MDD and CUDs, a recent study encompassing more than 28,000 cannabis users indicated that past year major depressive episode was associated with the increased number of DSM-IV cannabis dependence criteria, regardless of cannabis fre- quency of use (Dierker et al. 2018). In this study, participants with depression were signifi- cantly more likely to use cannabis than they intended to and spent much time on acquiring cannabis, using it or recovering from the effect of cannabis use compared to those without depression. They were also more likely to have continued to use cannabis despite negative consequences, repeatedly failed in efforts to stop or reduce cannabis use, have important activities in life superseded by cannabis use and needed an increasing amount of cannabis in order to obtain its effect.
5.2.2 Depression among Cannabis Users
According to data from the Epidemiologic Catch- ment Area study, more than half of the individuals who qualify for a lifetime diagnosis of DSM-IV CUD had a concurrent diagnosis of mental illness (Regier et al. 1990). According to a Dutch survey, the three-year incidence of MDD among cannabis users was 11.7% compared to 5% among nonusers (Van Laar et al. 2007). Data from NEASRC indicated that lifetime and past-year CUD were associated with a nearly three-fold increase in the risk for the past-year diagnosis of MDD (Odds Ratio (OR) 1⁄4 2.8, 95% Confidence Interval (CI) 1⁄4 2.33–3.41 for past-year use, and OR 1⁄4 2.6, 95% CI 1⁄4 2.26–2.95 for lifetime use) (Hasin et al. 2016). Odds for concurrent MDD were even higher among adolescents, with a study among 14–17 years old Europeans indicating that the lifetime prevalence of MDD was higher among individuals with lifetime cannabis use (OR 1⁄4 2.7, 95% Confidence Interval (CI) 1⁄4 1.6–4.4) and those with lifetime CUD (OR 1⁄4 4.7, 95% CI 1⁄4 2.3–9.4) compared to those who did not use cannabis (Wittchen et al. 2007).In conclusion : Cross-sectional studies have indicated that depression and cannabis use tend to co-occur.
5.3 Cannabis Use and Depression: Longitudinal Evidence
Longitudinal studies allow for further interpreting the cross-sectional association between cannabis use and depression by addressing two inverse temporal hypotheses. The first addresses the extent to which cannabis use is associated with a future onset of MDD or an incline in depressive symptoms.