This research update underscores the need to be well versed in the data in order to have meaningful conversations with our patients who are cannabis users or contemplate use.
Affective disorders are among the most debilitating psychiatric conditions and afflict 20% of the population while contributing to significant morbidity and mortality.1 The association between cannabis use and unipolar depression has been well documented, as individuals with cannabis dependence are almost three times more likely to suffer from depressive disorders than the general population.2 Those with depressive conditions are in turn twice as likely to use cannabis than the general population.3 In patients with bipolar depression, much of the same is true.4
In one longitudinal study by Henquet and colleagues,5 cannabis use at baseline predicted an increased risk of manic symptoms at the three-year follow-up. There is now also evidence from longitudinal population-based studies that suggest long-term cannabis use is associated with increased risk of suicidal ideation, suicide attempt, and death by suicide in a dose-dependent manner.6
According to the National Academy of Sciences, Engineering, and Medicine report,7 which summarizes the most comprehensive state of evidence regarding the health impacts of cannabis, there is a moderate level of evidence to support that cannabis use is associated with increased risk of developing depressive disorders; increased incidence of suicidal ideation and behavior (attempts as well as completion, particularly in heavy users); and increased symptoms of mania and hypomania in users with bipolar disorder. Limited evidence from statistical association raises concern that cannabis use increases the likelihood of developing bipolar disorder.8
The role of the endocannabinoid system has been of interest since the 1990s when it was first discovered. A reduction in serum levels of 2-arachidonoylglycerol, one of the endocannabinoids, has been noted in females diagnosed with major depressive disorder.9 Postmortem studies have also demonstrated variabilities in cannabinoid receptor type 1 density and mRNA levels in the dorsolateral prefrontal cortex of those with depression who died by suicide.10 There is abundant further evidence to support that deficiency and overall dysregulation in endocannabinoid signaling is implicated in the pathophysiology of affective disorders.
The only randomized controlled trials of cannabinoids in humans for affective disorders are rather limited and date back to the 1970s.11,12 Here the investigators attempted to use oral tetrahydrocannabinol (THC) only in the treatment of unipolar and bipolar depressive disorders. Not only was there a complete failure of an antidepressant response, but also poor tolerability was demonstrated in the form of dysphoric, psychotic, and anxiety reactions.
In a study by Kotin and colleagues,11 eight psychotropic-free hospitalized patients (four with bipolar depression and four with unipolar major depression) received under double blind conditions a seven-day course of placebo, followed by a seven-day course of twice daily oral THC 0.3 mg/kg, and then seven days of placebo. There was a 50% dropout during the THC treatment phase due to adverse effects such as severe anxiety attacks and depersonalization presenting as early as the first dose.
In a study by Ablon and Goodwin,12 13 hospitalized patients (five with bipolar depression and eight with unipolar major depression) were observed for 3 weeks and subsequently received, under double blind conditions, either oral THC titrated from 5 mg daily up to 20 mg twice daily or placebo. Seven participants experienced dysphoric reactions and six had to drop out due to panic reactions or psychotic disturbances, which occurred as early as the first dose.
Clinical bottom line
There is much to be learned about the exact implication of the endocannabinoid system in mental health symptoms and overall clinical conditions. However, the current body of available knowledge certainly suggests involvement. Although the majority of data provide mere association, if one accepts the implied bidirectional relationship, there is significant concern of harm in individuals with affective disorders and cannabis use should be discouraged.
Although a better understanding of the endocannabinoid system may unveil pharmacotherapeutic targets, this is likely years away. To expedite this, pharmaceutical-grade cannabinoids are now available and should be utilized in furthering such research.
At this point, all organizations for mental health have issued warnings discouraging endorsement of cannabis use in general, as well as for attempts at management of any mental health clinical conditions. As clinicians, we need to be well versed with the above data in order to have meaningful conversations with our patients who are cannabis users or contemplate use.
Dr Stanciu is Assistant Professor of Psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. Dr Teja is a PGY-4 General Psychiatry Resident at Dartmouth’s Geisel School of Medicine, Hanover, NH. The authors report no conflicts of interest concerning the subject matter of this article.
1. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382:1575-1586.
2. Compton WM, Grant BF, Colliver JD, et al. Prevalence of marijuana use disorders in the United States: 1991-1992 and 2001-2002. JAMA. 2004;291:2114–2121.
3. Pacek LR, Weinberger AH, Zhu J, Goodwin RD. Rapid increase in the prevalence of cannabis use among people with depression in the United States, 2005–17: the role of differentially changing risk perceptions. Addiction. 2019 Dec 4 [Epub ahead of print].
4. Lev-Ran S, Roerecke M, Le Foll B, et al. The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies. Psychol Med. 2014;44:797-810.
5. Henquet C1, Krabbendam L, de Graaf R, et al. Cannabis use and expression of mania in the general population. J Affect Disord. 2006;95:103-110.
6. Borges G, Bagge CL, Orozco R. A literature review and meta-analyses of cannabis use and suicidality. J Affect Disord. 2016;195:63-74.
7. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: National Academies Press; 2017.
8. Cousijn J, NÃºÃ±ez AE, Filbey FM. Time to acknowledge the mixed effects of cannabis on health: a summary and critical review of the NASEM 2017 report on the health effects of cannabis and cannabinoids. Addiction. 2018;113:958-966.
9. Hill MN, Miller GE, Ho WS, et al. Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry. 2008;41:48-53.
10. Hungund BL, Vinod KY, Kassir SA, et al. Unpregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Mol Psychiatry. 2004;9:184-190.
11. Kotin J, Post RM, Goodwin FK. Î9-tetrahydrocannabinol in depressed patients. Arch Gen Psychiatry. 1973;28:345-348.
12. Ablon SL, Goodwin FK. High frequency of dysphoric reactions to tetrahydrocannabinol among depressed patients. Am J Psychiatry. 1974;131:448-453.