Depression risk rises with cannabis exposure in the developing brain

Epidemiology suggests long-term cannabis use during adolescence increases risk of later depression and suicidal ideation, even when controlling for comorbid conditions. Causation is plausible given growing evidence that cannabinoids interact with brain systems regulating mood.

Long-term cannabis use in adolescence may increase the risk of depression and suicidality in young adulthood, according to a major meta-analysis conducted by Gabriella Gobbi (McGill University, Montréal, Québec, Canada) and colleagues,presented at CINP 2021 Virtual.

The association between cannabis use and subsequent depression is clear even in the absence of premorbid conditions and family history.

Compared with non-users, the odds ratio (OR) that cannabis users aged 13-18 years develop depression when aged 21-30 years is 1.37. The OR for suicidal ideation is 1.5, and for a suicide attempt 3.46. In contrast, adolescent cannabis use does not relate to anxiety in young adulthood.

Cannabis use in adolescence increases by 37% the risk of depression in young adulthood and doubles the risk of suicidal ideation


 A small risk multiplied by millions

In her plenary address, Professor Gobbi argued that the epidemiology is clear. The effect sizes are modest. But adolescent cannabis use is so common that the number of cases of depression in the population which can be attributed to it is enormous.

The adolescent brain is still developing, and this may account for its vulnerability, she suggested.

Although difficult to establish from epidemiology, a causal connection is made more likely by recent understanding of cannabinoid effects on neurobiology and animal models, she continued.

Cannabinoids affect brain areas and neurotransmitters regulating mood


Neurobiology suggests causal connection is likely

Electrophysiological experiments in rats show that cannabinoids interact directly with the serotoninergic system.2 While in the short-term cannabinoids enhance serotonin activity,2 long-term exposure of adolescent animals decreases serotonergic firing. This is accompanied by induction of a depression-like state.3-5

THC can cause “behavioral despair” in the forced-swim test, and anhedonia -- evidenced by a reduction in the preference for sucrose over water -- in adolescent but not adult rats.

In the clinical context, a causal connection is supported by the fact that depression improves if patients stop using cannabis. 6

In treating cannabis use disorder, an exciting development is randomized controlled trial evidence that an inhibitor of fatty acid amide hydrolase, an enzyme that degrades the endocannabinoid anandamide, reduces cannabis withdrawal and dependence.7


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Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.


1. Gobbi G et al. JAMA Psychiatry 2019;76(4):426-434

2. Bambico FR et al. J Neuroscience 2007;  27 (43) 11700-11711

3. Bambico FR et al. Neurobiol Dis 2010;37(3):641-55

4. Rubino T et al. Neuropsychopharmacology 2008;33:2760–2771

6. De Gregorio D  et al. Int J Neuropsychopharmacol 2020 ;23(11):751-761

7. Moitra E et al. Depress Anxiety 2016;33(4):332-8

8. D’Souza DC et al. Lancet Psychiatry 2019; 6:35-45