A study from the University of Rome is helping researchers understand the connection between endocannabinoids in the blood and major depressive disorder (MDD).  Previous research [2,3] has resulted in conflicting statements as to which, if any, endocannabinoids were involved in depression. However, based on the localization of cannabinoid 1 receptors (CB1) in the brain as well as past research [2,3] suggesting that depression is connected to dysregulation of the endocannabinoid system, further research was needed.
This study  aimed to investigate the blood plasma levels of the most abundant endocannabinoids, N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), in both healthy patients (N=12) and MDD outpatients not currently on anti-depressants (N=12). Further, the researchers aimed to investigate how blood plasma levels of endocannabinoids were affected after the anti-depressant escitalopram (10 mg/day) was given to patients. Escitalopram is a selective serotonin reuptake inhibitor (SSRI); monitoring the effects of this drug on endocannabinoid levels could help determine if endocannabinoids are regulated by serotonergic transmission or by other mechanisms.
The baseline levels of endocannabinoids taken on the first day of this study, before any treatments were given, showed no significant difference between the control subjects and the MDD subjects. However, as the study progressed, a significant inverse correlation between 2-AG and the severity of patients’ depressive symptoms became apparent. As plasma 2-AG levels dropped, patients felt more severely depressed. Treatment with the anti-depressant escitalopram did not alter the levels of endocannabinoids in patients with MDD although their subjective perception of the depressive symptoms did improve on the medication.
These data suggest that 2-AG, which is more abundant than AEA in the central nervous system, may alleviate the symptoms of depression through unknown mechanisms. Further, people who suffer from MDD may have altered regulation of endocannabinoid production in their body. Lastly, because escitalopram is an SSRI and did not alter plasma endocannabinoid levels, it is suggested that the endocannabinoid system is not regulated through serotonin-mediated mechanisms. 
As the ECS becomes more of an attractive target for new anti-depressant medications, it will be necessary to further understand how levels of endocannabinoids change with disease states and gain a deeper understanding of the mechanisms by which it is regulated.
- Bersani G, et al. Inverse correlation between plasma 2-arachidonoylglycerol levels and subjective severity of depression. Human Psychopharmacology. 2021; e2779. https://doi.org/10.1002/hup.2779. Times cited = n/a, Journal Impact Factor = 2.112
- Hungund BL, et al. Upregulation of CB1 receptors and agonist-stimulated [35S] GTPyS binding in the prefrontal cortex of depressed suicide victims. Molecular Psychiatry. 2004;9(2):184-190. Times cited = 181 (Semantic Scholar), Journal Impact Factor = 12.384
- Hill MN, et al. Serum endocannabinoid content is altered in females with depressive disorders: A preliminary report. Pharmacopsychiatry. 2008;41(2):48-53. Times cited = 182 (Semantic Scholar), Journal Impact Factor = 4.340