Plant cannabinoids and the endocannabinoid system have been mentioned as both risk factors for the development of depression and potential therapeutic targets for the treatment of depression.

In animal models for depression (forced swimming test, tail suspension test), Δ9THC showed anti-depressant properties at a dose of 2.5 mg/kg (El-Alfy et al., 2010). Similarly, CBD (200 mg/kg) and CBC (20 mg/kg) displayed significant anti-depressant activity. The anti-depressant effects of the different cannabinoids display different dose-dependency and are probably reached through different receptors. This indicates that the anti-depressant mechanism of action of various cannabinoids is complex, synergistic and probably depends on an entourage effect. CBG and CBN showed no anti-depressant potential in this study.

Another study found that CBG can activate α2 receptors and block CB1 and 5-HT1A receptors (Cascio et al., 2010), suggesting CBG does have therapeutic potential in the treatment of depression.

In rats, 10-60 nMol injected CBD straight into the prefrontal cortex reduced depressive behavior, possibly through 5-HT1A (Sartim et al., 2016). 

Exercise has been shown to be beneficial in neurological disorders like Alzheimer’s disease and depression. Exercise increases the production of new neurons in the hippocampus in rats. In addition, Anandamide levels (and to a lesser degree 2AG levels) and CB1 receptor availability are increased in the hippocampus (but not in the prefrontal cortex). Blocking the endocannabinoid system prevents the production of new neurons suggesting a role for cannabinoids in this process (Hill et al., 2010).

In a mouse model of depression, chronic unpredictable mild stress causes depression-like behavior, atrophy of hippocampus and frontal cortex and increases corticosterone levels. Oral application of OEA (1.5 – 6 mg/kg) reverted these effects suggesting therapeutic potential for OEA in the treatment of depression (Jin et al., 2015).  

References:

Cascio, M.G., Gauson, L.A., Stevenson, L.A., Ross, R.A., and Pertwee, R.G. (2010). Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br. J. Pharmacol. 159, 129–141.

El-Alfy, A.T., Ivey, K., Robinson, K., Ahmed, S., Radwan, M., Slade, D., Khan, I., ElSohly, M., and Ross, S. (2010). Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Pharmacol. Biochem. Behav. 95, 434–442.

Hill, M.N., Titterness, A.K., Morrish, A.C., Carrier, E.J., Lee, T.T.-Y., Gil-Mohapel, J., Gorzalka, B.B., Hillard, C.J., and Christie, B.R. (2010). Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus 20, 513–523.

Jin, P., Yu, H.-L., Tian-Lan, null, Zhang, F., and Quan, Z.-S. (2015). Antidepressant-like effects of oleoylethanolamide in a mouse model of chronic unpredictable mild stress. Pharmacol. Biochem. Behav. 133, 146–154.

Sartim, A.G., Guimarães, F.S., and Joca, S.R.L. (2016). Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex - possible involvement of 5-HT1A and CB1 receptors. Behav. Brain Res.