Raz Yirmiya Ph.D., Neta Rimmerman, Ph.D.

Ample research demonstrates that the endocannabinoid system as well as phytocannabinoids can modulate stress responsiveness and associated psychopathology, particularly depression and anxiety. However, the precise role cannabinoids in these processes is complex and the mechanisms underlying it are not fully understood. For example, in the few placebo-controlled studies that were previously reported, the effect of cannabis or purified THC were variable, with results including positive effects, no effects or even exacerbation of depression. Furthermore, in animal models of depression, some studies demonstrated that THC and other CB1 stimulators exert antidepressant effects, but treatment with the cannabinoid antagonist Rimonabant was also found to ameliorate depressive-like symptoms.

The inconsistent findings regarding the involvement of endo- and phyto-cannabinoids in depression are not surprising, considering that depression is a complex medical condition, with various etiologies and mechanisms of action. Indeed, we have previously argued that due to this complexity, depression should be treated by a personalized medical approach, identifying subgroups of depressed patients who will benefit from any particular antidepressant procedure (Yirmiya, Rimmerman and Reshef, TiNS, 2015). We further showed that the development of depression in specific animal models is causally associated with either over- or under-activation of inflammatory processes and microglia cells, and therefore should be treated by microglia suppressing or stimulating drugs, respectively.

Cannabinoids are known to exert potent microglia-modulating effects. Therefore, we are currently examining the role of specific cannabinoid-related processes in microglial biology and its contribution to stress responsiveness and depression. For example, we demonstrated that microglia-dependent changes in the expression of Pla2g4e, which regulates the production of anandamide and other endocannabinoids, is involved in the anti-depressive mechanism of action of electroconvulsive therapy. Furthermore, we are using specific models of microglia-dependent depression-like syndromes in mice for developing a cannabinoid-based personalized medical approach to depression.