Abstract
Substance use/abuse is one of the main causes of depressive symptoms. Cannabis and synthetic cannabinoids in particular gained significant popularity in the past years. There is an increasing amount of clinical data associating such compounds with the inflammatory component of depression, indicated by the up-regulation of pro-inflammatory cytokines. Pro-inflammatory cytokines are also well-known to regulate the enzymes of the kynurenine pathway (KP), which is responsible for metabolizing tryptophan, a precursor in serotonin synthesis. Enhanced pro-inflammatory cytokine levels may over-activate the KP, leading to tryptophan depletion and reduced serotonin levels, which can subsequently precipitate depressive symptoms. Therefore, such mechanism might represent a possible link between the endocannabinoid system (ECS) and the KP in depression, via the inflammatory and dysregulated serotonergic component of the disorder. This review will summarize the data regarding those natural and synthetic cannabinoids that increase pro-inflammatory cytokines. Furthermore, the data on such cytokines associated with KP activation will be further reviewed accordingly. The interaction of the ECS and the KP has been postulated and demonstrated in some studies previously. This review will further contribute to this yet less explored connection and propose the KP to be the missing link between cannabinoid-induced inflammation and depressive symptoms.
Highlights
Depression affects more than 264 million people around the world [1] and social, environmental, as well as genetic factors may contribute to its development
This paper summarized pre-clinical and clinical evidence on pro-inflammatory cytokines which are upregulated by natural and synthetic cannabinoids, might be contributing to the inflammatory component of depression induced by such compounds
The investigation on the molecular mechanisms by which cannabinoids could lead to increased inflammatory effects could potentially unravel important targets for controlling neuroinflammation associated with drug abuse and dependence and its emotional consequences
Summary
Depression affects more than 264 million people around the world [1] and social, environmental, as well as genetic factors may contribute to its development. The endocannabinoid system (ECS) and the kynurenine pathway (KP) have long been strongly implicated in this disorder Both systems contribute to the neuroinflammatory and serotonin hypothesis of depression, which will be discussed later on. This review will further support the link between the ECS and KP in the aspect of depression by summarizing the data of pro-inflammatory cytokines, which can be regulated by exogenous cannabinoids and at the same time which can regulate the KP. Pro-inflammatory cytokines, the ECS and KP in general, and regarding their role in depression will be briefly discussed. Reviewing such data will allow a better understanding of the effect of cannabinoids on the neuroinflammatory component of depression
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