Intertwined associations between oxidative and nitrosative stress and endocannabinoid system pathways: Relevance for neuropsychiatric disorders

Prog Neuropsychopharmacol Biol Psychiatry. 2022 Mar 2;114:110481. doi: 10.1016/j.pnpbp.2021.110481. Epub 2021 Nov 24.


The endocannabinoid system (ECS) appears to regulate metabolic, cardiovascular, immune, gastrointestinal, lung, and reproductive system functions, as well as the central nervous system. There is also evidence that neuropsychiatric disorders are associated with ECS abnormalities as well as oxidative and nitrosative stress pathways. The goal of this mechanistic review is to investigate the mechanisms underlying the ECS's regulation of redox signalling, as well as the mechanisms by which activated oxidative and nitrosative stress pathways may impair ECS-mediated signalling. Cannabinoid receptor (CB)1 activation and upregulation of brain CB2 receptors reduce oxidative stress in the brain, resulting in less tissue damage and less neuroinflammation. Chronically high levels of oxidative stress may impair CB1 and CB2 receptor activity. CB1 activation in peripheral cells increases nitrosative stress and inducible nitric oxide (iNOS) activity, reducing mitochondrial activity. Upregulation of CB2 in the peripheral and central nervous systems may reduce iNOS, nitrosative stress, and neuroinflammation. Nitrosative stress may have an impact on CB1 and CB2-mediated signalling. Peripheral immune activation, which frequently occurs in response to nitro-oxidative stress, may result in increased expression of CB2 receptors on T and B lymphocytes, dendritic cells, and macrophages, reducing the production of inflammatory products and limiting the duration and intensity of the immune and oxidative stress response. In conclusion, high levels of oxidative and nitrosative stress may compromise or even abolish ECS-mediated redox pathway regulation. Future research in neuropsychiatric disorders like mood disorders and deficit schizophrenia should explore abnormalities in these intertwined signalling pathways.

Keywords: Endocannabinoid system; Inflammation; Major depression; Mood disorders; Oxidative and nitrosative stress; Psychiatry; Schizophrenia.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain
  • Endocannabinoids / metabolism*
  • Humans
  • Inflammation
  • Mental Disorders* / metabolism
  • Mental Disorders* / physiopathology
  • Mitochondria / metabolism
  • Nitric Oxide / metabolism
  • Nitrosative Stress / physiology*
  • Oxidation-Reduction
  • Oxidative Stress / physiology
  • Receptor, Cannabinoid, CB1 / physiology
  • Receptor, Cannabinoid, CB2 / physiology
  • Signal Transduction*


  • Endocannabinoids
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Nitric Oxide