Epigenetic effects of cannabis: A systematic scoping review of behavioral and emotional symptoms associated with cannabis use and exocannabinoid exposure.

BACKGROUND: Recent research suggests that epigenetic modifications may mediate the behavioral effects of cannabis, influencing exocannabinnoids' long term effects in cognitive function and its role in the emergence of psychotic symptoms. BASIC PROCEDURES: In this systematic scoping review, we assessed the current evidence of epigenetic effects associated with the use of cannabis or exocannabinoid administration and their relationship with behavioral and emotional symptoms. We searched PubMed, Cochrane CENTRAL, and Web of Science, up to January 2022, using the terms "cannabis" and "epigenetics." The search yielded 178 articles, of which 43 underwent full article revision; 37 articles were included in the review. MAIN FINDINGS: The gathered evidence included observational cross-sectional studies conducted on human subjects and experimental designs using animal models that conveyed disparity in administration dosage, methods of cannabis use assessment and targeted epigenetic mechanisms. Nine studies performed epigenome-wide analysis with identification of differentially methylated sites; most of these studies found a global hypomethylation, and enrichment in genes related to cellular survival and neurodevelopment. Other studies assessed methylation at specific genes and found that cannabis exposure was associated with reduced methylation at Cg05575921, DNMT1, DRD2, COMT, DLGAP2, Arg1, STAT3, MGMT, and PENK, while hypermethylation was found at DNMT3a/b, NCAM1, and AKT1. CONCLUSIONS: The review found evidence of an exocannabinoid-induced epigenetic changes that modulate depressive-anxious, psychotic, and addictive behavioural phenotypes. Further studies will require dosage exposure/administration uniformization and a customized pool of genes to assess their suitability as biomarkers for psychiatric diseases.

Potential Mechanisms Influencing the Inverse Relationship Between Cannabis and Nonalcoholic Fatty Liver Disease: A Commentary.

Nonalcoholic fatty liver disease (NAFLD) develops when the liver is unable to oxidize or export excess free fatty acids generated by adipose tissue lipolysis, de novo lipogenesis, or dietary intake. Although treatment has generally been centered on reversing metabolic risk factors that increase the likelihood of NAFLD by influencing lifestyle modifications, therapeutic modalities are being studied at the cellular and molecular level. The endocannabinoid system has been of recent focus. The agonism and antagonism of cannabinoid receptors play roles in biochemical mechanisms involved in the development or regression of NAFLD. Exocannabinoids and endocannabinoids, the ligands which bind cannabinoid receptors, have been studied in this regard. Exocannabinoids found in cannabis (marijuana) may have a therapeutic benefit. Our recent study demonstrated an inverse association between marijuana use and NAFLD among adults in the United States. This commentary combines knowledge on the role of the endocannabinoid system in the setting of NAFLD with the findings in our article to hypothesize different potential mechanisms that may influence the inverse relationship between cannabis and NAFLD.

Mechanistic Potential and Therapeutic Implications of Cannabinoids in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is comprised of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). It is defined by histologic or radiographic evidence of steatosis in the absence of alternative etiologies, including significant alcohol consumption, steatogenic medication use, or hereditary disorders. NAFLD is now the most common liver disease, and when NASH is present it can progress to fibrosis and hepatocellular carcinoma. Different mechanisms have been identified as contributors to the physiology of NAFLD; insulin resistance and related metabolic derangements have been the hallmark of physiology associated with NAFLD. The mainstay of treatment has classically involved lifestyle modifications focused on the reduction of insulin resistance. However, emerging evidence suggests that the endocannabinoid system and its associated cannabinoid receptors and ligands have mechanistic and therapeutic implications in metabolic derangements and specifically in NAFLD. Cannabinoid receptor 1 antagonism has demonstrated promising effects with increased resistance to hepatic steatosis, reversal of hepatic steatosis, and improvements in glycemic control, insulin resistance, and dyslipidemia. Literature regarding the role of cannabinoid receptor 2 in NAFLD is controversial. Exocannabinoids and endocannabinoids have demonstrated some therapeutic impact on metabolic derangements associated with NAFLD, although literature regarding direct therapeutic use in NAFLD is limited. Nonetheless, the properties of the endocannabinoid system, its receptors, substrates, and ligands remain a significant arena warranting further research, with potential for a pharmacologic intervention for a disease with an anticipated increase in economic and clinical burden.