Abstract
BackgroundThe “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.Methodology/Principal FindingsWe searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the eCB system.Conclusions/SignificanceFew clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.
Highlights
The endocannabinoid system consists of receptors, endogenous ligands, and ligand metabolic enzymes
Cannabinoid receptor 1 (CB1) is the most abundant G protein-coupled receptor expressed in the brain, with dense expression in: the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala [1]
Because this review focuses upon clinical interventions affecting the eCB system, we deemed as irrelevant articles that described the reverse scenario, such as eCB ligands modulating opioid receptors, THC enhancing tobacco or alcohol abuse, etc
Summary
The endocannabinoid (eCB) system consists of receptors, endogenous ligands, and ligand metabolic enzymes. CB1 is expressed in non-neuronal cells, such as adipocytes and hepatocytes, and in musculoskeletal tissues. Cannabinoid receptor 2 (CB2) is principally associated with cells governing immune function, it may be expressed in the central nervous [2,3]. The quintessential eCB ligands are N-arachidonylethanolamide (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). AEA and 2-AG are released upon demand from cell membraneembedded phospholipid precursors. The ‘‘classic’’ endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation
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