title: Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system.
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  We 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
  Few 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.
authors.affiliation: GW Pharmaceuticals, Porton Down Science Park, Salisbury, Wiltshire, United Kingdom; Department of Family Medicine, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: McPartland
authors.affiliation: GW Pharmaceuticals, Porton Down Science Park, Salisbury, Wiltshire, United Kingdom.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Guy
authors.affiliation: Endocannabinoid Research Group, Istituto di Chimica Biomoleculare, CNR, Via Campi Flegrei, Pozzuoli, Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000818:Animals; D063388:Endocannabinoids / Q000378:metabolism*; D006801:Humans; D043882:Receptors, Cannabinoid / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D063388:Endocannabinoids; D043882:Receptors, Cannabinoid