PMC:3951193 / 83533-85446 JSONTXT

{"project":"2_test","denotations":[{"id":"24622769-20729846-95790496","span":{"begin":1196,"end":1199},"obj":"20729846"}],"text":"Conclusions\nMany randomized controlled trials identified in this systematic review have been conducted on lifestyle modifications (e.g., exercise, maintenance of ideal body weight) and CAM interventions (e.g., dietary supplements, stress modification, acupuncture, massage and manipulation). In our opinion these are sensible methods of enhancing the eCB system.\nPreclinical studies identified useful prescription drugs, such as SSRIs, anxiolytics, antipsychotics, and anticonvulsants. However, these drugs are generally administered in a chronic fashion, and this comes with a caveat: generating chronic elevations in AEA and 2-AG may be counterproductive. Faced with constant activation by agonists, CB1 and CB2 desensitize and downregulate. A desensitized receptor drives less receptor-mediated signal transduction, and develops cross-tolerance to all agonists—eCBs and phytocannabinoids alike. A downregulated receptor is not functional—either it does not bind ligand or has internalized away from the cell membrane.\nThe difference between acute and chronic augmentation has been demonstrated in rodent studies: acute blockade of MAGL with JZL184 elevated 2-AG levels and provided analgesia [324]. In the face of chronic blockade with JZL184 this analgesia was lost, because sustained elevation of 2-AG caused CB1 desensitization. This led to a loss in eCB-dependent synaptic plasticity, cross-tolerance to other cannabinoids, and physical dependence.\nOther drugs identified in preclinical studies have side effect profiles too severe to warrant their use for upregulating the eCB system (e.g., corticosteroids, opioids, nicotine). Preclinical studies suggest a number of over-the-counter medications, such as analgesics, seem to be acting through eCB-mediated mechanisms. Clinical trials are warranted, although over-the-counter medications lack patent protection, so expensive clinical trials seem unlikely."}