Presenter: Ethan Russo, MD

Original Date: July 10, 2016

Several years ago, a concept of clinical endocannabinoid deficiency (CED) was developed, hypothesizing that it might explain the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and some other disorders in which cannabinoid medicines seem to provide unique relief. Certain biochemical evidence and pathophysiological relationships lend credence to the concept.

For example, in migraine, the endocannabinoid, anandamide potentiates 5-HT1A and inhibits 5-HT2A receptors Ananadamide is also tonically active in the periaqueductal gray matter, a migraine generator and key central pain locus. Additionally, fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Idiopathic bowel syndrome has similar features.

The three conditions are frequently co-morbid, and a susceptible patient may progress from one syndrome to others over the course of their lives. Based on this evidence, it was suggested that an underlying clinical endocannabinoid deficiency might be treated successfully and appropriately with cannabinoid medicines. This talk briefly reviews these data, but also highlights recent research that supports the concept:

• Further investigation has demonstrated that anandamide is integral to pathophysiological mechanisms of vascular control, sterile inflammation and central neuropathic pain generation in brainstem structures in the trigeminovascular system (Akerman et al.).
• In female migraineurs, observed increased anandamide degradation in platelets, and reduced serum anandamide levels may explain decreased pain thresholds (Cupini et al.).
• Cerebrospinal fluid samples from migraineurs demonstrate suppression of anandamide levels (Sarchielli et al.).
• The statistically significantly reduced electrically-induced and spontaneous daily pain scores in fibromyalgia patients (Schley et al.).
• Sativex reduces peripheral neuropathic pain and allodynia scores (Numikko et al.).
• Anandamide co-localizes with cholinergic in human colon and inhibit contraction of circular and longitudinal muscle via a non-CB1 mechanism (Smid et al.).

Further approaches to investigating clinical endocannabinoid deficiency including biochemical experiments and clinical trial designs are also presented.

1.0 Pharmacology CEUs approved by OBNM