Endocannabinoid System and Migraine Pain: An Update

Abstract

The trigeminovascular system (TS) activation and the vasoactive release from trigeminal endings, in proximity of the meningeal vessels, are considered two of the main effector mechanisms of migraine attacks. Several other structures and mediators are involved, however, both upstream and alongside the TS. Among these, the endocannabinoid system (ES) has recently attracted considerable attention. Experimental and clinical data suggest indeed a link between dysregulation of this signaling complex and migraine headache. Clinical observations, in particular, show that the levels of anandamide (AEA)—one of the two primary endocannabinoid lipids—are reduced in cerebrospinal fluid and plasma of patients with chronic migraine (CM), and that this reduction is associated with pain facilitation in the spinal cord. AEA is produced on demand during inflammatory conditions and exerts most of its effects by acting on cannabinoid (CB) receptors. AEA is rapidly degraded by fatty acid amide hydrolase (FAAH) enzyme and its levels can be modulated in the peripheral and central nervous system (CNS) by FAAH inhibitors. Inhibition of AEA degradation via FAAH is a promising therapeutic target for migraine pain, since it is presumably associated to an increased availability of the endocannabinoid, specifically at the site where its formation is stimulated (e.g., trigeminal ganglion and/or meninges), thus prolonging its action.

Cannabinoids induce latent sensitization in a preclinical model of medication overuse headache

“…Medical marijuana has been reported to reduce the frequency of attacks in patients with migraine (19,48). The distribution of cannabinoid receptors is consistent with potential anti-migraine effects that have been reported in preclinical studies (16,17,49,50). Both brain and nociceptor expression of cannabinoid receptors might be relevant to reducing headache pain, and, in the trigeminal system, CB1 activation may inhibit the release of neuropeptides associated with migraine such as calcitonin gene-related peptide (CGRP) (51).…”

“…Both brain and nociceptor expression of cannabinoid receptors might be relevant to reducing headache pain, and, in the trigeminal system, CB1 activation may inhibit the release of neuropeptides associated with migraine such as calcitonin gene-related peptide (CGRP) (51). Cannabinoids, including Δ-9-THC, might represent an acute anti-migraine strategy (10–12,47,49,50). Nevertheless, these studies have not addressed the consequences of long-term use of marijuana or novel synthetic cannabinoid-derivate compounds referred to as “spices” that are 10–30 times more potent than the natural compounds (52–54).…”

Distinct Activity of Endocannabinoid-Hydrolyzing Enzymes MAGL and FAAH in Key Regions of Peripheral and Central Nervous System Implicated in Migraine

“…The main complaint of migraine patients is long-lasting pulsating pain, which is intractable in many cases thus leading to chronic stress and depression [ 3 , 13 , 14 ]. Known from ancient times [ 15 ], cannabinoids emerged recently as a promising analgesic approach to treat migraine pain [ 16 , 17 , 18 ]. In particular, cannabis, now legalized in many countries, has shown a therapeutic effect in migraine [ 16 , 19 ].…”

Short- and Long-Term Effects of Cannabis on Headache and Migraine

“…1 The fact that patients with chronic migraine have been found to be anandamide-deficient further suggests that an under-responsive endocannabinoid system contributes to migraine susceptibility. 10 In the present study, we used a large archival dataset obtained from the medical cannabis app Strainprint to address questions regarding the perceived efficacy of cannabis in medical cannabis users who used the app to track changes in headache or migraine from before to after cannabis use. The primary objective of the present study was to examine whether inhaled cannabis would decrease headache and migraine severity ratings.…”