The Endocannabinoid System and Migraine-Related Pain: A Review
Published: 10/03/2022

The Endocannabinoid System and Migraine-Related Pain: A Review

Migraine is a common primary headache disorder characterised by attacks of moderate or severe headache. These headaches often, but don’t always affect one side of the head and are most typically described as throbbing or pulsating. Migraines are also associated with sensitivity to light, sensitivity to sound, nausea, and vomiting. Depending on the frequency of attacks, migraines can either be classified as episodic (occurs less than 15 days/month) or chronic (headache on at least 15 days/month for more than 3 months)

Migraine is an extremely common condition, affecting 1 in 7 people, and disproportionally affects women. Whilst migraine symptoms typically improve over time migraine can lead to reduction in functional ability and quality of life. In rare circumstances sufferers of migraines can experience severe complications from migraines. Despite its frequency there is a distinct need for the development of novel therapeutics for prevention of migraine attacks. Most traditional therapies were initially intended for other purposes and are often associated with poor and unpredictable effectiveness with no more than one-third of patients experiencing a successful response.

Cannabis-based medicinal products (CBMPs) and/or other compounds which modulate the extended endocannabinoid system, the endocannabinoidome, have been proposed as potential therapeutics to meet this need. A recent review published in the journal Headache presented a review of current evidence of these compounds as potential therapeutics for migraine-related pain.

The Endocannabinoidome

The endocannabinoidome is composed of a complex system of inter-related receptors, ligands, and enzymes. The most well-recognised ligands are endocannabinoids, the most prevalent of which are anandamide and 2-arachidonoylglycerol (2-AG). Unlike traditional neurotransmitters endocannabinoids are not stored in vesicles but are produced on demand in response to cellular depolarisation. Anandamide is synthesised by the enzyme N-acyl-phosphatidyl-ethanolamine-selective phospholipase D for anandamide, whilst diacylglycerol lipases α and β synthesise 2-AG. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are responsible for the breakdown of anandamide and 2-AG, respectively. Anandamide is a partial agonist of cannabinoid receptor 1 (CB1R), which 2-AG is a full agonist of CB1 and cannabinoid receptor 2 (CB2R). CB1R is mainly expressed in the central nervous system and activation results in effects on mood, sensitivity, cognition, and movement. CB2R, contrastingly, is predominantly expressed in immune cells, however it is also present in lower density in the neurone and microglial cells within the central nervous system.

In addition to the classical endocannabinoid system, the endocannabinoidome comprises of the multitude of additional components with which it interacts. Anandamide also affects transient receptor potential (TRP) cation channels and peroxisome proliferator-activated receptors (PPARs), specifically TRPV1 and PPARγ. Anandamide activates TRPA1 and TRPV2 at high concentrations and inhibits TRPM8 and certain calcium ion channels. 2-AG activates TRPV1 channels and GABAA receptors. Moreover, orphan G-protein coupled receptors, opioid receptors, acylethanolamines, and long chain N-acyl-amides comprise of yet more diverse endocannbinoidome targets for modulation.

Within the context of migraine there is clinical evidence of dysregulation of the endocannabinoidome. Moreover, this dysregulation is more pronounced in those with chronic migraine and medication-overuse headache in comparison to those with episodic migraine or indeed healthy controls. Preclinical evince from nitro-glycerine and cortical spreading depression migraine-like models demonstrate cannabinoid receptor agonists, as well as FAAH and MAGL inhibitors as effective in reducing allodynia and hyperalgesia, as well as surrogate biomarkers (i.e. reduction of Calcitonin gene-related peptide levels in the brainstem).

With respect to the available evidence of medical cannabis, there is a small randomised controlled trial demonstrating a reduction of headache days and intensity of pain with 8 weeks of tetrahydrocannabinol (THC). In addition, a retrospective study of ‘medical marijuana’ patients in Colorado, found a reduction in headache days per month with ‘medical marijuana’ utilisation.


This study highlights the complexity of the endocannabinoidome, which with some respects we are still yet to fully elucidate. However, the preclinical and burgeoning clinical evidence is positive and suggests a potential role for the modulation of the endocannabinoids in migraine-related pain. Further, robust clinical evaluation shall hopefully help unlock the true potential of cannabis-based medicinal products for migraines.

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