The Endocannabinoid System and Related Lipids as Potential Targets for the Treatment of Migraine-related Pain

Rosaria Greco PhD; Chiara Demartini PhD; Anna Maria Zanaboni BSc; Miriam Francavilla MSc; Roberto De Icco MD, PhD; Lara Ahmad MD; Cristina Tassorelli MD, PhD


Headache. 2022;62(3):227-240. 

In This Article

Abstract and Introduction


Background: Migraine is a complex and highly disabling neurological disease whose treatment remains challenging in many patients, even after the recent advent of the first specific-preventive drugs, namely monoclonal antibodies that target calcitonin gene-related peptide. For this reason, headache researchers are actively searching for new therapeutic targets. Cannabis has been proposed for migraine treatment, but controlled clinical studies are lacking. A major advance in cannabinoid research has been the discovery of the endocannabinoid system (ECS), which consists of receptors CB1 and CB2; their endogenous ligands, such as N-arachidonoylethanolamine; and the enzymes that catalyze endocannabinoid biosynthesis or degradation. Preclinical and clinical findings suggest a possible role for endocannabinoids and related lipids, such as palmitoylethanolamide (PEA), in migraine-related pain treatment. In animal models of migraine-related pain, endocannabinoid tone modulation via inhibition of endocannabinoid-catabolizing enzymes has been a particular focus of research.

Methods: To conduct a narrative review of available data on the possible effects of cannabis, endocannabinoids, and other lipids in migraine-related pain, relevant key words were used to search the PubMed/MEDLINE database for basic and clinical studies.

Results: Endocannabinoids and PEA seem to reduce trigeminal nociception by interacting with many pathways associated with migraine, suggesting a potential synergistic or similar effect.

Conclusions: Modulation of the metabolic pathways of the ECS may be a basis for new migraine treatments. The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area. Multiple molecules related to the ECS or to allosteric modulation of CB1 receptors have emerged as potential therapeutic targets in migraine-related pain. The complexity of the ECS calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development.


Migraine is a complex neurological disorder characterized by pain and accompanying symptoms underpinned by involvement of multiple structures in the central and peripheral nervous systems (CNS and PNS). Migraine-related pain is linked to activation of the trigeminocervical complex, which is the main pain-processing interface between the CNS and PNS.[1,2] Calcitonin gene-related peptide (CGRP) and other neuropeptides are likely involved in migraine pathways,[2] and changes in sensory afferents may also contribute to abnormal pain processing. Acute treatment of migraine aims to minimize functional disability by aborting attacks once they have started, whereas preventive treatments are used to reduce attacks' frequency, duration, and intensity. Unfortunately, the current benchmarks for efficacy of acute and preventive antimigraine medications are far from satisfactory for both physicians and patients. Regarding acute medications, efficacy is defined as the achievement of freedom from pain or from the most bothersome symptom within 2 h, but only a minority of patients (19%–31%) have achieved this outcome in randomized clinical trials.[3] Similarly, the efficacy of preventive medications is defined as a 50% reduction in monthly migraine days, a benchmark achieved by 40% to 50% of patients.[4] Taking oral preventive drugs is frequently associated with adverse effects, and only a minority of patients persist with the treatment for an adequate period of time.[5] The potential mechanisms of antimigraine drugs include reduction of glutamatergic neurotransmission through inhibition of sodium and calcium channels, facilitation of GABAergic neurotransmission, reduction of central sensitization, and suppression of cortical spreading depression.[6] Several classes of drugs have been evaluated and recommended for migraine prevention, including the recently approved monoclonal antibodies that target CGRP.[7] Some of the available antimigraine drugs act by decreasing circulating levels of neuropeptides[8] and "hyperalgesic" cytokines, such as tumor necrosis factor α, interleukin-1β, and interleukin-6.[9] Additional signal molecules, such as adenosine triphosphate, nitric oxide (NO), neurotrophic factors, and other inflammatory mediators are released from the trigeminal ganglion and may interact with different cells (neurons and glia), thus modulating nociceptive transmission. Hence, migraine-related pain is regulated at multiple levels and pro-nociceptive agents may be reduced in the PNS and/or in the CNS before or during a migraine attack. In this context, endocannabinoids and related lipids may be good candidates for the treatment of migraine, because they interact with different pathways involved in pain modulation at multiple anatomic levels.[10]