Migraines, a debilitating neurological condition characterized by intense, throbbing headaches often accompanied by nausea, vomiting, and sensitivity to light and sound, affect millions of individuals worldwide. The search for effective treatments has led researchers to explore various avenues, including the therapeutic potential of cannabinoids. Despite still initial, a growing body of research highlights the potential benefits of cannabis-based therapeutics for migraine relief.

The Endocannabinoid System and Migraine Pathophysiology

The endocannabinoid system (ECS) plays a crucial role in maintaining homeostasis within the body. It comprises endogenous cannabinoids (endocannabinoids), receptors (CB1 and CB2), and enzymes such as monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) that degrade endocannabinoids. Recent insights suggest that modulating the ECS may offer a novel approach to pain management, particularly in the context of migraines.

Endocannabinoids, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), bind to CB1 and CB2 receptors to produce analgesic effects. By inhibiting the enzymes MAGL and FAAH, which degrade these endocannabinoids, it is possible to increase their levels in the body, thereby enhancing their natural pain-relieving properties. This approach targets the root cause of pain by regulating neurotransmitter release and reducing inflammation, both implicated in migraine pathophysiology.

The trigeminovascular system (TS) activation and the vasoactive release from trigeminal endings near the meningeal vessels are considered two main mechanisms of migraine attacks. Recent attention has been given to the ECS as a potential modulator of these processes. Experimental and clinical data suggest a link between dysregulation of this signaling complex and migraine headaches. Clinical observations indicate that the levels of AEA are reduced in the cerebrospinal fluid and plasma of patients with chronic migraine, and 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 receptors. AEA is rapidly degraded by the FAAH enzyme, and its levels can be modulated in the peripheral and central nervous system (CNS) by FAAH inhibitors. 

Clinical Evidence and Meta-Analyses

While much of the current evidence is anecdotal, over a dozen trials have directly examined the impact of modulating the ECS to induce analgesia in migraine patients. These studies have yielded promising results, indicating that cannabinoids may significantly reduce migraine frequency, duration, and intensity.

One of the most extensive meta-analyses, encompassing data from 12,293 cannabis treatment sessions, revealed that inhaled cannabis reduced self-reported headache and migraine intensity by approximately half. Additionally, patients reported improvements in the frequency and duration of migraines, as well as a reduction in associated symptoms such as nausea and vomiting. These findings underscore the potential of cannabis-based therapeutics to provide significant relief for migraine sufferers, particularly those who do not respond well to conventional treatments.

A systematic review aimed to assess the effectiveness and safety of medical cannabis in treating migraines in adults included 12 publications involving 1,980 participants from Italy and the United States. The results indicated that cannabis significantly reduced nausea and vomiting associated with migraine attacks after six months of use. Furthermore, cannabis reduced the number of migraine days after 30 days and the frequency of migraine headaches per month. Cannabis was found to be 51% more effective in reducing migraines than non-cannabis products. Compared to amitriptyline, cannabis aborted migraine headaches in some users (11.6%) and reduced migraine frequency. Adverse events were mostly mild, occurring in 43.75% of patients who used oral cannabinoid preparations.

Another study reviewed the clinical response, dosing, and side effects of cannabis in migraine management, following PRISMA guidelines. This review included nine studies and demonstrated that medical cannabis significantly reduced the length and frequency of migraines. No severe adverse effects were noted, highlighting its potential as a safe and effective treatment option.

Mechanisms of Action

The mechanisms by which cannabinoids exert their therapeutic effects in migraine patients are multifaceted. Activation of CB1 receptors in the central nervous system can inhibit the release of pro-inflammatory neurotransmitters and reduce neuronal excitability, both of which are critical in the development and maintenance of migraine headaches. CB2 receptors, predominantly found in peripheral tissues and immune cells, modulate immune responses and reduce inflammation, which may further contribute to pain relief.

Additionally, cannabinoids have been shown to interact with serotonin receptors, which are also involved in migraine pathophysiology. This interaction may help regulate the vascular component of migraines, as serotonin plays a crucial role in blood vessel constriction and dilation.

Future Directions and Considerations

Despite the promising findings, several challenges remain in the clinical application of cannabinoids for migraine treatment. The variability in cannabinoid formulations, dosages, and delivery methods can affect treatment outcomes, making it difficult to standardize protocols. To address these challenges, future research should focus on large-scale, randomized controlled trials to establish the efficacy and safety of specific cannabinoid formulations for migraine treatment. Additionally, exploring different cannabinoids may offer a safe alternative with few side effects.

References

• Baron E. P. (2015). Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been …. Headache, 55(6), 885–916. https://doi.org/10.1111/head.12570
• Okusanya BO, Lott BE, Ehiri J, McClelland J, Rosales C. Medical Cannabis for the Treatment of Migraine in Adults: A Review of the Evidence. Front Neurol. 2022 May 30;13:871187. doi: 10.3389/fneur.2022.871187. PMID: 35711271; PMCID: PMC9197380.
• Mechtler LL, Gengo FM, Bargnes VH. Cannabis and Migraine: It’s Complicated. Curr Pain Headache Rep. 2021 Feb 25;25(3):16. doi: 10.1007/s11916-020-00931-2. PMID: 33630181.
• Greco R, Demartini C, Zanaboni AM, Piomelli D, Tassorelli C. Endocannabinoid System and Migraine Pain: An Update. Front Neurosci. 2018 Mar 19;12:172. doi: 10.3389/fnins.2018.00172. PMID: 29615860; PMCID: PMC5867306.
• Sherpa ML, Shrestha N, Ojinna BT, Ravi N, Shantha Kumar V, Choday S, Parisapogu A, Tran HH, Kc A, Elshaikh AO. Efficacy and Safety of Medical Marijuana in Migraine Headache: A Systematic Review. Cureus. 2022 Dec 17;14(12):e32622. doi: 10.7759/cureus.32622. PMID: 36660507; PMCID: PMC9845509.