Cannabinoids and Migraine
Posted on June 26 2025,
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Cannabinoids and Migraine
Clinical Guide to Medical Cannabis for Migraine Treatment and Management
The Endocannabinoid System: A Crucial Regulator
The endocannabinoid system (ECS) is a complex cell-signaling system that plays a crucial role in regulating various physiological processes and maintaining homeostasis in the human body. Discovered in the early 1990s by researchers exploring the effects of THC, the ECS has opened up new avenues for understanding and treating migraine.
3
Main Components
Endocannabinoids, receptors, and enzymes
2
Primary Cannabinoids
Anandamide (AEA) and 2-AG
2
Main Receptors
CB1 and CB2 receptors
Components of the ECS
Key ECS Components
Endocannabinoids: Naturally produced lipid-based neurotransmitters including anandamide (AEA) and 2-arachidonoylglycerol (2-AG)
Cannabinoid Receptors: CB1 receptors (primarily in the brain and nervous system) and CB2 receptors (mainly in immune cells and peripheral tissues)
Enzymes: Fatty acid amide hydrolase (FAAH) breaks down AEA, while monoacylglycerol lipase (MAGL) breaks down 2-AG
ECS Functions in Pain Management
The ECS is involved in regulating mood, memory, appetite, and pain perception. CB1 receptors are abundant in the central nervous system and play a significant role in modulating pain transmission. CB2 receptors are primarily found in immune cells and are involved in reducing inflammation.
ECS Role in Homeostasis
The ECS is involved in a wide range of physiological processes, including appetite regulation, metabolism, pain modulation, inflammation, mood, learning and memory, and sleep. Its arguably key role in maintaining homeostasis highlights the potential for the ECS to be a very important therapeutic target for various conditions, including migraine.
Phytocannabinoids and Their Properties
Phytocannabinoids are cannabinoids that occur naturally in plants, with over 110 different cannabinoids identified in the cannabis plant alone. These compounds interact with the ECS network and influence various physiological processes.
Major Phytocannabinoids
Primary Cannabinoids for Migraine
THC (Delta-9-tetrahydrocannabinol) Psychoactive, analgesic, anti-inflammatory
CBD (Cannabidiol) Non-psychoactive, neuroprotective, anti-inflammatory
CBG (Cannabigerol) Potential neuroprotective effects
CBN (Cannabinol) Sleep aid, mild analgesic
THC vs CBD: Key Differences
THC is the primary psychoactive component that produces the "euphoria" associated with cannabis use. It's a partial agonist at both CB1 and CB2 receptors. CBD, unlike THC, does not directly bind to CB1 receptors or cause direct psychoactive effects and instead has been found to have numerous therapeutic antioxidant properties.
Understanding Cannabis Ratios
THC-dominant: Higher THC content, may provide stronger pain relief but with psychoactive effects
CBD-dominant: Higher CBD content, therapeutic benefits with minimal psychoactive effects
Balanced (1:1): Equal THC and CBD, may provide optimal therapeutic effects with reduced psychoactivity
ECS Involvement in Migraine Pathogenesis
Understanding how the endocannabinoid system interacts with migraine development and progression.
| ECS Component | Role in Migraine | Therapeutic Implications |
|---|---|---|
| CB1 Receptors |
Located in trigeminal system and pain pathways
|
Target for cannabinoid-based migraine treatments |
| Anandamide (AEA) |
Primary endocannabinoid in pain modulation
|
Low AEA levels may contribute to migraine susceptibility |
| CGRP Interaction |
Endocannabinoids can prevent CGRP-induced effects
|
Potential complement to CGRP antagonist therapies |
| Astrocyte Modulation |
ECS influences astrocyte function
|
May address neuroinflammation in chronic migraine |
Cannabinoid Pain Management Mechanisms
Phytocannabinoids achieve their analgesic effects by binding to CB1 receptors in the brain and spinal cord, thereby reducing the transmission of pain signals. They also reduce inflammation by activating CB2 receptors on immune cells, leading to a decrease in pro-inflammatory cytokine release.
Multiple Pathway Modulation
How Cannabinoids Reduce Migraine Pain
Direct pain inhibition: CB1 receptor activation reduces neurotransmitter release and neuronal excitability in pain pathways
Anti-inflammatory effects: CB2 receptor activation decreases pro-inflammatory cytokines and astrocyte dysfunction
Neurotransmitter modulation: Interactions with serotonin, dopamine, and GABA systems
Vascular effects: Potential modulation of cerebrovascular tone and trigeminal inflammation
Clinical Endocannabinoid Deficiency (CECD)
Research by Russo suggests that Clinical Endocannabinoid Deficiency (CECD) may be a contributing factor to enhanced pain facilitation in the spinal cord and the activation of the trigeminovascular system, which is responsible for migraine attacks. CECD is a condition where the body has a lower amount of endocannabinoids than it needs for optimal functioning.
Understanding CECD in Migraine
People with CECD may experience chronic pain, migraine, fibromyalgia, and irritable bowel syndrome. Supplementing the body's endocannabinoid system, suggesting that CECD may explain the therapeutic benefits of cannabis in treating these conditions.
Clinical Evidence for Medical Cannabis in Migraine
A growing body of research suggests that medical cannabis may be an effective treatment option for migraine in adults. Multiple studies have investigated the potential benefits and drawbacks of using medical cannabis for managing this debilitating neurological condition.
51%
More Effective
Medical cannabis vs. non-cannabis products for migraine reduction
60%+
Return to Activity
Patients resuming normal activities with THC-CBD combination
1st
Placebo-Controlled
Randomized trial of vaporized cannabis for acute migraine
Systematic Review Findings
A systematic review by Okusanya et al. (2022) found that medical cannabis significantly reduced nausea and vomiting associated with migraine attacks after 6 months of use, decreased the number of migraine days experienced by patients after 30 days, and lowered the overall frequency of migraine headaches per month.
Key Research Findings
- Medical cannabis was found to be 51% more effective in reducing migraines compared to non-cannabis products
- When compared to amitriptyline, a commonly prescribed migraine preventative medication, medical cannabis aborted migraine headaches in 11.6% of users
- Reduced migraine frequency and improved quality of life in chronic migraine patients
- 1:1 THC:CBD ratio showed particular promise for acute symptom relief
Landmark Placebo-Controlled Trial
A groundbreaking randomized, double-blind, placebo-controlled crossover trial (NCT04360044) led by Dr. Nathaniel M. Schuster at UC San Diego represents the first placebo-controlled study of vaporized cannabis for acute migraine. Presented at the 2025 American Headache Society Annual Meeting, this study provides the highest level of clinical evidence to date for cannabis in migraine treatment.
Schuster Trial Key Findings
The combination of 6% THC plus 11% CBD was superior to placebo for pain relief, pain freedom, and most bothersome symptom freedom at 2 hours, with sustained benefits at 24 and 48 hours.
Study Design and Results
Study Design: Patients had up to 1 year to treat four acute migraine attacks with vaporized cannabis from NIDA using research-grade Storz & Bickel Mighty vaporizers
Treatment Arms: THC 6%, CBD 11%, THC-CBD mix (6%/11%), and placebo in randomized order
Primary Findings: Both THC alone and THC-CBD combination showed positive results for 2-hour pain freedom, but THC-CBD mix demonstrated superior results across secondary endpoints
Adverse Effects: THC-related side effects were reduced when combined with CBD, confirming CBD's role as a negative modulator of CB1 receptors
Subgroup Analysis Insights
The Schuster trial included detailed subgroup analyses that provide crucial clinical guidance for different patient populations:
Treatment Timing Effects
Early Treatment (0-2 hours): Higher response rates when cannabis was used within 2 hours of migraine onset
Late Treatment (2-4 hours): Still reasonable response rates even when treatment was delayed, though not as high as early treatment
Clinical Implication: While early treatment is optimal, cannabis remains effective even with delayed administration
Challenging Patient Populations
Allodynia Patients: Despite lower overall treatment responses, patients with scalp sensitivity still achieved reasonably high response rates
Chronic vs Episodic Migraine: Similar 2-hour pain freedom and symptom relief rates whether patients had episodic or chronic migraine (15+ headache days/month)
Return to Function: Over 60% of patients returned to usual activities with THC-CBD combination, with minimal patients remaining disabled or sleeping
Real-World Evidence
In a study conducted by Rhyne et al., they reviewed the medical records of 121 adults with migraines who were referred for medical cannabis treatment and had at least one follow-up visit. The study found that the frequency of migraine headaches decreased significantly from 10.4 to 4.6 headaches per month, and 48 patients (39.7%) reported positive effects.
Important Considerations
While research shows promise, it's crucial to consider the safety and tolerability of these therapies. Some studies have reported mild to moderate adverse events associated with medical cannabis use, including dizziness, dry mouth, and fatigue. The use of medical cannabis for migraine was associated with the occurrence of medication overuse/adaptation headaches (MOH/MAH) in some cases.
Medical Cannabis Dosing Guidelines for Migraine
Evidence-based dosing recommendations for medical cannabis in migraine management, emphasizing a personalized approach.
| Protocol Type | Starting Dose | Titration Schedule | Maximum Dose |
|---|---|---|---|
| Routine Protocol |
5 mg CBD twice daily
|
Increase by 10 mg every 2-3 days
|
40 mg/day CBD total |
| Conservative Protocol |
5 mg CBD once daily
|
Increase carefully
|
40 mg/day with caution |
| Rapid Protocol |
Balanced THC:CBD (2.5-5mg each)
|
Adjust within safety margins
|
1-3 g dried cannabis/day maximum |
Safety Considerations and Risk Management
The use of cannabis for medicinal purposes has been around for a long time, with ancient civilizations recognizing its therapeutic benefits. However, recent legal restrictions have made it difficult for researchers and clinicians to determine proper dosing and administration.
Side Effect Profile
Common Side Effects
Cognitive Effects Memory impairment, concentration issues
Physical Effects Dizziness, dry mouth, fatigue
Respiratory (if smoked) Airway irritation, cough
Medication Overuse Headache Risk with frequent use
COMPASS Study Safety Data
According to the COMPASS trial, a groundbreaking Canadian study, medical cannabis was found to be a safe and effective treatment option for chronic pain. The study followed 215 patients with chronic pain who were prescribed standardized herbal cannabis for 1 year. Results showed no difference in the risk of serious adverse events between the cannabis group and the control group.
Key Safety Findings
The cannabis group reported significant improvements in pain and quality of life compared to the control group, with an average dose of 2.5 g per day appearing to be safe when used in a monitored treatment program for patients with chronic pain who had not responded to conventional therapies.
Drug Interactions
Cannabinoids are metabolized by cytochrome P450 enzymes and may have drug interactions. Most common drug interactions are with the anticoagulant warfarin, the imidazole antifungals (conazoles) due to cytochrome P450 (Cyp450) metabolism interactions making these medications more effective and also heightening the effect of cannabinoids.
Monitoring Recommendations
- Regular follow-up visits to assess effectiveness and side effects
- Monitor for signs of tolerance or dependence
- Review drug interactions with existing medications
- Assess impact on driving and cognitive function
- Screen for medication overuse headache development
Future Directions and Research Priorities
The future of medical cannabis in the treatment of migraines holds immense promise, yet it is not without challenges. Current research evidence supports the therapeutic potential of medical cannabis in the treatment of migraine headaches, particularly as preclinical studies demonstrate the involvement of the endocannabinoid system in migraine pathogenesis.
Research Gaps and Opportunities
Priority Research Areas
Large-scale randomized controlled trials: Need for definitive clinical trials with standardized cannabinoid formulations
Optimal dosing studies: Research into dose-response relationships and personalized dosing strategies
Long-term safety data: Extended follow-up studies to assess chronic use effects
Mechanism studies: Better understanding of ECS involvement in migraine pathophysiology
Combination therapies: Research into cannabis as adjunct to conventional migraine treatments
Emerging Cannabinoid Therapies
Research into phytocannabinoids' potential therapeutic applications continues to grow, particularly regarding their use as natural alternatives to traditional pain medications that can carry unwanted side effects or lead to addiction. As more research is conducted on the mechanisms by which phytocannabinoids modulate pain perception, their potential for treating a wide range of chronic pain conditions becomes increasingly apparent.
Future Treatment Approaches
Precision medicine: Genetic testing to predict cannabinoid response and optimize treatment
Novel delivery methods: Development of more precise dosing and delivery systems
Combination ratios: Research into optimal cannabinoid ratios for different migraine subtypes
Preventive protocols: Studies on cannabis for migraine prevention vs. acute treatment
Regulatory and Clinical Integration
As healthcare professionals, we must remain vigilant in monitoring the use of medical cannabis among our patients, educating ourselves and our patients about the potential benefits and risks associated with cannabinoid therapy, and working toward developing standardized treatment protocols that prioritize patient safety and well-being.
"The endocannabinoid system is a sophisticated internal network that has been quietly managing pain and neurological balance in our bodies. This little-known system may hold some answers to our most disabling and painful neurological conditions." - Cerebral Torque
Important Medical Disclaimer
This information is for educational purposes only and should not replace professional medical advice, diagnosis, or treatment. Always consult with a qualified healthcare provider before starting any cannabis-based therapy. Cannabis laws vary by jurisdiction, and patients should ensure compliance with local regulations.
References
- Russo, E.B. (2008). Cannabinoids in the management of difficult to treat pain. Therapeutics and Clinical Risk Management, 4(1), 245-259.
- Okusanya, B.O., et al. (2022). Medical cannabis for the treatment of migraine in adults: A systematic review. Complementary Therapies in Medicine, 64, 102793.
- Rhyne, D.N., et al. (2016). Effects of medical marijuana on migraine headache frequency in an adult population. Pharmacotherapy, 36(5), 505-510.
- 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.
- Cupini, L.M., et al. (2008). Degradation of endocannabinoids in chronic migraine and medication overuse headache. Neurobiology of Disease, 30(2), 186-189.
- Tassorelli, C., et al. (2019). The role of cannabinoids in migraine: A systematic review. The Journal of Headache and Pain, 20(1), 1-11.
- Leinurmanta, K., et al. (2018). Potential mechanisms and targets for the treatment of migraine with cannabinoids. Current Neuropharmacology, 16(4), 459-470.
- Schuster, N.M., et al. (2024). Effectiveness of vapourized cannabis for acute migraine relief: A randomized controlled trial. The Journal of Headache and Pain, 25(1), 15.
- Bell, A.D., et al. (2024). Clinical practice guidelines for cannabis and cannabinoid-based medicines in the management of chronic pain and co-occurring conditions. Cannabis and Cannabinoid Research, 9(2), 669-687.
- Bhaskar, A., et al. (2021). Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain. Cannabis and Cannabinoid Research, 6(3), 180-194.
- MacCallum, C.A., & Russo, E.B. (2018). Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine, 49, 12-19.
- Ware, M.A., et al. (2010). The effects of nabilone on sleep in fibromyalgia: Results of a randomized controlled trial. Anesthesia & Analgesia, 110(2), 604-610.
- Russo, E.B. (2004). Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinology Letters, 25(1/2), 31-39.
- Akerman, S., et al. (2013). Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and "triptan" receptors: Implications in migraine. Journal of Neuroscience, 33(37), 14869-14877.
- Schuster, N.M., et al. (2024). Vaporized Cannabis versus Placebo for Acute Migraine: A Randomized Controlled Trial. medRxiv preprint. doi:10.1101/2024.02.16.24302843
- Schuster, N.M. (2025). Vaporized Cannabis Versus Placebo for the Acute Treatment of Migraine: Final Results From a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial. Presented at: 2025 AHS Annual Meeting; June 19-22; Minneapolis, MN. Harold G. Wolff Lecture Award.
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