CBD for migraine

What is migraine and what mechanisms trigger migraine attacks?

Migraine is a neurological disorder characterized by recurring headache attacks and often accompanied by symptoms such as nausea, sensitivity to light and sound, and neurological disturbances. Worldwide, several hundred million people are affected by the condition, which according to epidemiological studies is among the most common causes of disease-related limitations in daily life. Migraine attacks do not arise from a single cause but from a complex interaction of neuronal, vascular, and inflammatory mechanisms.

What role does the trigeminovascular system play in migraine?

The so-called trigeminovascular system plays a central role in the development of migraine. It is a network of nerve fibers from the trigeminal nerve and the blood vessels of the meninges. When this system is activated, trigeminal nerve cells release various messengers that can trigger inflammatory processes and pain signals. The activation of these signaling pathways causes pain impulses from the meninges to be transmitted to the brain, where they are perceived as typical migraine headaches. An important component of this signal transmission is the neuropeptide Calcitonin Gene-Related Peptide (CGRP). This molecule is released in increased amounts during migraine attacks and leads to dilation of blood vessels as well as inflammatory reactions in the meninges. The central importance of CGRP is confirmed by the fact that modern migraine therapies specifically target this signaling pathway.

How do neurogenic inflammations develop and what is the significance of CGRP?

In addition to the activation of the trigeminovascular system, neurogenic inflammatory processes play an important role. Activated nerve cells release pro-inflammatory messengers. These lead to increased blood flow in the meninges and to sensitization of the pain receptors. These processes can contribute to migraine attacks lasting longer or being perceived as more intense. During a migraine attack, changes often occur in the processing of pain signals in the brain. Certain brain regions responsible for pain processing become more sensitive to stimuli. This process is called central sensitization and can explain why migraine patients are especially sensitive to light, sounds, or smells during an attack.

Why can migraine develop into a chronic condition?

In some affected individuals, migraine develops into a chronic condition over time. Chronic migraine is defined as having headaches on at least 15 days per month, some of which have the typical features of migraine. Various factors are discussed as possible causes for the development of chronic migraine, including genetic predisposition, hormonal influences, stress, and long-term sensitization of pain networks in the brain. Recent research has also shown that the endocannabinoid system may play a role in regulating pain processes. Changes in this system are considered a possible factor in various chronic pain syndromes, including migraine. These findings have increased interest in cannabinoids like CBD as a potential therapeutic approach.

What role does the endocannabinoid system play in migraine?

The endocannabinoid system (ECS) is an internal regulatory network that influences numerous physiological processes, including pain processing, inflammatory responses, and neuronal signaling. In recent years, research has increasingly found evidence that this system also plays an important role in the development and modulation of migraine.

What are CB1 and CB2 receptors, and where are they found in the body?

The endocannabinoid system mainly consists of cannabinoid receptors, endogenous ligands, and enzymes that synthesize and break down these signaling molecules. Of particular importance are the CB1 and CB2 receptors. CB1 receptors are primarily found in the central nervous system. They are located in numerous brain regions involved in pain processing, including the brainstem, thalamus, and cortical pain networks. By activating these receptors, CB1 can influence the release of various neurotransmitters, including glutamate, GABA, dopamine, and serotonin. This modulation of neuronal signaling can alter the perception and transmission of pain signals.

What functions do the endocannabinoids anandamide and 2-AG have?

Besides the receptors, the endocannabinoid system also includes endogenous messengers called endocannabinoids. The most important are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These molecules are produced in the body as needed and act as natural ligands for cannabinoid receptors. They play a key role in regulating pain, mood, appetite, and stress responses. After their release, they are broken down by specific enzymes such as FAAH or MAGL. Studies suggest that changes in the concentration of these endogenous cannabinoids can influence pain processing.

What does the clinical endocannabinoid deficiency hypothesis mean?

Some researchers have hypothesized that certain chronic diseases may be linked to a dysregulation of the endocannabinoid system. This theory is called the clinical endocannabinoid deficiency hypothesis. According to this, too low concentrations of endogenous cannabinoids could cause pain-modulating mechanisms in the nervous system to work less effectively. In fact, some studies have observed altered concentrations of endocannabinoids in the central nervous system of migraine patients. Such changes could contribute to easier activation of the trigeminovascular system and the onset of migraine attacks. These findings provide a possible biological explanation for why cannabinoids are discussed in research as a potential therapeutic approach for migraine. However, it is important to emphasize that these connections are not yet fully understood and further clinical studies are needed.

What is CBD and how does it differ from THC?

Cannabidiol (CBD) and tetrahydrocannabinol (THC) are among the best-known phytocannabinoids of the cannabis plant. Although they come from the same plant and are structurally related, they differ significantly in their pharmacological properties, mechanisms of action, and clinical effects. These differences are especially important when interpreting studies on the effects of cannabinoids in migraine.

Why does THC have psychoactive effects, but CBD does not?

The main difference between THC and CBD lies in their effects on the central nervous system. THC is psychoactive because it acts as a partial agonist at the cannabinoid receptor CB1. This receptor is widespread in the brain and influences various functions such as perception, mood, memory, and pain processing. By activating CB1 receptors, THC can cause changes in consciousness, euphoria, or cognitive effects. In contrast, CBD does not have a pronounced psychoactive effect. It binds only weakly to CB1 receptors and instead acts through a variety of indirect mechanisms on different molecular targets. These include certain ion channels, serotonin receptors, and enzymes involved in the breakdown of endogenous cannabinoids. Because of this different effect profile, CBD is often described as a non-intoxicating cannabinoid.

How do CBD and THC differ in their effects on cannabinoid receptors?

THC exerts its pharmacological effects mainly through the direct activation of CB1 and CB2 receptors. This allows THC to influence the release of various neurotransmitters and trigger both pain-relieving and psychoactive effects. CBD, on the other hand, acts primarily indirectly on the endocannabinoid system. For example, it can inhibit enzymes responsible for breaking down endogenous cannabinoids, thereby increasing the concentration of these natural signaling molecules. Additionally, CBD affects other receptor systems, including serotonergic pathways involved in regulating mood and pain. Due to these different mechanisms of action, CBD and THC can sometimes show complementary effects in research.

Why is the distinction between CBD and THC important in migraine research?

A clear distinction between CBD and THC is crucial, as most existing studies on migraine treatment examine cannabis products with varying proportions of THC and CBD. In many cases, the observed effects cannot be clearly attributed to a single cannabinoid. However, some clinical studies suggest that combinations of THC and CBD might be effective in treating migraines. At the same time, controlled studies have shown that CBD-dominant preparations alone have not yet demonstrated clear effects on acute migraine pain. These results highlight that the effects of cannabinoids strongly depend on the exact composition of the preparations, the dosage, and the method of application. For a scientifically sound evaluation, it is therefore important to carefully analyze cannabinoid studies and distinguish between CBD-specific data and results from THC-containing cannabis products.

How could CBD theoretically work for migraines?

In research, CBD is discussed as a potentially interesting active ingredient for migraines because several of its pharmacological properties could theoretically influence processes involved in the development of migraine attacks. These include mechanisms of pain modulation, inflammation regulation, and neuronal signal transmission. However, many of these findings so far come from experimental or preclinical studies, so their clinical significance is not yet fully clarified.

How does CBD affect pain receptors in the nervous system?

One possible mechanism of action of CBD is its effect on ion channels and pain receptors involved in transmitting pain signals. Of particular relevance are the so-called TRP channels (Transient Receptor Potential), which play an important role in the perception of pain and temperature. CBD can affect the TRPV1 receptor, also known as the capsaicin receptor. This receptor is involved in regulating nociceptive pathways and is found both in the peripheral nervous system and the brain. By modulating these receptors, CBD could theoretically alter the activity of pain fibers and thus influence the transmission of pain signals. Furthermore, it is discussed that CBD might indirectly modulate the activity of certain serotonergic receptors, especially the 5-HT1A receptor. Serotonin plays a central role in migraine pathophysiology, as evidenced by the effectiveness of triptans, which specifically target serotonergic pathways.

What anti-inflammatory properties does CBD have?

Migraine attacks are often associated with inflammation-like processes in the trigeminovascular system. Activated nerve cells release various neuropeptide messengers that can cause blood vessels to dilate and trigger inflammatory reactions in the meninges. Experimental studies attribute anti-inflammatory effects to CBD. For example, it can modulate the release of certain pro-inflammatory cytokines and influence the activity of immune cells. These effects could theoretically help reduce the inflammatory processes involved in the development of migraine attacks.

How does CBD interact with the endocannabinoid system?

Although CBD itself has only a low direct binding affinity for CB1 and CB2 receptors, it can indirectly modulate the endocannabinoid system. One possible mechanism is that CBD inhibits enzymes responsible for the breakdown of endogenous cannabinoids.

One example is the enzyme FAAH (Fatty Acid Amide Hydrolase), which breaks down the endocannabinoid anandamide. If this breakdown is inhibited, the concentration of anandamide in the nervous system can increase. Since anandamide plays an important role in regulating pain processes, such an increase could theoretically lead to stronger activation of the body's own pain-modulating systems. In summary, experimental studies show several possible mechanisms through which CBD could influence processes involved in migraine. These include effects on pain receptors, inflammatory signaling pathways, and the endocannabinoid system. These mechanisms provide a plausible biological basis for researching CBD as a potential therapeutic approach. At the same time, it is important to emphasize that biological plausibility does not automatically mean clinical effectiveness. To assess the actual therapeutic significance of CBD for migraine, controlled clinical studies are necessary. This exact study situation will be examined in more detail in the next section.

Which studies investigate cannabinoids for migraine?

Scientific research on cannabinoids for migraine includes various study types, such as retrospective clinical analyses, real-world data, and registry studies. A central methodological issue is that many studies investigate cannabis products with different THC and CBD ratios. This makes it difficult to clearly determine the effects of individual cannabinoids.

What results do observational studies show regarding medical cannabis for migraine?

Observational studies provide initial evidence that medical cannabis might influence the frequency of migraine attacks. For example, in a retrospective clinical analysis, the average number of monthly migraine attacks decreased from 10.4 to 4.6 per month. More than 85% of the individuals studied reported a reduction in attack frequency during medical cannabis use. These results suggest a possible therapeutic effect. However, this is a retrospective study without a control group, so factors such as placebo effects or differences in the cannabis products used cannot be ruled out.

What do real-world data from cannabis tracking apps show about migraine symptoms?

In real-world studies, data from the daily lives of patients using medical cannabis are analyzed. For example, an analysis of data from a cannabis tracking app evaluated more than 7,000 migraine treatments. After using inhaled cannabis, users reported an average reduction in pain intensity of about 50%. The study also showed that various factors can influence the perceived effect. For instance, stronger effects were sometimes observed with cannabis concentrates compared to flower. At the same time, researchers found indications that tolerance might develop with long-term use.

What insights do registry studies provide about cannabis use in migraine?

Registry and survey studies provide insight into the usage behavior of patients. In a large study with more than 2,000 medical cannabis patients, about a quarter of the participants reported using cannabis to treat headaches or migraine. Using a standardized migraine screening, it was estimated that approximately 88% of these individuals likely suffer from migraine. The study also showed that many patients preferred THC-rich cannabis profiles, while CBD-rich preparations were chosen less often. This observation could suggest that certain cannabinoid combinations are subjectively perceived as more effective for migraine.

What do scientific studies specifically show about CBD and migraine?

The scientific evidence for the effect of CBD alone on migraine is currently limited. While numerous studies investigate the effects of cannabis or THC-containing cannabinoid preparations, there are only a few controlled studies focusing exclusively on CBD-dominant preparations. Therefore, it is important not to automatically transfer the results of cannabis studies to CBD.

What results do randomized studies on CBD-dominant preparations provide?

The most important controlled study to date is a randomized, double-blind crossover study in which various inhaled cannabinoid formulations were tested during acute migraine attacks. Four different preparations were compared: a THC-dominant product, a CBD-dominant product, a combination of THC and CBD, and a placebo. The results showed that the combination of THC and CBD was significantly more effective than the placebo on several endpoints. These included pain reduction two hours after treatment and complete pain relief in some of the treated individuals. The CBD-dominant preparation, however, did not show significant superiority over placebo on the main primary endpoints in this study. This suggests that CBD alone may not have the same therapeutic effect on acute migraine pain as certain cannabinoid combinations.

Why might combinations of THC and CBD be more effective than CBD alone?

One possible reason for the observed differences could be the different mechanisms of action of the cannabinoids. THC directly activates CB1 receptors in the central nervous system, which play an important role in modulating pain signals. CBD, on the other hand, acts more indirectly on the endocannabinoid system and additionally influences other molecular target structures. Some researchers therefore discuss the so-called entourage effect, where several cannabinoids together can produce stronger pharmacological effects than individual substances alone. However, this hypothesis has not yet been conclusively proven scientifically.

Which clinical studies on CBD for migraines are currently underway?

Since the current evidence is limited, several research groups are currently investigating the effects of CBD-rich extracts on migraines. For example, a clinical study is testing a preparation with a high CBD content and a very low THC level in adolescents with chronic migraine. The main goal of this study is to analyze the safety and tolerability of the preparation as well as possible effects on the frequency of migraine attacks. The results of this and similar studies will be crucial in determining whether CBD could play a role in migraine therapy in the future. 

What side effects and risks can occur when using cannabinoids?

Cannabinoids like CBD and THC are increasingly studied in medical research, yet side effects and unwanted effects can occur during their use. These depend, among other things, on the dosage, the composition of the product, the form of administration, and individual patient factors. While THC is more often associated with central nervous system side effects due to its psychoactive properties, CBD is generally considered better tolerated. Nevertheless, certain unwanted effects can also occur with CBD.

What acute side effects have been observed in studies?

In clinical studies on cannabinoids, participants occasionally report temporary side effects such as fatigue, dizziness, dry mouth, or changes in concentration. These effects occur more frequently with THC-containing products because THC acts directly on CB1 receptors in the central nervous system. Side effects are less commonly reported with CBD. However, some studies have observed symptoms like fatigue, diarrhea, or changes in appetite. Such effects usually occur at higher doses and are often reversible.

Can tolerance develop with long-term use?

Another aspect discussed in studies is the possible development of tolerance with long-term use of cannabinoids. Real-world data from cannabis use studies suggest that the body may adapt with repeated use, causing the perceived effect to diminish over time. Such tolerance development is mainly described for THC-containing products. For CBD alone, only limited data on long-term use is currently available.

What interactions with migraine medications are possible?

Cannabinoids can also interact with other medications. For example, CBD is metabolized by enzyme systems in the liver that are also responsible for breaking down many other drugs. This theoretically means that CBD could affect the concentration of certain medications in the blood. This could be especially relevant for migraine patients who are simultaneously taking medications such as triptans, antiepileptics, or certain antidepressants. Since data on such interactions is still limited, experts generally recommend integrating cannabinoids into existing treatment plans only after consulting a doctor. In summary, studies show that cannabinoids can cause various side effects. THC-containing products are more often associated with central nervous system effects than CBD. CBD alone is generally described as having a more favorable safety profile. However, further studies are needed, especially for long-term use in migraines.

Can CBD relieve migraines and how do researchers assess the current state of studies?

Current research suggests that cannabinoids may play a role in treating migraine. However, specific evidence for the effect of CBD alone is still limited. Numerous observational studies and real-world data report positive effects of cannabis on migraine, but controlled clinical studies show that therapeutic effects are often associated with THC-containing preparations or combinations of THC and CBD. Observational studies provide initial indications that cannabinoids could influence the frequency or intensity of migraine attacks. In clinical analyses, many patients reported a significant reduction in their monthly migraine attacks during the use of medical cannabis. 

At the same time, real-world data from applications documenting cannabis use show that users often perceive a noticeable reduction in pain intensity after use. However, these results must be interpreted with caution, as such studies usually lack control groups, standardized dosages, or consistent cannabinoid profiles. Randomized, controlled studies are considered the most important scientific standard for evaluating a therapy. In one such study, various inhaled cannabinoid preparations were tested during acute migraine attacks. It was found that a combination of THC and CBD was more effective than placebo in several clinical endpoints. The CBD-dominant preparation, however, did not show a significant improvement in the main endpoints in this study. 

These findings suggest that possible therapeutic effects of cannabinoids in migraine could at least partly be due to THC or the combination of multiple cannabinoids. So far, only a few controlled clinical data exist for CBD alone.

In summary, cannabinoids are increasingly being studied in migraine research, and several studies suggest possible positive effects. At the same time, clinical evidence specifically for CBD in migraine is currently limited, so further randomized studies are necessary to better assess its actual therapeutic significance.

What research gaps currently exist regarding CBD and migraine?

Although cannabinoids are increasingly the subject of scientific research, there are still several important knowledge gaps in the study of CBD and migraine. These particularly concern dosage, long-term use, and the exact role of CBD compared to other cannabinoids.

Why are standardized CBD dosages important in studies?

A major problem with many previous studies is that the preparations used are not standardized. Observational studies often use cannabis products with varying concentrations of THC and CBD. This makes it difficult to determine which active ingredient is actually responsible for the observed effects. For future clinical studies, it is therefore essential to use clearly defined CBD dosages and standardized preparations. Only in this way can it be investigated whether CBD alone has a measurable effect on migraine attacks.

Why are long-term clinical studies needed?

Migraine is often a chronic condition that can persist for many years. Therefore, it is important to understand the effects that potential therapies may have with long-term use. However, the focus of many studies available so far has been on short-term effects or the analysis of retrospective data from clinical practice. Long-term, randomized studies could provide important information on whether CBD might reduce the frequency of migraine attacks or influence disease progression.

How could CBD be integrated into migraine therapy in the future?

Future studies could clarify whether CBD can be used as an adjunct therapy option for migraine. It might be possible to use it in combination with established migraine medications or as part of certain cannabinoid formulations. However, to answer these questions, further well-designed clinical studies are first required to systematically investigate the efficacy and safety of CBD in migraine.

What conclusion can be drawn from the current research on CBD for migraine?

Scientific research shows that the endocannabinoid system may play a role in regulating pain processes, which are also involved in migraine. These findings provide a plausible biological basis for investigating cannabinoids as a possible therapy option. Observational studies and real-world data often report positive experiences from patients using medical cannabis. At the same time, controlled clinical studies show that THC-containing or combined cannabinoid preparations have been studied more extensively than CBD alone.

Currently, there are only a few high-quality clinical data available for CBD-dominant preparations, and previous studies have not been able to demonstrate a clear effectiveness in acute migraine attacks. Therefore, further research is necessary to better understand the potential role of CBD in migraine. Overall, CBD remains an interesting but not yet sufficiently researched approach in migraine therapy. Future clinical studies will be crucial to clarify whether and under what conditions CBD could offer therapeutic benefits for migraine patients.

Sources

Greco, R., Demartini, C., Zanaboni, A. M., Piomelli, D., & Tassorelli, C. (2018). Endocannabinoid System and Migraine Pain: An Update. Frontiers in Neuroscience, 12, 172. https://doi.org/10.3389/fnins.2018.00172

Tassorelli, C., Greco, R., & Silberstein, S. D. (2019). The endocannabinoid system in migraine: from bench to pharmacy and back. Current Opinion in Neurology, 32(3), 405–412. https://doi.org/10.1097/WCO.0000000000000688

Lo Castro, F., Baraldi, C., Pellesi, L., & Guerzoni, S. (2022). Clinical Evidence of Cannabinoids in Migraine: A Narrative Review. Journal of Clinical Medicine, 11(6), 1479. https://doi.org/10.3390/jcm11061479

Poudel, S., Quinonez, J., Choudhari, J., Au, Z. T., Paesani, S., Thiess, A. K., Ruxmohan, S., Hosameddin, M., Ferrer, G. F., & Michel, J. (2021). Medical Cannabis, Headaches, and Migraines: A Review of the Current Literature. Cureus, 13(8), e17407. https://doi.org/10.7759/cureus.17407

Sherpa, M. L., Shrestha, N., Ojinna, B. T., Ravi, N., Shantha Kumar, V., Choday, S., Parisapogu, A., Tran, H. H., Kc, A., & Elshaikh, A. O. (2022). Efficacy and Safety of Medical Marijuana in Migraine Headache: A Systematic Review. Cureus, 14(12), e32622. https://doi.org/10.7759/cureus.32622

Schuster, N. M., Wallace, M. S., Marcotte, T. D., Buse, D. C., Lee, E., Liu, L., & Sexton, M. (2024). Vaporized Cannabis versus Placebo for Acute Migraine: A Randomized Controlled Trial. medRxiv: The Preprint Server for Health Sciences, 2024.02.16.24302843. https://doi.org/10.1101/2024.02.16.24302843

Greco, R., Gasperi, V., Maccarrone, M., & Tassorelli, C. (2010). The endocannabinoid system and migraine. Experimental Neurology, 224(1), 85–91. https://doi.org/10.1016/j.expneurol.2010.03.029

Chhabra, M., Lewis, E. C., Balshaw, R., Stewart, B., Zaslawski, Z., Lowthian, T., Alidina, Z., Chesick-Gordis, M., Xie, W., Drögemöller, B. I., Wright, G. E. B., Birnie, K. A., Boerner, K. E., Tsang, V. W. L., Irwin, S. L., Pohl, D., Weil, A. G., Sell, E., Penz, E., Robson-MacKay, A., … Kelly, L. E. (2024). A multi-center tolerability study of a cannabidiol-enriched Cannabis Herbal Extract for chronic headaches in adolescents: The CAN-CHA protocol. PLOS ONE, 19(9), e0290185. https://doi.org/10.1371/journal.pone.0290185

Rhyne, D. N., Anderson, S. L., Gedde, M., & Borgelt, L. M. (2016). Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population. Pharmacotherapy, 36(5), 505–510. https://doi.org/10.1002/phar.1673

Cuttler, C., Spradlin, A., Cleveland, M. J., & Craft, R. M. (2020). Short- and Long-Term Effects of Cannabis on Headache and Migraine. The Journal of Pain, 21(5-6), 722–730. https://doi.org/10.1016/j.jpain.2019.11.001

Baron, E. P., Lucas, P., Eades, J., & Hogue, O. (2018). Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. The Journal of Headache and Pain, 19(1), 37. https://doi.org/10.1186/s10194-018-0862-2