An Update on Nutraceuticals for Migraine Management

Integrative medicine brings mainstream and complementary treatments together, emphasizing a person-focused approach to wellness. Whereas 28% to 82% of people with headache use integrative approaches, more than half do not discuss their use of these approaches with their clinician.¹ The most commonly used integrative modalities in headache medicine include nutraceutical supplements, mind/body therapies, and manipulation therapies.² This article focuses on recent updates in nutraceuticals for the management of migraine.

This article details 4 supplements for which clinicians should be aware of the current evidence for their safety, efficacy, and other nuances regarding their use. Other supplements, namely magnesium and riboflavin, also have a use in migraine prevention that has been discussed in established guidelines elsewhere but were not included herein for the sake of brevity.

Butterbur

Butterbur (Petasites hybridus) is a perennial herb native to northern Europe. The main constituents of the petasin chemotype of butterbur are the active ingredients petasin and isopetasin. P hybridus exerts anti-inflammatory properties, can dampen nociceptive pathways, and has been studied for migraine and allergic rhinitis.^3,4 Petasins—the primary active component in butterbur—have been found to inhibit prostaglandin and leukotriene biosynthesis.^5,6

Whereas many formulations of butterbur extract without petasins are available, 1 extract—Petadolex—contains at least 15% petasins and isopetasins. Petadolex has been established for the prevention of migraine from both a safety and efficacy standpoint, and it is the only butterbur formulation associated with these data.⁷ Participants taking 50 mg twice daily saw a reduction in migraine days from 3.4 to 1.8 after 3 months compared with 2.9 to 2.6 in the placebo arm.⁷ A dose comparison study of 75 mg twice daily, 50 mg twice daily, and placebo over 4 months of treatment reported a reduction in migraine frequency of 48%, 36%, and 26%, respectively.⁸ The most common adverse effects in this trial were gastrointestinal complications (mainly burping).⁸

The latest data discuss the effects of P hybridus on conditions such as asthma and other inflammatory conditions.^4,5,9 According to Borlak et al⁴ and Thomet et al,⁵P hybridus (of the petasin chemotype) contains sesquiterpene ester components (eg, petasin and isopetasin) and blocks inflammatory factors such as inflammatory mediators prostaglandin E2, leukotriene B4, and cysteinyl-leukotrienes. Petasins have also been found to block intracellular calcium influx in animal models.¹⁰ This calcium channel–blocking effect results in relaxation within the smooth muscle found in blood vessels. Petasins are thought to decrease cardiac contraction and relax blood vessels in hypertensive animal models.^4,10 In regard to migraine, basic research has also found that petasins dampen pain perception by desensitizing calcium-conducting transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) ion channels of primary sensory neurons. New research shows that Petadolex inhibits the release of calcitonin gene-related peptide of meningeal afferents during migraine attacks.

Safety concerns have been raised about noncommercially prepared butterbur formulations because of the presence of pyrrolizidine alkaloids, which can be toxic to the liver and cause herbal-induced liver injury.¹ There have been no reported cases of herbal-induced liver injury with the commercially prepared Petadolex in the United States or Canada since its launch in 1999, but the risk exists with other commercially available products that have not undergone the purification process for plant carcinogens and hepatotoxic alkaloids. The risk is especially relevant for people who use such butterbur supplements for prevention along with other medications that affect the liver.¹¹ Butterbur products should only be taken if they are labeled and certified as pyrrolizidine alkaloid–free, they have a minimum of 15% petasins, and serial liver function tests are performed in people with a history of impaired liver function or comedication with drugs that may have toxic effects on the liver.

Coenzyme Q10

Coenzyme Q10 (CoQ10) has been used for episodic migraine prevention based mostly on small randomized controlled trials (RCTs). The mechanism by which CoQ10 may prevent migraine is unclear. However, CoQ10 appears to reduce inflammatory markers associated with migraine as well as cytokines and matrix metalloproteinase-9, the latter of which has been found to be elevated in cortical spreading depression.^12,13 A meta-analysis by Sazali et al¹⁴ collected 6 small RCTs totaling 371 participants in whom CoQ10 was studied vs placebo for migraine prevention. The dose of CoQ10 varied across studies from 30 mg/d to 800 mg/d. The meta-analysis found no difference in headache severity in those taking CoQ10 compared with those taking a placebo. The analysis found a reduction in the duration of headache episodes (–0.19 hours), and a reduction in headache frequency (–1.52 times per month). Two previous smaller meta-analyses had less favorable conclusions: 1 found no difference in headache duration, frequency, or severity; the other only found a reduction in headache frequency.^15,16

CoQ10 has poor bioavailability, which may be a confounding factor in these studies. Supplementation with the reduced form of CoQ10, also known as ubiquinol, is technically better absorbed and significantly raises CoQ10 levels compared with supplementation with oxidized CoQ10.¹⁷ The bioavailability of oxidized CoQ10 can be increased greatly through the use of lipids (Q-Sorb), incorporation into an oligosaccharide complex (Hydro-Q-Sorb), or bonding to nanobeadlets dispersed into a water-soluble gelatin matrix (All-Q), with significantly increasing rates of bioavailability associated with each binding agent, respectively.¹⁸ Nevertheless, the clinical relevance of CoQ10 preparation bioavailability is unknown.¹⁹ Furthermore, the effect of other drugs on CoQ10 levels confounds our understanding. For example, people with depression have lower CoQ10 levels compared with healthy individuals, but people with depression exposed to amitriptyline had significantly lower CoQ10 levels compared with an unexposed cohort with depression.²⁰ There is no evidence to suggest a benefit of CoQ10 supplementation in people taking amitriptyline.

Vitamin D

Vitamin D deficiency is associated with 1.2 times more migraine headache days, and higher circulating levels of vitamin D are associated with reduced migraine risk.^21,22 An explanation for the relationship of vitamin D with migraine remains elusive. Several specific single nucleotide variants in the vitamin D receptor gene (VDR) have been associated with increased migraine risk, and although a recent study failed to duplicate the findings, the authors reported another VDR variant that may be associated with migraine triggered by ethanol exposure.²³ A recent meta-analysis of 6 RCTs (n=301) reported that vitamin D supplementation decreased the number of headache attacks per month, headache days per month, and Migraine Disability Assessment (MIDAS) scores but did not change attack duration or headache severity.²⁴ Dosing varied among studies, with 3 studies using vitamin D3 2,000 IU/day, 1 study using vitamin D3 4,000 IU/day, 1 using vitamin D2 50,000 IU weekly, and 1 using vitamin D3 500,000 IU weekly.

Vitamin D supplementation in people already predisposed to hypercalciuria may be associated with a higher risk for nephrolithiasis.²⁵ Caution is advised with vitamin D supplementation in people predisposed to hypercalciuria or those with a history of kidney stone formation. Vitamin D3 2000 IU/day in an individual with vitamin D deficiency typically is enough to achieve an adequate vitamin D level of 40 ng/mL, although doses several times higher may be necessary in people with obesity or morbid obesity because of higher volume of distribution. Levels of 25-hydroxyvitamin D should be checked periodically to monitor response and avoid toxicity.

Curcumin

Curcumin is a bioactive polyphenol derived from turmeric, with long-purported anti-inflammatory benefits. Curcumin is also a VDR ligand.²⁶ Curcumin has extremely poor water solubility and bioavailability, and different techniques are used to improve absorption. Older techniques, such as pairing curcumin with an absorption enhancer such as black pepper extract (BioPerine), yield only modest improvement in bioavailability. More recent technologies have been developed to increase curcumin bioavailability, including incorporating curcumin in lipophilic turmeric oils (BCM-95), liposomes (Meriva, Longvida), nanoparticles (Theracurmin), cyclodextrin complexes (Cavacurmin), or nanomicelles (NovaSOL).²⁷ These technologies are proprietary, and the products are sold and branded to companies for the consumer market. Although the companies behind these technologies advertise higher bioavailability, the extent of in vivo exposure area under the curve is unknown, and the potency of different curcumin preparations is not directly comparable in milligrams. One study compared native, BioPerine, Longvida, Meriva, BCM-95, Cavacurmin, Theracurmin, and NovaSOL curcumin preparations at identical dosages, and found that only NovaSOL and, to a lesser degree, Cavacurmin demonstrated significantly higher area under the curve in the first 24 hours vs other preparations. The authors provided evidence to suggest that postdigestive solubility and stability, not just increased bioavailability, may have accounted for the difference.²⁸

For migraine prevention, 1 RCT from Iran, using a nanomicelle curcumin agent (SinaCurcumin), showed potential migraine prevention benefits.²⁹ The 8-week study involved nearly 100 participants with episodic migraine randomly assigned to nanocurcumin plus CoQ10, nanocurcumin only, CoQ10 only, or placebo. Participants received amitriptyline or topiramate starting 1 month before the start of the trial for ethical purposes. Whereas the study showed synergistic benefits in the nanocurcumin plus CoQ10 cohort, most of the benefits appeared to be from CoQ10. SinaCurcumin is not available in the United States.

Curcumin preparations tend to be very well-tolerated, although a small study using NovaSOL reported that 7 out of 23 participants experienced nausea.³⁰ Turmeric extracts can have high oxalate levels, increasing the risk for calcium oxalate nephrolithiasis, but higher-quality curcumin extracts generally include independent testing verification to be reportedly free of oxalates.

Conclusion

Butterbur may reduce migraine frequency in a predictable dose–response relationship. CoQ10 supplementation appears to reduce headache frequency and duration, although the bioavailability of products varies, which may or may not influence efficacy. Vitamin D supplementation may help reduce headache frequency. Further research is needed to determine the safety and efficacy of curcumin in migraine prevention.