By Concepta Merry, MB, BCh, BAO, BA

Associate Professor, Global Health, School of Medicine, Trinity College Dublin; Integrative Medicine Fellow, University of Arizona, Tucson

Dr. Merry reports no financial relationships relevant to this field of study.

SYNOPSIS: A well-conducted, randomized, placebo-controlled trial has shown that the combination of simvastatin (20 mg twice daily) plus vitamin D3 (1,000 international units twice daily) is effective in the prevention of headaches in adults with episodic migraine.

SOURCE: Buettner C, Nir RR, Bertisch SM, et al. Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial. Ann Neurol 2015;78:970-981.

Migraine headaches are a leading cause of disability worldwide.1 Unfortunately, the natural history of migraine demonstrates that headaches tend to become more frequent and more severe with advancing age. Prevention of migraine relies on avoidance of known triggers and prophylaxis with agents such as beta-blockers, tricyclic antidepressants, and anticonvulsants.2 An integrative health approach also might include butterbur or riboflavin in the prophylactic armamentarium.3 Despite all of this, some continue suffering from debilitating migraine headaches.

A double-blind, randomized, placebo-controlled trial showed that the novel combination of simvastatin plus vitamin D is safe and effective at preventing migraine headaches. The rationale for the new study was two-fold. First, there is a possible biological explanation for the clinical effect. Migraine headaches are associated with endothelial dysfunction and inflammation. Statin therapy fills an established role in modulating endothelial dysfunction.4 Vitamin D acts synergistically with statins to exert an additional anti-inflammatory effect.5 Vitamin D also modulates the musculoskeletal pain associated with statin therapy.6 Second, a previous study conducted by the same research group showed a favorable effect of statin therapy plus vitamin D in migraine.7

The new study recruited 57 adults with a history of at least three years of episodic migraine living in Boston. Baseline data were collected over an initial 12-week period. Participants were randomly allocated to either take simvastatin 20 mg twice daily plus vitamin D3 1,000 international units twice daily or matching placebo. Study participants in both groups continued their usual abortive and prophylactic migraine management. Adherence was measured by pill counts and changes in low-density lipoprotein cholesterol measurements in the active group. Study participants kept a detailed migraine diary throughout the study period. Study participants were followed over a 24-week period.

The good news for migraine sufferers is that the treatment group experienced a significant reduction in the number of migraine days (P < 0.001). The active group used abortive medication on fewer days (P < 0.001) and used fewer doses of these medications (P < 0.001) as compared with their own baseline. Interestingly, there was no significant change in either group compared with baseline in terms of the symptoms associated with migraine such as migraine severity, migraine duration, or the proportion of headaches that occurred with throbbing, photophobia, or nausea. In effect, there was no benefit in terms of severity or duration once the migraine headache took off. Finally, the combination treatment demonstrated a good safety profile, and researchers noted no significant side effects attributable to the prescribed medication (including muscle pains).


Migraine headaches can negatively affect quality of life. Migraine sufferers, their families, coworkers, and healthcare providers will likely welcome this study. Essentially, the novel combination of simvastatin with vitamin D was effective in preventing migraine headaches and was well tolerated. It is worth noting that the study sample size was small, but this is balanced to some degree by the fact that the study was well conducted. Another plus for the study results is the fact that statin and/or vitamin D therapy have other health benefits, especially for patients living in northern climates. Theoretically, the benefits observed in the study with simvastatin could reasonably be expected to extend to other statins too, but it is hard to say for sure at this stage.

The Buettner et al study was not powered to evaluate the relative contributions of the statin alone vs. vitamin D alone vs. the combination. Finally, it is worth mentioning that primary investigators have filed a patent for the combination of a statin plus vitamin D for migraine prevention.

One shortcoming of the study from an integrative health perspective is the fact that there was no mention of integrative therapies. Consider this when thinking about introducing the results of this study into patients who are using complementary therapies for migraine. A practical approach might be to monitor liver function tests in patients taking butterbur with pravastatin, as both agents can cause clinically significant rises in liver function tests.8 The bottom line is that this is definitely worth a try.


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  2. Hepp Z, Bloudek LM, Varon SF. Systematic review of migraine prophylaxis adherence and persistence. J Manag Care Pharm 2014;20:22-33.
  3. Rios J, Passe MM. Evidence-based use of botanicals, minerals, and vitamins in the prophylactic treatment of migraines. J Am Acad Nurse Pract 2004;16:251-256.
  4. Tousoulis D, Psarros C, Demosthenous M, et al. Innate and adaptive inflammation as a therapeutic target in vascular disease: The emerging role of statins. J Am Coll Cardiol 2014;63:
  5. Hewison M, Freeman L, Hughes SV, et al. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 2003;170:5382-5390.
  6. Morioka TY, Lee AJ, Bertisch S, et al. Vitamin D status modifies the association between statin use and musculoskeletal pain: A population based study. Atherosclerosis 2015;238:77-82.
  7. Buettner C, Burstein R. Association of statin use and risk for severe headache or migraine by serum vitamin D status: A cross-sectional population-based study. Cephalalgia 2015;35:757-766.
  8. National Center for Complementary and Integrative Health. Butterbur. Available at: Accessed May 25, 2016.