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. 2025 Jan 13;65(5):863–870. doi: 10.1111/head.14901

Low serum 25‐hydroxyvitamin D levels in migraine are not related to headache frequency: A case‐control study in patients with high‐frequency/chronic migraine

Marina Haro 1, Gabriel Gárate 2, José Luis Hernández 1, José Manuel Olmos 1, María Muñoz BBiot 2, Vicente González‐Quintanilla 2, Julio Pascual 2,✉
PMCID: PMC12005613  PMID: 39803802

Abstract

Background

Serum 25‐hydroxyvitamin D (25[OH]D) concentrations have been shown to be low in patients with migraine, but results are controversial regarding the current role of vitamin D in migraine severity. Using a case–control design, we aimed to evaluate serum 25(OH)D levels in a group of females with high‐frequency episodic migraine/chronic migraine (HF/CM) and analyze its association with headache frequency and serum calcitonin gene–related peptide (CGRP) levels.

Methods

Serum 25(OH)D levels were measured in 97 females with HF/CM (age 48.9 ± 9.4 years) and 146 healthy females (47.4 ± 8.1 years). Participants taking vitamin D supplements were excluded. Serum concentrations of 25(OH)D were determined by electrochemiluminescence (Roche, Germany), and CGRP levels were measured by enzyme‐linked immunosorbent assay (Abbexa, UK).

Results

Mean 25(OH)D levels in females with HF/CM (median [interquartile range] 19.0 [13.0–24.5] ng/mL) were below the values considered for insufficiency or deficiency and significantly lower than controls (25.0 [19–29.8] ng/mL; p < 0.0001). Fifty (51.5%) patients with HF/CM had levels below 20 ng/mL. There was no significant association between vitamin D levels and monthly headache days (Spearman's rank correlation coefficient [rho]: −0.086; p = 0.404) or with serum α (rho: 0.114; p = 0.267) and β‐CGRP (rho: 0.113; p = 0.276) levels. Serum 25(OH)D levels in females with HF/CM with a minimum daily sunlight exposure were significantly higher than those without (23.0 [15.0–26.0] ng/mL vs. 14.0 [10.0–20.0] ng/mL; p < 0.001). Females with HF/CM who performed exercise had higher, albeit not significant, plasma 25(OH)D levels than those who did not (21.0 [15.5–28.0] ng/mL vs. 16.5 [12.0–24.0] ng/mL; p = 0.059).

Conclusions

Serum concentrations of 25(OH)D were low in many patients with HF/CM. Because there was no correlation with migraine frequency or serum CGRP levels, this deficiency seems to be a direct consequence of the migraine impact. Our data do not support either a relationship of 25(OH)D levels with migraine severity or the use of vitamin D supplements as a specific migraine treatment, although further studies are needed.

Keywords: 25‐hydroxyvitamin D, calcitonin gene–related peptide, migraine, vitamin D, α‐calcitonin gene–related peptide, β‐calcitonin gene–related peptide

Plain Language Summary

Past research has shown that vitamin D levels are lower in people with migraine compared to people without migraine, but it is unclear if this is related to the frequency of migraine attacks or the severity of attacks. In this study, we measured blood levels of vitamin D in a group of 97 female patients with high‐frequency headaches compared to 146 female patients without migraine, and we looked at how these levels related to headache frequency and calcitonin gene–related peptide (CGRP) levels in the blood. While we did find that vitamin D levels were lower in the participants with migraine, this was not correlated with levels of CGRP in the blood or with the frequency of migraine attacks; therefore, it may be that decreases in vitamin D levels are a consequence of migraine rather than a cause, but we need to do more research on this.

Abbreviations

25(OH)D

25‐hydroxyvitamin D

BMI

body mass index

CGRP

calcitonin gene–related peptide

CV

coefficient of variation

HF/CM

high‐frequency/chronic migraine

IQR

interquartile range

BACKGROUND

Both genetics and environmental factors have been involved in the development of migraine attacks. For instance, obesity; lack of exercise; or several nutrients, especially vitamins and minerals, appear to be associated with migraine. 1

Vitamin D is a fat‐soluble vitamin present in animal sources and produced by skin exposure to sunlight. It performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. Thus, it is argued that vitamin D levels are inversely associated with inflammation. 2 Moreover, vitamin D deficiency has been related to a variety of neurological disorders, including migraine. 3 , 4 Vitamin D deficiency refers to serum levels of vitamin D (serum total 25‐hydroxyvitamin D [25(OH)D]) that are inadequate to support bodily needs. Serum total 25(OH)D is currently considered the best marker of vitamin D status. However, there is no consensus regarding the serum level of 25(OH)D that represents optimal health or deficiency. Thus, the figure recommended by the Institute of Medicine is 20 ng/mL and the Endocrine Society defines vitamin D deficiency as a plasma 25(OH)D concentration below 20 ng/mL, and vitamin D insufficiency as a 25(OH)D level between 20 and 30 ng/mL. 5

There are several potential links between migraine and hypovitaminosis D. The first regards basic mechanisms, such as the anti‐inflammatory actions of vitamin D as well as the role of calcium in the contraction and dilation of the smooth muscle cells of blood vessel walls. In fact, the vascular theory of migraine involves the release of calcitonin gene–related peptide (CGRP), a powerful vasodilator of meningeal vessels. 6 Second, vitamin D levels have been, almost uniformly, lower than normal in patients with migraine. 7 Third, it has been proposed that the status of vitamin D could explain the apparent seasonal or latitude migraine variation. 8 , 9 Finally, some studies have suggested an improvement in migraine headaches with vitamin D supplementation and even an inverse correlation between migraine frequency and vitamin D levels, although data in this regard are preliminary and far from homogeneous. 10

Our hypothesis was that there is a potential role of vitamin D in migraine and in migraine severity, and this role is not determined by other known factors that are involved in the regulation of vitamin D levels but rather by the migraine itself. We aimed to evaluate serum 25(OH)D levels in a group of females with high‐frequency/chronic migraine (HF/CM) and the potential association of vitamin D concentrations with headache frequency and serum CGRP levels as clinical and laboratory biomarkers.

METHODS

Ethics

The study was approved by the Ethics Committee of Investigations with Medications of Cantabria, and its approval was published on record 28/2020, 11th December. All participants gave and signed written informed consent.

Study participants

We recruited females fulfilling HF/CM criteria 11 aged ≥18 years attending our headache clinic between October 2020 and March 2023, who had not responded to at least three oral preventatives and, in the case of patients with CM, to onabotulinumtoxin type A. Patients who were taking vitamin D supplements were excluded from the study.

Serum 25(OH)D and CGRP levels were measured just before the initiation of CGRP monoclonal antibodies. All females with HF/CM kept a monthly headache diary in which they recorded headache days and the use of symptomatic medication. We analyzed two additional parameters with potential influence on vitamin D levels by an ad hoc questionnaire: a minimum of physical activity (at least 30 minutes of exercise 3 days a week) and sunlight exposure (at least 15 minutes/day on face and arms during spring, summer, and fall). All females with HF/CM were on preventatives at the time of the laboratory determinations. As healthy controls for this case–control design, we recruited females with similar age and sex distribution as the HF/CM group with subjective absence of headache, without a history of migraine, and who were not taking any medication.

Blood extraction, serum processing, and laboratory procedures

Serum 25(OH)D and CGRP levels were determined in the same morning (9–12 am). Blood samples were obtained in females on migraine‐free days and without using symptomatic medication in the previous 24 hours. Concentrations of 25(OH)D were determined by electrochemiluminescence (Elecsys 2010, Roche Diagnostics, GmbH, Mannheim, Germany), as performed in previous studies. 12 The detection limit of serum 25(OH)D was 4 ng/mL, its intraassay coefficient of variation (CV) 5%, and its interassay CV 7.5%.

Serum α‐ and β‐CGRP levels were determined by using commercial enzyme‐linked immunosorbent assays (Abbexa, UK and CUSABIO, China, respectively), as previously described. 13

Statistical analysis

Categorical variables are expressed as frequencies and percentages, whereas continuous variables are reported as mean ± standard deviation for normally distributed data and together with median and interquartile range (IQR) for non‐normally distributed data. The normality assumption of continuous and count data has been checked using the Shapiro–Wilk test. For normally distributed continuous data, the assumption of equal variances was verified by the F‐test of equality of variances. Continuous variables were assessed using the t‐test or Mann–Whitney U test as appropriate. Analysis of the correlation between Vitamin D levels and monthly headache days, α‐CGRP, and β‐CGRP levels was performed by using Spearman's rank correlation analysis. A multivariable general linear model with Bonferroni correction, adjusted by age, body mass index (BMI), season, and glomerular filtration rate, according to the Modification of Diet in Renal Disease 4‐variable equation, was built to test the differences in 25(OH)D levels between patients with migraine and controls.

All tests were two‐tailed, and significance was set at p < 0.05. All analyses were performed using GraphPad Prism version 9.4.1 (GraphPad Software, Boston, MA, USA) except the sample size calculation, for which we used EPIDAT 4.1 (Servizo Galego de Saúde, Santiago de Compostela, Galicia, Spain).

Based on the literature results and our previous studies on vitamin D and CGRP levels, 12 , 13 we calculated that with an expected difference mean of 20%, an alpha equal to 0.05, and a power of 80%, we had to include a minimum of 40 participants per group.

RESULTS

Characteristics of participants

We asked 123 individuals with HF/CM to participate, and none declined the invitation. Twenty‐six patients were excluded: 14 were on active vitamin D supplements at recruitment, and the other 12 were males. The final sample comprised 97 females with HF/CM and 146 healthy controls (Figure 1). The mean age of patients with HF/CM was 48.9 ± 9.4 years, and that of healthy controls was 47.4 ± 8.1 years (p = 0.373). The detailed clinical features from the final group of participants included are summarized in Table 1. There were no missing data for any of the variables recorded.

FIGURE 1.

FIGURE 1

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Flow diagram of participants, controls, and patients included and excluded in this study. HF/CM, high‐frequency chronic migraine. [Colour figure can be viewed at wileyonlinelibrary.com]

TABLE 1.

Baseline characteristics of patients with migraine and control females.

Migraine Controls p‐value
Age (years; mean ± SD) 48.9 ± 9.4 47.4 ± 8.1 0.373
BMI (Kg/m2; mean ± SD) 25 ± 5.2 27.1 ± 5.8 0.066
Serum 25(OH)D (ng/mL; median [IQR]) 19.9 ± 8.9 25.0 ± 8.0 p < 0.001
GFR (mL/min/1.73 m2) 101 ± 18 98 ± 15 0.17
Serum 25(OH)D ≥20 ng/mL: n (%) 47 (48.5) 108 (74.0) p < 0.001
Serum 25(OH)D ≥30 ng/mL: n (%) 11 (11.3) 38 (26.0) p = 0.005
Obesity: n (%) 16 (16.5) 32 (21.9) 0.298
Current smoker: n (%) 22 (22.7) 43 (29.5) 0.243
Season sample (winter): n (%) 42 (43.3) 60 (41.1) 0.733
Arterial hypertension: n (%) 20 (20.6) 27 (18.5) 0.681
Anxiety‐depressive syndrome: n (%) 59 (60.8) 26 (17.8) p < 0.001
Fibromyalgia: n (%) 25 (25.8) 6 (4.1) p < 0.001
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Abbreviations: 25(OH)D, 25‐hydroxyvitamin D; BMI, body mass index; GFR, glomerular filtration rate according to the Modification of Diet in Renal Disease formula; SD, standard deviation.

Serum 25(OH)D and CGRP levels and association with clinical variables

Serum 25(OH)D levels in females with HF/CM were: 19.9 ± 8.9 ng/mL (median [IQR]; 19 [13.0–24.5] ng/mL). These values were below the range considered as insufficiency or even deficiency, 5 and were significantly lower than those observed in healthy females (mean: 25.0 ± 8.0 ng/mL; median [IQR]: 25 [19–29.8] ng/mL; p < 0.0001; Figure 2). These results remained significant after adjusting for age, BMI, season, and glomerular filtration rate in the multivariable model (21.0 ng/mL in cases and 24.2 ng/mL in controls; p = 0.014). Fifty‐one percent of patients with migraine and 25.3% of controls had serum 25(OH)D levels < 20 ng/mL (p < 0.0001).

FIGURE 2.

FIGURE 2

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Serum 25(OH)D levels in patients with HF/CM and healthy females (p < 0.001). 25(OH)D, 25‐hydroxyvitamin D; HC, healthy control; HF/CM, high‐frequency chronic migraine.

In females with HF/CM, the 25(OH)D concentration was uniformly lower independent of season, and they did not show differences when sorted by this criterion. Females with migraine and obesity tended to have lower concentrations of serum 25(OH)D (15.9 ± 6.4 ng/mL; median [IQR]: 14.0 [10.0–24.0] ng/mL) than those with normal weight (20.7 ± 9.1 ng/mL; median [IQR]: 20.0 [14.0–25.0] ng/mL) although it did not reach significance (p = 0.056). The presence of aura, fibromyalgia, anxiety‐depressive syndrome, or the use of anticonvulsants (topiramate or valproic acid) as migraine preventatives did not have any influence on serum 25(OH)D levels.

Serum α‐CGRP levels in the migraine group (mean: 58.1 ± 59.9 pg/mL; median [IQR]: 45.2 [31.0–68.8] pg/mL) were significantly higher than those found in the control group (p = 0.007), while β‐CGRP levels (mean: 3.9 ± 2.9 pg/mL; median [IQR]: 3.2 [1.8–6.1] pg/mL) were similar in both groups (p = 0.728).

We did not find any significant correlation between serum 25(OH)D levels and monthly headache days (Spearman's rank correlation coefficient [rho]: −0.086; p = 0.404), serum α‐CGRP (rho: 0.114; p = 0.267), and β‐CGRP (rho: 0.113; p = 0.276) levels in females with HF/CM (Figure 3). When performing the same correlation tests but only in patients with vitamin D deficiency, there was no significant correlation between serum 25(OH)D levels and monthly headache days (rho: −0.153; p = 0.348), serum α‐CGRP (rho: −0.060; p = 0.667), and β‐CGRP (rho: 0.012; p = 0.957).

FIGURE 3.

FIGURE 3

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Correlation between 25(OH)D levels and (A) monthly headache days (p = 0.404), (B) α‐CGRP (p = 0.267), and (C) β‐CGRP (p = 0.276) levels in females with HF/CM. 25(OH)D, 25‐hydroxyvitamin D; CGRP, calcitonin gene–related peptide; HF/CM, high‐frequency chronic migraine. [Colour figure can be viewed at wileyonlinelibrary.com]

Females with migraine who had serum 25(OH)D levels < 20 ng/mL had no significant difference in monthly headache days compared to those with 25(OH)D levels ≥20 ng/mL (p = 0.996). We did not find any significant difference concerning serum α‐ and β‐CGRP (p = 0.102 and p = 0.535, respectively) in both groups of patients.

Exercise and sunlight exposure and serum 25(OH)D levels

Thirty‐seven (38.1%) females with HF/CM performed the minimum required exercise (30 minutes 3 days a week). Serum 25(OH)D concentrations in females performing exercise (mean: 22.1 ± 9.5 ng/mL, median [IQR]: 21.0 [15.5–28.0] ng/mL) tended to be higher than in the 60 (61.9%) who did not perform any kind of exercise (mean 18.5 ± 8.2 ng/mL; median [IQR]: 16.5 [12.0–24.0] ng/mL; p = 0.059).

Thirty‐four (35.1%) females with HF/CM did not reach the required minimum daily sunlight exposure, while the remaining 63 (64.9%) had sun exposure of more than 15 minutes a day. When 25(OH)D concentrations were analyzed in both groups of patients, it was observed that females with a minimum of sunlight exposure (mean 22.1 ± 9.2 ng/mL; median [IQR]: 23.0 [15.0–26.0] ng/mL) had significantly higher levels than those found in patients who do not meet the minimum required sunlight exposure (mean 15.9 ± 6.6 ng/mL; median [IQR]: 14.0 [10.0–20.0] ng/mL; p < 0.001).

Females with HF/CM who fulfilled both of these criteria, exercise and sunlight exposure (n = 30; 30.9%), had significantly higher serum 25(OH)D concentrations (mean 23.1 ± 9.5; median [IQR]: 23.0 [17.0–28.3] ng/mL) than those (n = 67; 69.1%) who failed to fulfill one or both criteria (mean 18.5 ± 8.2 ng/mL; median [IQR]: 17.0 [12.0–24.0] ng/mL; p = 0.018; Figure 4).

FIGURE 4.

FIGURE 4

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Serum 25(OH)D levels in females with HF/CM (A) performing and not performing exercise, (B) with/without minimum sunlight exposure, and (C) with/without fulfilling both criteria. 25(OH)D, 25‐hydroxyvitamin D; HF/CM, high‐frequency chronic migraine.

DISCUSSION

We found serum 25(OH)D levels below the range considered as insufficient or deficient in a cohort of females with HF/CM and lower compared to a control group of healthy females. These results are in line with previous studies that have shown a decrease in the levels of this vitamin in patients with migraine almost uniformly. 3 , 4 , 14 However, we did not find any relationship between serum 25(OH)D levels and migraine severity, as measured by clinical and biological parameters. Both the number of headache days and α‐ and β‐CGRP levels in females with HF/CM showed no correlation with 25(OH)D levels, which indicates that vitamin D does not play a key role in the mechanisms involved in migraine severity or its chronification. Data on the influence of low vitamin D levels on migraine severity are controversial, with some studies suggesting an inverse correlation 15 , 16 , 17 , 18 that has not been confirmed by others. 19 , 20 , 21

The same occurs with the effect of vitamin D supplementation in patients with migraine. The first uncontrolled studies indicated some benefit, 22 , 23 but, concurring with our results, a recent controlled clinical trial showed no benefit in migraine frequency or severity in adults receiving vitamin D supplementation. 24

We found a clear correlation between low serum 25(OH)D levels and the lack of exercise 25 or sunlight exposure, 26 which suggests that low vitamin D levels are one of the consequences of experiencing migraine. Migraine, especially in its more severe forms of HF/CM, is known to negatively influence many aspects of daily life, including physical activity, which characteristically worsens migraine pain, or sunlight exposure, which can develop a migraine attack or impair photophobia. 27 Therefore, our results for migraine are in line with those obtained in other neuropsychiatric disorders, such as multiple sclerosis, depression, or chronic pain, in which low serum 25(OH)D levels also seem to be a consequence of the disease because vitamin D supplementation does not result in an improvement of this demyelinating disease. 28 , 29 The reduced levels of 25(OH)D seen in migraine and these diseases suggest a compelling rationale to investigate the potential association between single nucleotide variants in vitamin D–related genes and their risk. 30

In addition to the effects on tissues directly responsible for calcium homeostasis, vitamin D regulates the function of a wide number of other tissues. Vitamin D deficiency should be treated, especially in persons with little or no sunlight exposure and patients with malabsorption or osteoporosis. 31 Although vitamin D supplementation seems to not prevent or improve bone fractures, cancer, cardiovascular disease, cognitive impairment, atrial fibrillation, stroke outcomes, age‐related macular degeneration, knee pain, or migraine frequency, even in the presence of low serum 25(OH)D levels, it is estimated that at least one third of US adults older than 60 years take vitamin D supplements. Therefore, with the available evidence, there is no justification for measuring vitamin D or treating it to a target serum level in the general population. 31 , 32

The main limitation of our study could be that our results are not necessarily valid for the general population of patients with migraine, as they come from a selected cohort of refractory females with HF/CM (not males) who were studied before the treatment with anti‐CGRP monoclonal antibodies. Even with the potential exception of obesity, 33 we found no influence of several clinical variables, such as depression 34 or the use of antiseizure medications, on serum 25(OH)D levels. 35 As other neuropeptides have been involved in migraine, the lack of association between 25(OH)D and CGRP levels does not necessarily preclude the role of vitamin D in migraine. One further limitation of this study would be the fact that measuring serum CGRP levels is not fully standardized. Our results must be interpreted with caution, considering the relatively small sample size in these subgroups.

CONCLUSIONS

In summary, females experiencing HF/CM migraine had lower serum 25(OH)D levels than age‐matched healthy controls, with half of them in the range of insufficiency or deficiency (<20 ng/mL). Nevertheless, we did not find any association between either serum 25(OH)D levels and the severity of migraine or baseline serum CGRP levels, suggesting that the routine use of vitamin D supplements in patients with migraine on anti‐CGRP antibodies does not seem to be justified. However, whether vitamin D supplementation could improve migraine severity in these patients should be tested in a randomized clinical trial focused on patients with migraine with 25(OH)D deficiency.

AUTHOR CONTRIBUTIONS

Gabriel Gárate: Data curation; formal analysis; investigation; methodology; software; writing – review and editing. José Luis Hernández: Data curation; formal analysis; methodology; validation; writing – review and editing. José Manuel Olmos: Conceptualization; investigation; validation; writing – review and editing. Marina Haro: Data curation; investigation; writing – review and editing. María Muñoz: Data curation; investigation; methodology; writing – review and editing. Vicente González‐Quintanilla: Data curation; investigation; writing – review and editing. Julio Pascual: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; supervision; validation; writing – original draft; writing – review and editing.

FUNDING INFORMATION

This study has been founded by Instituto de Salud Carlos III (ISCIII) through the project PI20/01358 co‐funded by Fondos Europeos de Desarrollo Regional (FEDER), “Una manera de hacer Europa,” and PI21/00532 from ISCIII co‐funded by FEDER.

CONFLICT OF INTEREST STATEMENT

Marina Haro, Gabriel Gárate, José Luis Hernández, José Manuel Olmos, María Muñoz, Vicente González‐Quintanilla, and Julio Pascual declare no conflicts of interest.

ACKNOWLEDGMENTS

We are grateful to our nurses María Victoria Sánchez and Nadia Carmen Cavada for their continuous support.

Haro M, Gárate G, Hernández JL, et al. Low serum 25‐hydroxyvitamin D levels in migraine are not related to headache frequency: A case‐control study in patients with high‐frequency/chronic migraine. Headache. 2025;65:863‐870. doi: 10.1111/head.14901

Marina Haro and Gabriel Gárate contributed equally to this work.

DATA AVAILABILITY STATEMENT

The data, laboratory methods, and study materials are available to other researchers upon reasonable request.

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Data Availability Statement

The data, laboratory methods, and study materials are available to other researchers upon reasonable request.

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