Heavy Metal and Trace Element Alterations Observed in Patients During a Migraine Attack

Sevilay Vural, MD

A recently published prospective study of patients with migraine and sex-matched healthy controls revealed alterations in heavy metal and trace elements (HMTE) among those with migraine, suggesting a role of HMTE in migraine pathogenesis. All told, patients with migraine had higher Arsenic (As), cobalt (Co), lead (Pb), nickel (Ni), and magnesium (Mn), while having lower chromium (Cr), magnesium (Mg), and zinc (Zn) blood levels.

Published in Headache, the Turkey-based study included 100 participants, 50 of which with migraine and 50 age- and sex-matched healthy controls. Overall, the median age of the cohort was 27 (range, 23-37) years, and the female/male ratio was 37/13 for both groups. Coming into the study, the mean/median levels of tested HMTEs did not exceed the internationally determined biological exposure indices (BEI), which are values used to guide and assess biological monitoring results.

Led by Sevilay Vural, MD, an associate professor at Yozgat Bozok University, the analysis was performed by an inductively coupled plasma mass spectrometry (ICP-MS) instrument (iCAP qc; Thermo Fisher Scientific). A total of 7 heavy metal (As, Cd, Co, Pb, mercury [Hg], Ni, and tin [Sn]) and 8 trace element parameters (antimony [Sb], Cr, copper [Cu], iron [Fe], Mg, manganese [Mn], molybdenum [Mo] and Zn) were measured in the samples.

Nitric acid was used for the sample and certified reference material (CRM) digestion. For more context, Seronorm Trace Elements Whole Blood L-2 was the commercial CRM product used in the study while Ultra-pure water was used for dilution of calibration standards, and sample preparation. CRM standards were tested 5 times to increase the accuracy of the results and reduce the relative standard deviation (SD).

In comparison with healthy controls, those with migraine showed increased levels of certain heavy metals, including As (4.79 [±1.04] vs 5.39 [±1.39] μg/L; P = .033), Co (0.80 [±0.47] vs 1.05 [±0.54] μg/L; P = .017), Pb (24.27 [±19.00] vs 34.28 [±23.63] μg/L; P = .022), and Ni (0.94 [±0.23] vs 1.12 [±0.48]; P = .021). Levels of Cd and Sn were similar for patients with migraine (P = .165) and controls (P = .997). Although Hg levels were analyzed for both groups, the relevant levels were found to be below the detection limit.

READ MORE: NeuroVoices: Jessica Ailani, MD, on Implications of DELIVER Analysis With Eptinezumab for Migraine Prevention

In terms of trace elements, those with migraine had decreased levels of Cr (8.39 [±1.45] vs 7.64 [±1.27] μg/L; P = .0007), Mg (16.52 [±4.97] vs 14.48 [±3.84] μg/L; P = .024) and Zn (3498.55 [1647.33-9243.83] vs 1641.98 [1078.06-2752.21] μg/L; P <.001). In contrast to the decreased Cr, Mg, and Zn observed among those with migraine, Mn levels were significantly higher in this group (6.48 [±2.43] vs 9.68 [±5.37] μg/L; P = .001). There were no statistically significant differences between groups on other levels of Sb, Cu, Fe, and Mo

"The elevated levels of Mn can be considered surprising as we had anticipated a general downward trend in trace elements," the study authors wrote.¹ "Mn is essential for human health by acting as a cofactor in the active centers of various enzymes and is required for numerous vital processes, including normal nerve and brain development, cognitive functions, and more; however, overexposure to this metal can be toxic to many organ systems at different life stages. It has been associated with other negative outcomes, including parkinsonism, learning deficits, and neurodegeneration. By altering neurotransmission via low concentrations of gamma-aminobutyric acid (GABA), Mn may play a role in the pathophysiology of migraine and other central pain syndromes."

The study had several strengths and limitations, including that it was performed in a larger population with a wider collection of HMTEs than previous notable studies. Overall, the analysis was limited by the fact that the related symptoms and clinical findings of migraine, like pain severity or frequency, were not considered. In addition, there were other confounding factors, like living location, water source, food/diet type, or unmentioned supplement use, that may have caused alterations in HMTEs.

Vural et al concluded that, “the relationships among HMTEs can be instructive for future studies and may gain importance over time. In light of previous reports, expecting higher heavy metal and/or lower trace element levels was a reasonable assumption in the patients with migraine group. Therefore, inverse relationships between heavy metals and trace elements would not be surprising, which we found not true for all. Nevertheless, our aim was to establish a foundation for future research by reporting relatively common HMTE parameter levels and highlighting the general trends between them in patients with migraine."

REFERENCE
1. Vural S, Turksoy VA, Akgeyik AU, Kusdogan M. Heavy metal and trace element alterations in patients during a migraine attack. Headache. 2024;64(7):764-771. doi:10.1111/head.14748