Magnesium and the Brain: A Big Roundup of Depression, Migraine, and Dementia—Where the Evidence Is Strongest

Magnesium has long figured in conversations about the “nervous system”: it is involved in hundreds of reactions, modulates neuronal excitation, and influences vascular tone and inflammation. A team from Semmelweis University collected clinical data from 2000 to 2025 and published a review in Nutrients on the role of magnesium in depression, migraine, Alzheimer’s disease, and cognitive aging. The basic idea is simple but practical: magnesium deficiency is more common in patients with these conditions and is associated with worse outcomes; magnesium supplements sometimes help – but the effect depends on the diagnosis, the form of magnesium, the dose, and the baseline status, and the data are mixed.

Background

Magnesium is one of the key "brain electrolytes". It is a natural NMDA receptor blocker (inhibits excitotoxicity), participates in GABAergic transmission, regulates the hypothalamic-pituitary-adrenal axis, vascular tone, inflammatory and antioxidant pathways. At the population level, chronic magnesium deficiency is not uncommon: diets with excess ultra-processed foods, low proportion of whole grains/legumes/greens and risk factors (insulin resistance, alcoholism, old age, PPI and diuretic use) increase the likelihood of latent hypomagnesemia. However, standard serum concentration is a crude marker: significant intracellular deficiencies can be hidden with "normal" serum, which complicates the selection of participants and explains the inconsistency of clinical results.

Interest in magnesium in neurology and psychiatry is fueled by three lines of evidence. First, observational studies: patients with depression, migraine, and cognitive decline are more likely to have lower magnesium status; in the elderly, serum magnesium shows a U-shaped relationship with dementia risk (both low and high levels are dangerous). Second, mechanistic models: magnesium shifts the excitation/inhibition balance, improves neurovascular reactivity, modulates proinflammatory cascades and the stress response; for migraine, effects on cortical excitability and the trigeminovascular system are added. Third, clinical trials: a number of RCTs and practical schemes show benefits of magnesium supplementation in migraine (especially oral forms and combination nutritional protocols), and in depression, mainly as an adjuvant in people with deficiency; for cognitive impairment, the signals are heterogeneous and depend on the form of magnesium and baseline status.

The gaps are also clear. The formulations (oxide, citrate, chloride, L-threonate, etc.), doses, and durations vary between studies; participants are rarely stratified by baseline magnesium status and associated deficiencies (vitamin D, B-group). Biomarkers of status (serum vs. ionized Mg, red blood cell Mg) are poorly standardized, and clinical outcomes (depression scales, migraine, cognitive tests) are often not fully comparable. Finally, it is important to consider the balance with calcium and the overall diet: the effect of magnesium is not a “pill in a vacuum,” but part of a dietary pattern.

Against this background, this systematic review aims to break down the picture by diagnosis, form and dose, to separate situations where magnesium can already be recommended as an adjuvant (e.g. migraine, depression with confirmed hypomagnesemia) from areas where more evidence is still needed (cognitive aging/dementia), and to indicate how to improve the design of future RCTs: precise selection by magnesium status, choice of bioavailable forms, standardized outcomes and control of confounding factors.

What's new in the review

• Depression: observational studies consistently link low magnesium with more severe symptoms; RCTs show mixed but occasionally positive results (improvement in depression scales with MgO/MgCl₂, especially in patients with documented hypomagnesemia). Possible mechanisms include effects on glutamate/GABA, the HPA axis, and anti-inflammatory effects.
• Migraine: some patients have low blood/CSF magnesium; clinical trials show that oral complexes (eg, magnesium + riboflavin + coenzyme Q10) and Mg-citrate can reduce the frequency/intensity of attacks; intravenous MgSO₄ does not always help and is inferior to standard antiemetics/neuroleptics in acute pain in the emergency department.
• Alzheimer's disease and cognition: in older adults, the relationship with magnesium is non-linear: both too low and too high serum magnesium levels are associated with a higher risk of dementia (Rotterdam Study). In some cohorts, higher dietary/total magnesium intake and a "healthy" calcium:magnesium ratio are associated with better cognitive function and a lower risk of MCI/dementia; there are also intervention studies with improved memory with magnesium L-threonate, but the evidence is mixed.

Under the hood of this picture is physiology: magnesium blocks NMDA receptors (restraining excitotoxicity), maintains antioxidant protection, and affects vascular and immune regulation. In migraine, control of the trigeminovascular system and cortical excitability is added; in depression, the balance of mediators and the stress axis; in dementia, a hypothetical slowing of neurodegenerative pathways. But, as the authors emphasize, the road from the mechanism to the clinic is thorny.

What exactly was tested in the clinic (from the review examples)

• Depression (RCT):
  - MgO 500 mg/day for 8 weeks: decrease in BDI scores, increase in serum Mg;
  - MgCl₂ in elderly people with diabetes and hypomagnesemia: increase in Mg level, clinical effect comparable to imitramine;
  - Combinations with vitamin D showed a more pronounced decrease in inflammatory markers and symptoms in individual studies. Conclusion: adjuvant, especially in magnesium deficiency.
• Migraine:
  - Oral complexes (Mg + riboflavin + CoQ10): fewer days of pain, lower intensity, better subjective efficacy;
  - Mg-citrate 600 mg/day: fewer attacks, reduced severity, increased cortical perfusion according to SPECT;
  - Comparison with valproate: both options are safe and effective, no clear differences were found in the crossover design;
  - IV MgSO₄ in the emergency department: in some places better than placebo according to pain scales, but loses to procloperazine in terms of the proportion of pain relief.
• Cognitive aging/dementia:
  - US, Japanese, etc. cohorts: higher Mg intake → better composite cognitive scores (especially in women, non-Hispanic whites, and with adequate vitamin D);
  - Ca:Mg ratio matters (too much calcium with too little magnesium - risk);
  - Single brief interventions (magnesium L-threonate) - signals of improved memory in older adults, larger RCTs needed.

Important Disclaimers

• This is a review of clinical studies: many observational data and heterogeneous RCTs; causal inferences are limited.
• The effect of supplementation is greater in people with baseline magnesium deficiency and in combination approaches (diet/cofactors).
• Forms and doses vary, as does the duration of courses; there are no uniform “magic” protocols.

What does this mean for the reader?

• Nutrition first: Most of the signals come from dietary studies - regular dietary magnesium (whole grains, legumes, nuts, greens, fish) maintains normal levels without the risk of "overdoing it".
• Supplements - as indicated: in depression and migraine, magnesium may be an adjuvant, especially with laboratory-confirmed hypomagnesemia; in cognitive decline - there are prospects, but large RCTs are needed. Discuss with a doctor, taking into account the kidneys, medications and concomitant diseases.
• Balance, not maximalism: in cognition, the optimal corridor is important: both too low and too high serum magnesium levels are associated with greater risk (Rotterdam data).

Summary

Magnesium is definitely not out of place in the conversation about the brain - it "holds" excitability, blood vessels and inflammation. But to turn this into clear clinical recommendations "for everyone", science must refine the doses, forms and patient groups where the benefit is maximal. For now, a reasonable strategy is diet, screening for deficiency and careful adjuvant use as indicated.

Source: Varga P. et al. The Role of Magnesium in Depression, Migraine, Alzheimer's Disease, and Cognitive Health: A Comprehensive Review. Nutrients (2025) 17(13):2216. https://doi.org/10.3390/nu17132216