Magnesium is a vital micronutrient involved in more than 600 enzymatic reactions, playing indispensable roles in energy metabolism, neuromuscular conduction, neurotransmitter synthesis, and cellular stress resilience.^1,2 As the second most abundant intracellular cation after potassium, magnesium plays a critical role in maintaining ionic gradients, regulating intracellular hydration, and supporting cellular homeostasis under both physiological and stress conditions.³ Yet despite its ubiquity, magnesium deficiency, both overt and subclinical, is remarkably common and clinically underrecognized, especially in the context of chronic stress, poor sleep, and physical exertion.⁴

Recent insights underscore the need for targeted magnesium repletion using highly bioavailable, physiologically compatible forms. In particular, magnesium glycinate and magnesium citrate offer complementary benefits in supporting central nervous system regulation, sleep architecture, and muscle recovery.⁵ This review outlines the mechanistic rationale and evidence base for these applications, while also comparing the physiological characteristics of various magnesium salts and chelates.

Magnesium and the Neuroendocrine Stress Axis: Restoring Calm and Resilience

Magnesium is fundamental in regulating the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system.⁵ Sufficient magnesium levels temper the release of stress hormones, whereas deficiency may lead to HPA overactivity and heightened cortisol levels.⁵ Mechanistically, magnesium functions as a natural calcium antagonist and blocks voltage-gated NMDA receptors, thereby reducing excessive glutamate-mediated excitatory neurotransmission. At the same time, it facilitates GABAergic inhibitory signaling, which collectively contributes to a calmer neural environment and improved emotional regulation.⁵

Under acute stress, magnesium shifts from intracellular compartments into the extracellular fluid to buffer vasoconstrictive responses, leading to increased renal excretion. If stress persists, this pattern results in systemic magnesium depletion, which in turn exacerbates stress sensitivity and perpetuates a cycle of neuroendocrine dysregulation.^6,7 This mechanism explains why magnesium insufficiency often presents with symptoms such as irritability, heightened anxiety, and physical tension.

A clinical trial in adults with elevated stress levels (DASS-42 scores >18) demonstrated that 300 mg/day of elemental magnesium for 8 weeks resulted in a 42.4% reduction in perceived stress, with near normalization in nearly half of participants.⁸ In a 2017 systematic review of 18 studies, magnesium supplementation was associated with significant reductions in subjective anxiety, particularly in vulnerable samples.⁹ These findings support magnesium’s ability to break the so-called “vicious circle” of stress and magnesium loss.

Magnesium’s Role in Sleep Architecture and Circadian Recovery

Magnesium plays a multi-faceted role in sleep regulation. It stabilizes neuronal membranes and dampens nocturnal cortical hyperactivity by blocking NMDA receptors and enhancing GABA receptor activity.¹⁰ Additionally, magnesium is a cofactor in the enzymatic conversion of tryptophan to serotonin and subsequently melatonin, thereby directly influencing circadian rhythm and sleep-wake cycling.¹⁰

As a result, magnesium deficiency is often linked to insomnia characterized by difficulty falling asleep, frequent awakenings, or early morning arousals. In a double-blind trial involving older adults with primary insomnia, 500 mg daily magnesium supplementation over eight weeks led to significant improvements in sleep time, sleep efficiency, and latency to sleep onset, alongside reduced evening cortisol and elevated serum melatonin and renin.¹⁰ These biochemical shifts are consistent with enhanced parasympathetic activity and entrained circadian patterns.

It is worth noting that magnesium formulation may influence outcomes for sleep. Magnesium glycinate (magnesium bound to the amino acid glycine) is frequently recommended for sleep support due to glycine’s additional calming properties. Glycine itself acts as an inhibitory neurotransmitter at NMDA and glycine receptors, improving sleep continuity and next-day alertness.¹¹ Although specific trials comparing magnesium glycinate to other forms for sleep are limited, the combined biochemical rationale and extensive clinical observations support its frequent use for individuals experiencing insomnia linked to stress or neuromuscular hyperexcitability.

Muscular Relaxation, Recovery, and Cramp Prevention

Skeletal muscle function relies heavily on adequate magnesium levels. More than 20% percent of body magnesium resides in muscle tissue,¹² where it orchestrates contraction-relaxation cycling by competing with calcium at troponin C and activating the SERCA pump that sequesters calcium into the sarcoplasmic reticulum post-contraction.^13,14 Magnesium also modulates acetylcholine release at neuromuscular junctions, reducing the likelihood of sustained muscle excitation that underlies spasms and cramps.

Exercise increases magnesium requirements, and marginal magnesium deficiency can impair physical performance and recovery. Conversely, repleting magnesium may reduce muscle cramps, improve oxygen uptake, and limit biochemical signs of muscle damage after intense exercise.¹⁴

These cellular effects translate into tangible clinical outcomes. A controlled trial in cyclists undergoing a rigorous multi-stage race found that 400 mg/day of magnesium for 3 weeks reduced serum myoglobin levels, preserved erythrocyte magnesium stores, and improved perceived muscle soreness compared to placebo, indicating less muscle damage and enhanced recovery.¹⁵ In populations prone to nocturnal muscle cramping, such as those with restless leg syndrome, magnesium supplementation has shown benefits in reducing cramp frequency and improving subjective muscular comfort.^16,17

In patients with restless leg syndrome, 250 mg/day of magnesium supplementation for 8 weeks improved sleep quality and reduced symptom severity.¹⁶ Similar effects were observed in a randomized controlled trial of individuals with persistent leg cramps, where magnesium citrate (300 mg/day) showed a trend toward reduced cramp frequency and improved subjective symptoms after 8 weeks.¹⁷ Together, these findings support magnesium’s use as part of an integrative approach to reducing muscle tension and supporting post-exertional recovery.

Magnesium’s role as a major intracellular cation is essential for maintaining cell volume and hydration. It stabilizes cell membranes, regulates ion transport through Na⁺/K⁺-ATPase, and contributes to osmotic equilibrium within the intracellular environment.³ A deficiency in intracellular magnesium disrupts water balance and impairs mitochondrial and metabolic efficiency, contributing to fatigue, decreased thermotolerance, and diminished resilience under physical stress.

Formulations that restore intracellular magnesium stores may therefore enhance water retention at the cellular level—an underappreciated strategy for improving hydration status, muscle recovery, and cellular energy output.

Comparing Forms of Magnesium: Mechanisms and Bioavailability

Different magnesium compounds vary in their absorption kinetics, tolerability, and physiological impact.^18-24 The form selected can influence not only total magnesium delivery but also site-specific therapeutic effects.

Magnesium glycinate stands out for individuals prioritizing stress reduction, sleep improvement, and muscle relaxation. Its absorption via dipeptide transporters bypasses typical ion competition, leading to excellent systemic availability without the gastrointestinal disturbances sometimes associated with other forms.11,24 The glycine component further enhances its calming effects. Magnesium citrate, while also bioavailable, introduces a mild osmotic effect, making it useful in populations with concurrent constipation or sluggish motility.²⁰ For comprehensive benefits across neuroendocrine balance, sleep architecture, and muscle function, formulations that combine glycinate and citrate are sometimes employed to leverage their complementary mechanisms.

Conclusion: Precision Magnesium Supplementation for Whole-Body Recovery

Magnesium’s central role in modulating neurotransmission, calcium homeostasis, mitochondrial function, and muscle relaxation makes it a critical nutrient for supporting the modern lifestyle—one often characterized by stress, poor sleep, and physical overexertion.

The glycinate and citrate forms of magnesium stand out for their high absorption, clinical tolerability, and targeted physiological benefits. Magnesium glycinate, with its dual bioavailability and neuroinhibitory synergy, supports relaxation and sleep architecture while avoiding gastrointestinal discomfort. Magnesium citrate complements this with gentle laxative activity and utility in muscle tension and renal calcium management.

By tailoring magnesium form to individual needs—whether for enhancing parasympathetic tone, improving sleep quality, or facilitating muscular recovery—clinicians can implement science-based strategies to restore balance, promote resilience, and support whole-body repair.

By: Yekta Dowlati, PhD

References

1. Krose JL et al. Nephrol Dial Transplant. 2024;39(12):1965-1975.
2. Al Alawi AM et al. Int J Endocrinol. 2018;2018:9041694.
3. Mathew AA et al. Biometals. 2021;34(5):955-986.
4. DiNicolantonio JJ et al. Open Heart. 2018;5(1):e000668.
5. Pickering G et al. Nutrients. 2020;12(12):3672.
6. Romani AMP. Arch Biochem Biophys. 2011;512(1):1-23.
7. Vink R et al. Magnesium in the Central Nervous System. University of Adelaide Press; 2011.
8. Pouteau E et al. PLoS One. 2018;13(12):e0208454.
9. Boyle NB et al. Nutrients. 2017;9(5):429.
10. Abbasi B et al. J Res Med Sci. 2012;17(12):1161-1169.
11. Bannai M et al. Front Neurol. 2012;3:61.
12. EFSA Panel on NDA. EFSA J. 2015;13:4186.
13. Souza ACR et al. Nutrients. 2023;15(24):5127.
14. Nielsen FH et al. Magnes Res. 2006;19(3):180-189.
15. Cordova A et al. Nutrients. 2019;1(8):1927.
16. Jadidi A et al. BMC Complement Med Ther. 2022;23(1):1.
17. Roffe A et al. Med Sci Monit. 2002;8(5):CR326-CR330.
18. Blancquaert L et al. Nutrients. 2019;11(7):1663.
19. Uysal N et al. Biol Trace Elem Res. 2019;187(1):128-136.
20. Kappeler D et al. BMC Nutrition. 2017;3:7.
21. Zhang X et al. J Nutr. 2016;146(3):595-602.
22. Boulis M et al. J Prim Care Community Health. 2021;12:21501327211038433.
23. Hausenblas HA et al. Sleep Med X. 2024;8:100121.
24. Schuette SA et al. JPEN J Parenter Enteral Nutr. 1994;18(5):430-435.

Yekta Dowlati, PhD, serves as the Medical Education Manager at Metagenics. Dr. Dowlati earned her PhD in Medical Sciences from the University of Toronto, along with her MSc in Pharmacology. Her academic credentials also include a BSc in nutrition. She furthered her expertise with a postdoctoral fellowship in Neuropsychopharmacology at the Centre for Addiction and Mental Health in Toronto. Dr. Dowlati’s research portfolio includes multiple clinical trials, and she has contributed to the scientific community through her authorship and co-authorship of articles in prestigious journals, alongside presenting her work at numerous national and international conferences. Before her tenure at Metagenics, she excelled as a senior medical writer and led medical writing teams, demonstrating her passion for learning and education to improve public health. Beyond her professional commitments, Dr. Dowlati cherishes family time, indulging in travel, fitness, and cooking, which speaks to her balanced approach to life.