Editorial note: We only cite studies published in peer-reviewed journals. We summarize findings without overstating conclusions.
Published in Frontiers in Ophthalmology in June 2022, this mini-review by researchers at the University of Birmingham’s Institute of Clinical Sciences examines a question that has received relatively little clinical attention: whether magnesium deficiency plays a meaningful role in the development and progression of primary open angle glaucoma (POAG), and whether magnesium supplementation could address the disease at a level that current treatments do not. The full study is available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11182183/
The Problem With How Glaucoma Is Currently Treated
Glaucoma is the leading cause of irreversible blindness worldwide, affecting more than 70 million people. Primary open angle glaucoma is by far the most common form, accounting for approximately 70 percent of all glaucoma cases globally. The disease causes progressive damage to the optic nerve and a gradual loss of visual field, typically starting at the periphery and advancing inward — often without noticeable symptoms until significant vision has already been lost.
The only currently recognized modifiable risk factor for POAG is elevated intraocular pressure (IOP) — the pressure of the fluid inside the eye. All existing treatments, whether eye drops, laser procedures, or surgery, are aimed at lowering that pressure. They work by reducing the production of the eye’s internal fluid (aqueous humor) or by improving its drainage. While effective at slowing disease progression in many patients, these treatments address the symptom of elevated pressure rather than the underlying cellular and molecular dysfunction that caused the pressure to rise in the first place.
The authors of this review argue that this gap — between pressure management and pathogenesis — is exactly where new therapeutic approaches like magnesium deserve scientific attention.
What Actually Causes Pressure to Rise in POAG
To understand why magnesium is relevant, it helps to understand what goes wrong structurally in POAG.
Aqueous humor is a clear fluid continuously produced inside the eye that circulates and drains through a specialized tissue called the trabecular meshwork (TM) — a sponge-like filtering structure located at the angle where the iris meets the cornea. From the TM, fluid passes into a circular drainage channel called Schlemm’s canal and from there into the bloodstream. In a healthy eye, this drainage system maintains pressure within a normal range.
In POAG, the trabecular meshwork undergoes a fibrotic transformation — essentially, it stiffens and scars. This process is driven by several interconnected events: elevated levels of a signaling protein called TGF-β2 prompt TM cells to behave more like scar-forming cells, depositing abnormal amounts of structural proteins and reducing the tissue’s flexibility. At the same time, the TM experiences increased oxidative stress, mitochondrial dysfunction, chronic low-level inflammation, and a loss of TM cell populations. The combined result is that fluid encounters mounting resistance on its way out of the eye, and pressure rises.
The review identifies each of these processes — fibrosis, oxidative stress, mitochondrial dysfunction, and inflammation — as areas where magnesium appears to play a meaningful regulatory role.
Magnesium’s Role in the Body and the Eye
Magnesium is the fourth most abundant mineral cation in the human body and serves as a cofactor in more than 300 enzymatic reactions. It is particularly concentrated in energy-intensive organelles: the mitochondria, the endoplasmic reticulum, and the cell nucleus each maintain internal magnesium levels of approximately 15 to 18 millimolar — tightly regulated by the cell because magnesium is so critical to so many processes.
Among magnesium’s most important functions is its role in ATP production — the energy currency that powers virtually all cellular activity. It is also a natural physiological antagonist to calcium: where calcium tends to promote cell contraction, excitation, and inflammatory signaling, magnesium tends to have calming, stabilizing effects on the same pathways. When magnesium is insufficient, calcium can accumulate inside cells at harmful levels, triggering a cascade that includes cellular swelling, mitochondrial dysfunction, and ultimately cell death.
Within the eye specifically, magnesium is found in significant concentrations in the cornea, lens, retina, and the aqueous humor of the anterior chamber. The review cites a striking finding: the aqueous humor of healthy eyes contains approximately 6.7 mg/L of magnesium, while the aqueous humor of POAG patients contains roughly 3 mg/L — less than half the normal level. This measurement, though from limited studies, establishes that magnesium deficiency is measurably present in the ocular environment of glaucoma patients, not merely in systemic circulation.
How Magnesium Deficiency Contributes to POAG: Four Pathways
1. Mitochondrial Dysfunction and Oxidative Stress
The trabecular meshwork contains cells with unusually high metabolic activity. Like all metabolically active tissues, TM cells generate free radicals as a byproduct of energy production — primarily within the mitochondria. Under normal conditions, these are managed by antioxidant systems. But in POAG, there is an established defect in the mitochondrial electron transport chain — specifically at a component called Complex I — that causes an overproduction of reactive oxygen species (ROS). This excess oxidative stress damages TM cell membranes, disrupts normal protein function, causes DNA damage, promotes abnormal extracellular matrix accumulation, and eventually triggers cell death.
Magnesium deficiency compounds this problem directly. Magnesium is essential for the enzymes that drive the Krebs cycle and for maintaining the integrity of the electron transport chain itself. When magnesium is insufficient, the electron transport chain operates less efficiently, producing more free radicals as electrons “leak” from the chain rather than completing their normal pathway. Computer simulation models of the Krebs cycle confirm that mitochondrial magnesium levels are critical for regulating both the cycle’s enzymes and its overall output. Laboratory studies have shown that magnesium-deficient rats sustain greater oxidative damage than controls and exhibit higher circulating levels of oxidized lipoproteins — a marker of systemic oxidative stress.
2. Calcium Dysregulation
One of magnesium’s key physiological roles is as a natural calcium channel blocker — it moderates the flow of calcium into cells and competes with calcium at many cellular binding sites. When magnesium levels fall, calcium floods into cells at abnormally high concentrations. In TM cells specifically, research has documented that this calcium overload causes mitochondrial dysfunction, disrupts the cytoskeleton, and promotes cell death through apoptosis. The review notes that this calcium-driven cell death is particularly relevant to the progressive loss of TM cellularity documented in POAG patients compared to age-matched healthy controls.
The same calcium dysregulation is also relevant to the loss of retinal ganglion cells (RGCs) — the nerve cells whose axons form the optic nerve. RGC death is the final common pathway of glaucomatous vision loss. Research cited in the review shows that magnesium acts as a neuroprotective and anti-apoptotic agent in RGCs specifically, reducing nitric oxide synthase activity and blocking the calcium channel activation that leads to RGC death.
3. Vascular Dysregulation and Reduced Ocular Blood Flow
POAG is associated not only with elevated pressure but also with inadequate blood supply to the optic nerve and retina. Reduced blood flow to these tissues creates hypoxic (low-oxygen) conditions that trigger their own wave of oxidative stress and worsen neural damage — even in some patients whose IOP is successfully controlled by medication.
A key driver of this vascular dysfunction is a potent vasoconstrictor molecule called endothelin-1 (ET-1), which acts on blood vessels via calcium-dependent channels to cause constriction. Elevated ET-1 has been observed in POAG patients, and it appears to also act directly on TM tissue, increasing resistance to fluid outflow. Magnesium, as a physiological calcium channel antagonist, has been shown in laboratory studies to reduce ET-1’s vasoconstrictive effect in ocular blood vessels. One clinical study cited by the authors — a small trial from 1995 — found that magnesium supplementation in glaucoma patients led to improvements in both peripheral circulation and visual fields, suggesting a real functional impact. Though this trial has not been replicated at larger scale, the authors consider it consistent with the mechanism described.
Magnesium deficiency also promotes endothelial dysfunction — impaired function of the cells lining blood vessel walls — by increasing the production of nitric oxide and a related damaging molecule called peroxynitrite, both of which generate additional reactive oxygen species. This creates a self-reinforcing cycle: magnesium deficiency worsens vascular function, reduced blood flow causes more oxidative stress, and oxidative stress causes further vascular damage.
4. Inflammation and Fibrosis
The TM’s fibrotic transformation in POAG is driven in part by chronic low-level inflammation, mediated through a signaling pathway involving a transcription factor called NF-κB and the cytokine TGF-β2. NF-κB activation promotes the release of inflammatory molecules including IL-1β and IL-6; TGF-β2 stimulates TM cells to take on scar-forming characteristics, depositing abnormal quantities of structural proteins and stiffening the tissue.
The review argues that magnesium may interrupt this process at multiple points. Most directly, by reducing mitochondrial ROS production, magnesium may reduce the oxidative stress that activates TGF-β2 expression — since laboratory research has shown that mitochondrial antioxidants can suppress TGF-β2 in TM cells. And by dampening NF-κB activity, magnesium may reduce the downstream inflammatory response. Evidence for the anti-inflammatory effect of magnesium supplementation comes from non-ocular studies: short-term supplementation reduced NF-κB activity and IL-6 production in clinical subjects, and lower serum magnesium levels in middle-aged women correlated with significantly elevated C-reactive protein — a standard marker of systemic inflammation.
The review draws an instructive parallel with hepatic (liver) fibrosis, which shares key features with TM fibrosis: both involve highly metabolic cells, activation of scar-forming pathways via NF-κB, and overproduction of the same structural proteins (including alpha-smooth muscle actin, fibronectin, and collagen). Animal studies of hepatic fibrosis showed that magnesium supplementation reduced expression of these profibrotic proteins, suppressed ROS generation, and reduced NF-κB activation. Similar results have been reported in animal models of pulmonary fibrosis. The authors propose that if magnesium has demonstrated antifibrotic effects in both liver and lung tissue — where the fibrotic process is mechanistically similar to that in the TM — it is a reasonable hypothesis that it could have analogous effects in the trabecular meshwork.
What the Evidence Currently Shows — And What It Does Not
This review is important for what it assembles, but equally important for what it candidly acknowledges it cannot yet conclude. The authors are explicit: the direct link between magnesium deficiency and increased oxidative stress specifically within the human eye has not yet been fully established. The only clinical trial testing magnesium supplementation in glaucoma patients was small, conducted in 1995, and has not been followed up with larger randomized controlled trials. The studies establishing antifibrotic effects of magnesium in liver and lung tissue are suggestive of relevance to the eye, but direct evidence in ocular tissue is still lacking.
In that sense, the paper’s title — which ends with a question mark — is honest. This is a scientific argument for why magnesium deserves serious investigation as a therapeutic target in POAG, not a claim that supplementation has been proven to treat the disease.
What the paper does establish firmly is that magnesium deficiency is measurably present in POAG patients’ eyes; that the cellular pathways disrupted by magnesium deficiency are the same pathways driving POAG pathogenesis; and that magnesium supplementation has demonstrated meaningful effects on those same pathways in other fibrotic disease contexts. Together, these constitute a coherent and well-reasoned scientific rationale for further study.
Why This Matters: Treating the Disease, Not Just the Pressure
The deeper significance of this line of research is what it implies about the future of glaucoma treatment. Current POAG therapies are effective at delaying vision loss in many patients — but they do not stop the underlying biological deterioration of the trabecular meshwork. As a result, patients often require increasingly aggressive interventions over time, and a meaningful proportion still progress to significant vision loss despite treatment.
A therapy that could reduce trabecular meshwork fibrosis, dampen oxidative stress within the drainage apparatus, protect retinal ganglion cells from calcium-mediated death, and improve ocular blood flow — all simultaneously, through a single mechanism — would represent a fundamentally different kind of intervention. Magnesium, the review argues, has the biological profile to do all of these things. What it lacks, for now, is the clinical trial evidence to confirm it.
Summary of Key Takeaways
- Primary open angle glaucoma is the world’s most common cause of irreversible blindness, and all current treatments target elevated eye pressure rather than the underlying disease mechanisms.
- The root cause of pressure elevation in POAG is a fibrotic transformation of the trabecular meshwork — a process driven by oxidative stress, mitochondrial dysfunction, calcium dysregulation, and chronic inflammation.
- Magnesium concentrations in the aqueous humor of POAG patients have been measured at approximately half the level found in healthy eyes — a finding that points to a specific ocular magnesium deficiency in the disease.
- Magnesium deficiency disrupts mitochondrial energy production, worsens oxidative stress, allows excess calcium to accumulate inside cells, promotes vascular constriction, and facilitates the inflammatory and fibrotic signaling pathways that damage the trabecular meshwork.
- Evidence from animal and human studies of liver and lung fibrosis — which shares key mechanistic features with trabecular meshwork fibrosis — shows that magnesium supplementation can reduce oxidative stress, suppress profibrotic protein expression, and dampen NF-κB-driven inflammation.
- A small 1995 clinical trial found that magnesium supplementation improved visual fields and peripheral circulation in glaucoma patients. This result has not yet been replicated in larger trials.
- The authors conclude that magnesium has a strong biological rationale as a potential therapeutic for POAG, but call for further clinical research to establish its efficacy and appropriate role in glaucoma management.
Source: Elghobashy M, Lamont HC, Morelli-Batters A, Masood I, Hill LJ. Magnesium and Its Role in Primary Open Angle Glaucoma; A Novel Therapeutic? Front Ophthalmol. 2022 Jun 9;2:897128. doi: 10.3389/fopht.2022.897128. Full text available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11182183/
