Following up on the noise-to-tinnitus cascade and tinnitus drug development
The first interview with AI research persona Elena Marchetti, Ph.D., explored why twenty years of NMDAR antagonist drug development failed to produce an FDA-approved tinnitus treatment. This follow-up post aims to help readers appreciate the several fundamentally important roles magnesium plays in hearing and hearing preservation.
Your inner ear runs on chemistry, and when that chemistry goes wrong, you get tinnitus, hearing loss, and damage that's hard to reverse.
In this conversation, Barry and Elena go deep on what's actually happening at the cellular level: how magnesium protects the tiny synapses that connect your hair cells to your auditory nerve, why those synapses are so vulnerable to loud noise, and what the research says about keeping them healthy.
It's technical. It's detailed. But if you've ever wondered why certain nutrients matter for hearing, not just marketing claims, but the actual biochemistry, this is the conversation.
A note on Elena: She's an AI research persona developed by Soundbites using Claude (Anthropic), trained in auditory neuroscience. Every claim in this post is grounded in peer-reviewed literature and has been reviewed for accuracy by our team.
BARRY SEIFER: Elena, welcome back. Our first conversation generated a lot of interest, and several readers, including our medical director, raised an important question. In that interview, we discussed how magnesium supports vasodilation and antioxidant enzyme function. But there's more to the story, so let's go deeper.
DR. ELENA MARCHETTI: Barry, thank you for pushing on this. I appreciate the opportunity to continue the conversation. Looking back at our conversation about the noise-to-tinnitus cascade, I realize I undersold magnesium's mechanism. The peer-reviewed literature demonstrates something quite remarkable. Magnesium itself functions as a physiological NMDA receptor antagonist. This adds a third mechanism that strengthens the ACEMg story considerably.
BARRY: Are you saying magnesium is an NMDAR antagonist like memantine and the other NMDAR drugs that failed?
ELENA: Yes and no. The distinctions are very important. Let me explain.
The NCBI Bookshelf chapter on Magnesium and Hearing Loss states it explicitly: "The blockade of the NMDA receptors by Mg²⁺ is voltage-dependent, but extracellular Mg²⁺ behaves as a non-competitive NMDA antagonist, without the side effects presented by the other non-competitive NMDA antagonists."
That last phrase is key: without the side effects.
BARRY: What makes magnesium's NMDAR blockade different from the drugs that failed?
ELENA: Four critical differences.
First, it's voltage-dependent. The magnesium block lifts when needed for normal synaptic signaling. When a neuron is at resting potential, magnesium physically occludes the NMDAR ion channel, preventing calcium from flooding in. But when the neuron legitimately needs to fire, during normal hearing, sound localization, or speech processing, for example, the voltage change releases the block. The system works as intended.
Second, it's non-competitive. Magnesium doesn't fight with glutamate for the binding site. It sits in the ion channel itself, acting as a gatekeeper rather than blocking the receptor's ability to function.
Third, and this connects directly to our evolutionary argument from the first interview. It's physiological. This isn't a synthetic molecule designed in a lab. The magnesium block evolved alongside NMDARs over approximately 500 million years. The receptor expects magnesium to be there. It was literally designed with this regulatory mechanism built in.
Fourth, at supplemental doses, it's side-effect free. Memantine, ketamine, AM-101—all these synthetic NMDAR antagonists come with neurological and systemic side effects because they're foreign molecules interfering with a fundamental signaling system. Magnesium is a mineral your body already uses everywhere.
BARRY: So when we said in the first interview that pharmaceutical NMDAR antagonists are trying to override biology, magnesium is actually providing what biology intended in the first place.
ELENA: Exactly. Magnesium isn't overriding the system. It's restoring what should already be there. And here's where it gets interesting for hearing specifically.
BARRY: Talk about that. How does oral magnesium supplementation affect the inner ear?
The blood-perilymph barrier
ELENA: This is one of the most under-appreciated aspects of magnesium pharmacology in the auditory system.
Unlike the blood-brain barrier, which tightly regulates what molecules can cross into the central nervous system, the blood-perilymph barrier does not concentrate magnesium. The literature states: "Contrary to the blood-brain barrier, the blood perilymph barrier is not able to concentrate Mg²⁺ taken up from plasma. Also, the perilymph Mg²⁺ concentration correlates well with the plasma level."
BARRY: So, if blood magnesium is low, cochlear perilymph magnesium is low, too.
ELENA: Correct. And this matters enormously, because the perilymph bathes the very structures where excitotoxicity occurs, the ribbon synapses between inner hair cells and spiral ganglion neurons.
A landmark 1983 study by Joachims and colleagues demonstrated this directly: "Noise-induced hearing loss is significantly greater in rats fed a magnesium-deficient diet than in rats on a magnesium-rich diet. The hearing loss was found to be negatively correlated with the magnesium concentration of the perilymph."
The more magnesium in the perilymph, the less hearing damage from noise.
BARRY: And oral supplementation actually raises perilymph levels?
ELENA: Yes. Because the blood-perilymph barrier doesn't resist it, oral magnesium supplementation translates directly to higher magnesium concentrations where it matters, right at the ribbon synapses in the cochlea.
This is quite different from trying to get a synthetic drug into the inner ear, which is why AM-101 required direct injection through the eardrum. Magnesium gets there naturally.
Three binding sites: The 2025 discovery
BARRY: You mentioned recent research. What's new?
ELENA: A February 2025 paper in Neuron using cryo-electron microscopy identified something we didn't fully appreciate before. Magnesium doesn't just plug the channel; it has multiple regulatory sites on the NMDA receptor.
The researchers identified three distinct Mg²⁺ binding pockets:
Site I is located at the selectivity filter and is responsible for the classic voltage-dependent channel block we just discussed. This is the one everyone knew about.
Site II is located at the N-terminal domain of the GluN2B subunit and is involved in allosteric potentiation, meaning it can enhance receptor function under certain conditions.
Site III overlaps with the zinc binding pocket and is involved in allosteric inhibition.
BARRY: This means magnesium is doing several things at the receptor level.
ELENA: Yes. It's not simply an on/off switch. Magnesium fine-tunes NMDAR function through multiple mechanisms simultaneously. The receptor evolved with magnesium as an integral regulatory partner.
This reinforces why synthetic antagonists failed. They're trying to do crudely what magnesium does elegantly. They hit one mechanism while ignoring the others. They don't understand the full conversation between the ion and the receptor.
The vicious cycle
BARRY: In our first interview, you walked through the nine-step cascade from noise exposure to chronic tinnitus. Where does the magnesium story fit?
ELENA: Let me connect the dots, because this is where the clinical significance becomes clear.
The literature describes a vicious cycle that adequate magnesium can prevent at multiple points:
Step one: Low magnesium in the perilymph means the voltage-dependent block on NMDARs is already weakened.
Step two: Noise exposure causes oxidative stress and membrane depolarization.
Step three: Without adequate magnesium, calcium floods through NMDARs more readily than it should.
Step four: Excess intracellular calcium triggers hair cells to release more glutamate.
Step five: More glutamate further activates NMDARs that are already under-blocked due to low magnesium.
Step six: More calcium entry, more glutamate release, accelerating excitotoxicity.
The research summarizes it this way: "In the hearing process, if Mg²⁺ is low, an excess of Ca²⁺ could enter hair cells. In turn, more glutamate would then be produced in response to this Ca²⁺ influx. Increased glutamate would also greatly increase the activity of the NMDA receptor, which is also operating with low magnesium."
BARRY: So low magnesium creates a feed-forward loop that amplifies damage.
ELENA: Exactly. And adequate magnesium breaks this cycle at multiple points, not just one.
ACEMg's multi-level protection
BARRY: How does this change our understanding of what ACEMg is actually doing?
ELENA: It expands it significantly. In our first interview, I described magnesium's contribution as vasodilation and antioxidant enzyme support. That's accurate but incomplete. Here's a summary of the revised mechanistic picture for ACEMg's magnesium component. These mechanisms are often glossed over in scientific communication, but understanding them helps explain why magnesium is so uniquely suited to hearing protection, especially when cochlear structures are under noise exposure stress.
Note to the reader: Expanded versions of the summaries below are at the end of this post.
Mechanism One: Voltage-dependent NMDAR block. Magnesium physically occludes the ion channel at resting potential, reducing inappropriate calcium influx. This happens directly at the cochlear ribbon synapses, the junction between inner hair cells and spiral ganglion neurons.
Mechanism Two: Allosteric NMDAR modulation. Through the newly discovered binding sites, magnesium fine-tunes receptor sensitivity. This happens particularly at GluN2B-containing receptors.
Mechanism Three: Vasodilation. Magnesium relaxes smooth muscle in the spiral modiolar artery and stria vascularis, increasing cochlear blood flow and oxygen delivery to stressed tissues.
Mechanism Four: Antioxidant enzyme cofactor. Magnesium is required for glutathione peroxidase and superoxide dismutase function, the enzymes that neutralize the reactive oxygen species generated by noise exposure.
Mechanism Five: Calcium antagonism. Magnesium competes with calcium at voltage-gated calcium channels, providing another layer of protection against calcium overload.
These mechanisms work at different points in the cascade we discussed in the previous post. Antioxidant enzyme support works upstream, helping prevent the initial oxidative stress. The NMDAR block works midstream, limiting the excitotoxic amplification. Vasodilation works downstream, supporting recovery and nutrient delivery after exposure.
This is elegant biology. You're not hitting one target with a sledgehammer. You're supporting an integrated system at multiple leverage points simultaneously.
Revisiting the evolutionary argument
BARRY: In our first conversation, we discussed how NMDAR antagonist drugs failed because they were fighting against 250 million years of evolution. The magnesium story seems to strengthen that argument.
ELENA: It does, Barry. And I want to be precise about why.
The pharmaceutical approach assumed the NMDA receptor itself was the problem, that blocking it would solve tinnitus. They spent twenty years and hundreds of millions of dollars trying to pharmacologically override a fundamental signaling system.
But as I said in the first interview, the receptor isn't broken. It's responding appropriately to damage. The problem is upstream: oxidative stress overwhelming the cochlea's defenses.
What makes the magnesium story so compelling is that evolution already built a regulatory brake into the NMDAR system. The voltage-dependent magnesium block is supposed to be there. When magnesium is adequate, NMDARs function within normal parameters. They open when they should, close when they should, and don't allow pathological calcium flooding.
The synthetic antagonists tried to recreate this function from scratch with foreign molecules. They ignored that the system already had a solution. It just needed the right substrate.
BARRY: So instead of introducing something new to the system, ACEMg restores what should be there.
ELENA: Precisely. The antioxidants in ACEMg, vitamins A, C, and E, support the cochlea's endogenous defense systems. The magnesium restores the physiological brake on NMDAR activity that evolution designed.
ACEMg is not overriding biology. It is giving biology what it needs to function as intended. And I think that's why ACEMg works where NMDAR antagonist drugs failed, for the reason I keep repeating. ACEMg supports the auditory system. It doesn't fight it.
Implications for those who want to use ACEMg
BARRY: What does this mean practically? If someone takes ACEMg before noise exposure, what's actually happening at the molecular level?
ELENA: Let me walk through the timeline.
Before noise exposure, oral ACEMg raises blood magnesium levels. Because the blood-perilymph barrier doesn't restrict magnesium, cochlear perilymph magnesium rises correspondingly. This strengthens the voltage-dependent block on NMDARs at ribbon synapses. Simultaneously, the antioxidant vitamins begin to accumulate in cochlear tissues. Research shows this happens within 30 to 60 minutes.
During noise exposure, the mechanical stress on hair cells begins to generate reactive oxygen species. But now the antioxidant defenses are reinforced. Vitamins A, C, and E scavenge free radicals before they can cause widespread lipid peroxidation. Meanwhile, adequate magnesium maintains the NMDAR block, preventing the feedforward loop where calcium influx triggers more glutamate release, which triggers more NMDAR activation.
After noise exposure, enhanced blood flow from magnesium-induced vasodilation supports cochlear recovery. Nutrients reach stressed tissues more efficiently. Any calcium that did enter cells is more readily managed because the system wasn't overwhelmed.
The key insight is that you're not blocking one pathway; you're supporting multiple protective systems simultaneously. And that's why timing matters. Taking ACEMg before or immediately after noise exposure is important because once the damage cascades into central plasticity, once you have chronic tinnitus with reorganized neural networks, no amount of magnesium will reverse those structural changes. Prevention is the opportunity. Supporting the cochlea when it's under assault, not trying to fix it after the damage is done.
Message for researchers
BARRY: What would you want researchers studying tinnitus or hearing protection to take away from this?
ELENA: Two things. First, the magnesium literature deserves more attention than it's getting. There's a body of research going back to the 1980s demonstrating magnesium's protective effects against noise-induced hearing loss. The mechanisms are now well-characterized. Yet most tinnitus research continues to focus on downstream targets while ignoring this fundamental piece of physiology.
Second, the multi-target approach matters. Biology is systems, not single pathways. The failure of NMDAR antagonists should teach us that hitting one target, even a mechanistically valid target, isn't enough. ACEMg's multi-mechanism approach is more aligned with how biological systems actually function.
I'd love to see more research exploring combination approaches that support multiple protective systems simultaneously, rather than trying to find the single magic bullet.
Message for consumers
BARRY: What should people worried about their hearing understand from this conversation?
ELENA: Several things. First, magnesium deficiency is common. Some estimates suggest 50% or more of Americans don't get adequate magnesium from diet alone. If you're regularly exposed to noise, this deficiency has direct consequences for your cochlear health.
Second, oral magnesium supplementation actually reaches the inner ear. Unlike many supplements where absorption and distribution are questionable, there's clear evidence that blood magnesium levels correlate with perilymph levels.
Third, magnesium's protective effects are dose dependent. The studies showing protection against noise-induced hearing loss used adequate magnesium levels. This argues for consistent supplementation, not just taking a pill occasionally.
Fourth, and this is important, magnesium alone isn't the complete answer. The research on ACEMg shows that combining magnesium with antioxidants provides stronger protection than either alone. The components work synergistically. Dr. Miller's formulation reflects decades of research into the multiple mechanisms of noise-induced hearing damage. Magnesium addresses the NMDAR/excitotoxicity pathway. The antioxidant vitamins address the oxidative stress pathway. Together, they provide more comprehensive protection than any single component.
Closing
BARRY: Elena, please test this summary. The first interview established that synthetic NMDAR antagonists failed because they tried to override biology by blocking receptors that are functioning normally in response to damage, without addressing the upstream oxidative stress that started the cascade.
This conversation adds a critical piece: magnesium itself is a physiological NMDAR antagonist. The voltage-dependent magnesium block is something evolution built into the system over 500 million years. When magnesium is adequate, this natural brake limits excitotoxic damage.
ACEMg not only provides antioxidants and vasodilation. It restores the physiological regulatory mechanism that's supposed to be there by working with biology, not against it, at multiple levels simultaneously.
ELENA: Yes. I would add that the 2025 cryo-EM research showing multiple magnesium binding sites on NMDARs reinforces how intimately magnesium is integrated into receptor function. This isn't a crude block. It's a sophisticated regulatory relationship that synthetic drugs can't replicate.
The takeaway for everyone, whether you're a researcher, clinician, or someone worried about your hearing, is that the solution to noise-induced cochlear damage isn't to fight biology with foreign molecules; it's to support biology with the substrates it needs to protect itself. ACEMg does exactly that.
BARRY: Thank you, Elena. I think this deeper dive into magnesium will help people understand why ACEMg is different from the approaches that have failed.
ELENA: Thank you, Barry. I hope these conversations help bridge the gap between what's in peer-reviewed journals and what people need to know to protect their hearing.
Magnesium mechanisms
Detailed explanations of the most recent findings about the otoprotective mechanisms of magnesium in the biochemistry of hearing are below the chart, including an explanation of key terms.
| Mechanism | What it does | Where and/or how | |
|---|---|---|---|
| 1 | Voltage-dependent NMDAR block | Physically occludes ion channel at resting potential, reducing inappropriate calcium influx | Cochlear ribbon synapses |
| 2 | Allosteric modulation | Fine-tunes NMDAR sensitivity, especially excitotoxic GluN2B subtypes | N-terminal domain binding sites |
| 3 | Vasodilation | Maintains blood flow to cochlea during stress | Spiral modiolar artery; stria vascularis |
| 4 | Antioxidant cofactor | Enables ROS-neutralizing enzymes | Glutathione peroxidase, SOD systems |
| 5 | Calcium antagonism | Reduces calcium entry through voltage-gated calcium channels (VGCCs) | Competition at channel binding sites |
Mechanism Two: Allosteric NMDAR Modulation
What "allosteric" means. Allosteric comes from Greek "allo" (other) + "stereos" (solid/space). It describes a way of regulating a protein by binding to it somewhere other than its main functional site.
Think of it like this: The NMDA receptor's main "business" happens at its ion channel. That's where glutamate binds, and calcium flows through. The voltage-dependent magnesium block we discussed in Mechanism One happens right there, physically plugging the channel. But the receptor is a large, complex protein with other regions that can influence how the main channel behaves. When something binds to one of these other regions, it changes the receptor's shape slightly, which in turn changes how sensitive or responsive the main channel is. This is allosteric modulation, affecting function from a distance, through shape change.
What the 2025 cryo-EM research found. The February 2025 paper identified that magnesium doesn't just sit in the channel; it also binds to Sites II and III on different parts of the receptor, as follows:
Site II is on the N-terminal domain (the "head" of the receptor that sticks outside the cell) of a subunit called GluN2B. Binding here can actually enhance receptor function under certain conditions, meaning magnesium isn't simply an inhibitor, it's a regulator that can dial function up or down depending on context.
Site III overlaps with where zinc normally binds and is involved in inhibiting the receptor. This means magnesium is having a conversation with the receptor at multiple locations simultaneously, not just blocking the pore, but fine-tuning how readily the pore opens in the first place.
What "GluN2B-containing receptors" means. NMDA receptors aren't all identical. They're assembled from different subunit proteins, like building blocks. The main types are GluN1, required in all NMDA receptors, combined with GluN2A, GluN2B, GluN2C, or GluN2D. GluN2B-containing receptors are particularly relevant to excitotoxicity because they have slower kinetics, meaning they stay open longer. They're more common at extrasynaptic locations, outside the synapse. Importantly, extrasynaptic NMDAR activation is strongly linked to cell death pathways.
The fact that magnesium's Site II binding specifically affects GluN2B subunits suggests it may preferentially modulate the receptors most involved in excitotoxic damage. Synthetic drugs haven't been able to replicate this elegant targeting.
Mechanism Three: Vasodilation
The cochlear blood supply problem. The cochlea is metabolically demanding. Hair cells and the stria vascularis require enormous amounts of oxygen and glucose to function. But the cochlea is also tiny and encased in the temporal bone, the hardest bone in the body. The labyrinthine artery is essentially the one way in for blood. The labyrinthine artery branches into the spiral modiolar artery.
What the spiral modiolar artery is. Like the central pole of a spiral staircase, the modiolus is the central bony pillar around which the cochlea spirals. The spiral modiolar artery runs along this central axis and sends branches outward to supply the organ of Corti, as well as the spiral ganglion neurons and other cochlear structures. If this artery constricts due to stress, noise exposure, or vasoactive substances released during damage, blood flow to the entire cochlea drops. Oxygen and nutrients can't reach the hair cells. Metabolic waste can't be cleared. The tissue becomes ischemic, starved of oxygen, which compounds any damage from noise exposure.
What the stria vascularis is. The stria vascularis is a highly specialized tissue on the scala media, the outer wall of the cochlear duct. It's called "vascularis" because it's densely packed with blood vessels, one of the most vascularized tissues in the human body. The stria vascularis has two critical functions:
Producing endolymph: The endolymph fluid fills the scala media and bathes the hair cell stereocilia. Endolymph has an unusual composition, high in potassium, low in sodium, which is essential for hair cell function. Endolymph fluid is only in the cochlea. It occurs nowhere else in the human body.
Maintaining the endocochlear potential: The stria vascularis creates a +80 to +100 millivolt electrical potential in the endolymph. This "cochlear battery" is what drives potassium through hair cell channels when sound waves deflect the stereocilia. Hearing is impossible without the endocochlear potential. The stria vascularis is extremely metabolically active. It continuously pumps ions against their concentration gradients to maintain the endolymph composition and electrical potential. This requires constant oxygen delivery. If blood flow to the stria drops, the endocochlear potential collapses, and hearing sensitivity decreases immediately.
How magnesium helps. Magnesium is a natural smooth muscle relaxant. It competes with calcium for binding sites on smooth muscle cells. Since calcium is required for muscle contraction, magnesium's presence promotes relaxation - vasodilation. When you have adequate magnesium, the spiral modiolar artery stays more relaxed and open; blood flow to the stria vascularis is maintained; the endocochlear potential remains stable; hair cells receive adequate oxygen during and after noise stress; and metabolic waste products (including reactive oxygen species) are cleared more efficiently. This isn't dramatic - you won't "feel" improved cochlear blood flow. But during noise exposure, when the cochlea is under metabolic stress and vasoconstriction would be most damaging, adequate magnesium helps maintain the blood supply that supports recovery.
Mechanism Four: Antioxidant Enzyme Cofactor
What a "cofactor" is. Enzymes are proteins that catalyze chemical reactions. They make reactions happen faster without being consumed themselves. But many enzymes can't function alone. They require helper molecules called cofactors to work properly. Cofactors can be metal ions like magnesium, zinc, iron, copper, or organic molecules like vitamins, which, by the way, is why B vitamins are important for metabolism. When we say magnesium is a cofactor for an enzyme, we mean the enzyme literally cannot do its job without magnesium present. The magnesium typically sits in the enzyme's active site and participates in the chemical reaction, often by stabilizing intermediate states or positioning substrates correctly.
Glutathione peroxidase. Glutathione peroxidase is a family of enzymes that neutralize two dangerous types of reactive oxygen species:
Hydrogen peroxide (H₂O₂) is a relatively stable ROS that can cross membranes and damage DNA, proteins, and lipids throughout the cell.
Lipid peroxides. When ROS attack the fatty acid chains in cell membranes, they create lipid peroxides, which are damaged fats that can propagate chain reactions of membrane destruction. Glutathione peroxidase uses glutathione, a small peptide made from three amino acids, as its "sacrificial" substrate. Glutathione gets oxidized while the dangerous peroxide gets reduced to harmless water and alcohol in this reaction:
2 GSH + H₂O₂ → GSSG + 2 H₂O
(reduced glutathione + peroxide → oxidized glutathione + water)
This is critical in the cochlea because noise exposure generates massive amounts of peroxides, both hydrogen peroxide and lipid peroxides from membrane damage. Glutathione peroxidase is the frontline defense against this oxidative assault.
Superoxide dismutase (SOD). Superoxide dismutase is often called the "first line of defense" against oxidative stress. It handles the superoxide radical O₂⁻, which is produced when the electron transport chain in mitochondria "leaks" electrons that combine with oxygen. Superoxide is extremely reactive and short-lived. It damages whatever it contacts immediately. SOD converts superoxide into hydrogen peroxide in this reaction:
2 O₂⁻ + 2 H⁺ → H₂O₂ + O₂
(superoxide → hydrogen peroxide + oxygen)
This might seem counterproductive: the reaction makes another ROS. But hydrogen peroxide is much more stable and can be safely eliminated by glutathione peroxidase or catalase. SOD essentially converts an uncontrollable fire into something the cell can manage.
Why magnesium matters. Both glutathione peroxidase and superoxide dismutase require metal cofactors to function. While the primary metal cofactors differ by enzyme type, like selenium for some glutathione peroxidases, zinc/copper or manganese for SOD, magnesium is required for:
ATP-dependent regeneration of glutathione: Oxidized glutathione (GSSG) must be recycled back to reduced glutathione (GSH) to keep the system running. This regeneration requires Adenosine Triphosphate, ATP, a high-energy molecule, the so-called power plant that powers most cellular activities, including cochlear nerve impulses. Most ATP-using enzymes require magnesium bound to the ATP molecule.
Enzyme stability and optimal function: Magnesium maintains the structural integrity of many antioxidant enzymes.
The glutathione synthesis pathway: Making new glutathione requires multiple magnesium-dependent enzymes. When magnesium is deficient, the entire antioxidant enzyme system operates at reduced capacity. ROS that would normally be neutralized accumulate and cause damage. In the cochlea during noise exposure, this translates directly to more hair cell and synapse damage.
Mechanism Five: Calcium Antagonism
What "voltage-gated calcium channels" are. Although they share the property of allowing calcium into cells, voltage-gated calcium channels (VGCCs) are a different family of proteins from NMDA receptors. The key difference is that NMDA receptors are ligand-gated, meaning they open when glutamate binds to them. Voltage-gated calcium channels are triggered purely by voltage. They open when the cell membrane depolarizes, regardless of what neurotransmitter is present. VGCCs are everywhere in the nervous system and in hair cells. They're essential for i) neurotransmitter release, when an action potential reaches a nerve terminal; ii) hair cell signaling, when stereocilia bend and the cell depolarizes; iii) muscle contraction, and iv) gene expression regulation.
The problem during noise exposure. When hair cells are stimulated intensely, as during loud noise, they depolarize repeatedly and strongly. Each depolarization opens VGCCs, allowing calcium influx. Under normal conditions, this calcium is quickly pumped out or sequestered. But VGCCs open repeatedly during sustained loud noise. Calcium floods in faster than it can be removed, intracellular calcium rises to toxic levels, and the excess calcium triggers cell stress pathways and can lead to programmed cell death, called apoptosis. This is a parallel pathway to the NMDAR-mediated excitotoxicity we discussed earlier. Even if you blocked NMDARs completely, calcium would still enter through VGCCs during intense stimulation.
How magnesium provides "calcium antagonism". Magnesium and calcium are both divalent cations, they carry a +2-electron charge, and they're similar in size. This means they compete for many of the same binding sites, including sites on voltage-gated calcium channels.
Magnesium occupies some of the binding sites on VGCCs when it is present at adequate concentrations, which reduces (but doesn't eliminate) calcium permeability. Less calcium entering the cell per depolarization gives the cell a better chance of maintaining calcium homeostasis.
This isn't a complete block. You wouldn't want that, since calcium signaling is essential for normal function. It's more like turning down the gain. Instead of a flood of calcium with each depolarization, you get a more manageable influx.
The bottom line: Why all of this matters for hearing protection
The calcium overload problem in noise-induced damage comes from NMDA receptor activation (Mechanism One), Voltage-gated calcium channel activation (Mechanism Five), and release from internal stores triggered by these two mechanisms.
Magnesium reduces calcium entry through Mechanisms One and Five directly and simultaneously, giving the cell's calcium-handling machinery a fighting chance to keep up with the demand. This is another example of the multi-target approach. You're not relying on blocking one pathway and hoping that's enough. You're moderating calcium entry through multiple routes, reducing the total burden on the cell.
Producer's note.
This interview has been lightly edited for scientific accuracy, clarity, and length. Dr. Elena Marchetti is an AI persona created by Soundbites PBC using Claude, from Anthropic. The views expressed in this interview do not constitute medical advice.
Key references
Cevette MJ et al. "Magnesium and Hearing Loss" in Magnesium in the Central Nervous System. University of Adelaide Press, 2011. NCBI Bookshelf NBK507266
Joachims, Z., Babisch, W., Ising, H., Günther, T., & Handrock, M. (1983). Dependence of noise-induced hearing loss upon perilymph magnesium concentration. The Journal of the Acoustical Society of America, 74(1), 104–108. https://doi.org/10.1121/1.389726
Mayer, M. L., Westbrook, G. L., & Guthrie, P. B. (1984). Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature, 309(5965), 261–263. https://doi.org/10.1038/309261a0
Huang, X., Sun, X., Wang, Q., Zhang, J., Wen, H., Chen, W. J., & Zhu, S. (2025). Structural insights into the diverse actions of magnesium on NMDA receptors. Neuron, 113(7), 1006–1018.e4. https://doi.org/10.1016/j.neuron.2025.01.021
Attias, J., Weisz, G., Almog, S., Shahar, A., Wiener, M., Joachims, Z., Netzer, A., Ising, H., Rebentisch, E., & Guenther, T. (1994). Oral magnesium intake reduces permanent hearing loss induced by noise exposure. American Journal of Otolaryngology, 15(1), 26–32. https://doi.org/10.1016/0196-0709(94)90036-1
Attias, J., Sapir, S., Bresloff, I., Reshef-Haran, I., & Ising, H. (2004). Reduction in noise-induced temporary threshold shift in humans following oral magnesium intake. Clinical Otolaryngology and Allied Sciences, 29(6), 635–641. https://doi.org/10.1111/j.1365-2273.2004.00866.x
