Mushrooms and ALS: Emerging Neuroprotective Research

Mushrooms & Brain Health

30% survival improvement

Ergothioneine, a compound found almost exclusively in mushrooms, extended survival approximately 30% in a murine model of spinal muscular atrophy, a motor neuron disease related to ALS. Published in FEBS Letters, 2025.

Cadile et al., FEBS Letters, 2025

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ALS-specific studies for any mushroom compound, documented by the ALSUntangled medical review team in 2024

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ALS pathological pathways that mushroom compounds theoretically address: oxidative stress, neuroinflammation, mitochondrial dysfunction, protein aggregation, and motor neuron apoptosis

2025

year of the most relevant motor neuron disease study for any mushroom compound (Cadile et al., FEBS Letters)

Cadile et al., FEBS Letters, 2025

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No mushroom compound has been tested in an ALS clinical trial. The medical community has documented this explicitly. The ALSUntangled research team, an ALS specialist group that systematically evaluates therapies popular in the ALS patient community, published their assessment of lion's mane in 2024 and concluded: zero studies in ALS cell models, animal models, or humans.^[1] The mechanisms are theoretically relevant to ALS. The ALS-specific evidence does not yet exist.

That gap matters because people living with ALS and their caregivers deserve accurate information, not the distorted picture that supplement marketing tends to provide. What also exists alongside that gap is the most relevant motor neuron disease data for any mushroom compound published to date: a 2025 study finding that ergothioneine, a compound found almost exclusively in mushrooms, improved survival approximately 30% in mice with spinal muscular atrophy, a motor neuron disease related to ALS.

This article covers both. The purpose of the overview is the same as that of the ALSUntangled framework: give people accurate information so they can make their own judgments. This is part of the broader mushrooms and brain health research guide.

What the Official ALS Medical Review Found About Mushrooms

The ALSUntangled initiative reviews complementary and alternative treatments that ALS patients commonly inquire about, publishes findings in peer-reviewed journals, and provides the ALS community with evidence-graded assessments. Their 2024 review of lion's mane, published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, is the most authoritative document on this topic.^[1]

Their findings, stated plainly: no preclinical studies of lion's mane in ALS cell or animal models have been published. No clinical trials exist. The neuroprotective mechanisms documented in non-ALS models, including NGF stimulation, anti-inflammatory effects, oxidative stress protection, and neurite promotion, are theoretically relevant to ALS biology, but theoretical relevance is not the same as tested efficacy. The ALSUntangled assessment: the mechanisms are plausible; the evidence is absent; the compound appears safe.

This is not a negative finding in the traditional sense. A failed trial would be a negative finding. The current situation is a research absence. No one has studied it.

A 2023 comprehensive review of lion's mane across all neurodegenerative diseases reached a similar conclusion about the broader field: strong preclinical evidence and robust mechanistic reasoning, but the translation from bench to clinical application remains incomplete across all neurodegenerative conditions including ALS.

Why ALS Biology Makes Mushroom Compounds Theoretically Interesting

ALS destroys motor neurons through at least five distinct pathological processes that operate simultaneously:

Oxidative stress: Motor neurons are among the most metabolically active cells in the body. When their antioxidant defenses fail, as happens with SOD1 gene mutations and TDP-43 aggregation, free radical damage accumulates faster than neurons can repair it.

Neuroinflammation: Microglia, the brain's immune cells, become chronically activated in ALS and create a toxic environment around motor neurons. The inflammatory cascade accelerates neuron loss beyond what the initial oxidative stress would cause alone.

Mitochondrial dysfunction: Motor neurons depend heavily on mitochondria for the energy required to maintain long axons. Mitochondrial failure in ALS is an early event that precedes visible neuron death.

Protein aggregation: TDP-43, which normally helps regulate gene expression, forms toxic clumps inside motor neurons in about 97% of ALS cases. These aggregates impair normal cell function and eventually kill the neuron.

Motor neuron apoptosis: The endpoint of the above processes is programmed cell death in the anterior horn of the spinal cord, which houses the lower motor neurons that control voluntary movement.

The reason mushroom compounds attract research interest is that several of them have documented effects on these exact pathways in other neurological disease models. A 2023 review of Hericium erinaceus neuroprotective mechanisms catalogued the relevant evidence: NGF stimulation supports neuron survival and axon maintenance; anti-inflammatory compounds reduce the microglia-driven toxic environment; antioxidant pathways counter free radical damage; anti-apoptotic effects slow the programmed death cascade.^[4]

None of this has been specifically tested in ALS models. But the mechanistic map is coherent, which is why the ALSUntangled team's assessment was "theoretically plausible" rather than "implausible."

The Most Relevant Motor Neuron Data: Ergothioneine in SMA Mice

The most directly relevant preclinical study for any mushroom compound in motor neuron disease was published in 2025. Cadile and colleagues tested ergothioneine in the SMNΔ7 mouse model of spinal muscular atrophy (SMA).^[2]

SMA is a motor neuron disease caused by loss of the SMN1 gene. It preferentially destroys spinal motor neurons, which are the same lower motor neurons that ALS destroys. The overlap in pathology between SMA and ALS is not perfect. SMA is caused by a single gene defect, ALS by a more complex combination of genetic and environmental factors. The cellular vulnerability is directly shared.

The outcome: ergothioneine supplementation extended survival approximately 30% compared to controls. The pups treated with ergothioneine lived significantly longer than untreated littermates with the same genetic condition.

The mechanisms behind this result are specific. Ergothioneine stimulated mitophagy, the cellular process by which damaged mitochondria are cleared and replaced. In ALS, mitochondrial damage accumulates because the clearance process fails; ergothioneine appears to restore it. Ergothioneine also activated the NRF2 signaling pathway, which is the master regulator of the cellular antioxidant response and is reduced in motor neurons under ALS-related stress. A third effect was increased GPX (glutathione peroxidase) enzyme activity, which directly scavenges the reactive oxygen species that damage motor neuron membranes and DNA.

These three mechanisms, mitophagy restoration, NRF2 activation, and GPX upregulation, address three of the five ALS pathological pathways described above. The SMA model is not an ALS model, and the translation is not guaranteed. But no previous mushroom compound study has gotten this close to a direct test in motor neuron disease.

Ergothioneine's Biology: Why It Has a Dedicated Transporter

The 2025 SMA result did not emerge from nowhere. Ergothioneine has a distinctive biological profile that had already drawn scientific attention before the motor neuron data appeared.

Halliwell and colleagues published a comprehensive 2020 review of ergothioneine biology that laid out why the compound is unusual among dietary antioxidants.^[3] Ergothioneine has its own dedicated transporter protein, OCTN1 (gene SLC22A4), which humans have evolved specifically to absorb ergothioneine from food and concentrate it in tissues. The existence of a specific high-affinity transporter is evolutionarily unusual: it suggests ergothioneine plays a biologically important role important enough to maintain a dedicated absorption mechanism.

The tissues with the highest OCTN1 expression include bone marrow, the lens of the eye, and neurons. Ergothioneine is found in the highest concentrations in the mitochondria of metabolically active cells, which is exactly where mitochondrial dysfunction in ALS causes the most damage.

Ergothioneine levels also decline with age and are lower in people with neurodegeneration than in age-matched controls. Whether this decline is a cause or consequence of neurodegeneration has not been resolved, but the correlation exists.

Mushrooms are the primary dietary source of ergothioneine. Oyster mushrooms (Pleurotus ostreatus) and king oyster mushrooms (Pleurotus eryngii) contain the highest concentrations. Shiitake, porcini, and most other edible mushrooms also contain ergothioneine, though at lower levels. Plant foods contain negligible ergothioneine. Meat contains small amounts accumulated from mushrooms in the animal's diet.

What Erinacines and Neurotrophins Mean for Motor Neurons

The erinacines, diterpenoid compounds found in lion's mane mycelium, have a different mechanism from ergothioneine and add a second independent theoretical pathway for motor neuron support.

A 2025 systematic review of erinacines across preclinical models documented activation of three neurotrophins in multiple experimental systems: BDNF (brain-derived neurotrophic factor), NGF (nerve growth factor), and neurotrophin-3 (NT-3).^[5]

The motor neuron relevance is specific. BDNF supports the survival of spinal motor neurons during development and in adult nerve injury models. NGF supports the sensory and autonomic neurons that run alongside the motor pathways. NT-3 specifically supports the fast motor neuron subtypes, fast-fatiguing motor neurons, that ALS preferentially destroys first. The fact that erinacines activate all three is more than incidental. These three neurotrophins together represent the primary survival signaling that motor neurons depend on.

The caveat remains unchanged: no ALS-specific testing has been done with erinacines. Their effects in motor neuron survival have not been tested in SOD1 or TDP-43 ALS mouse models. The mechanistic case exists; the experimental validation does not.

For more on erinacines specifically, see Lion's Mane for Motor Neuron Disease: Preclinical Evidence and Mushroom Compounds and Motor Neuron Protection.

Why the Research Gap Exists

ALS affects roughly 2-3 people per 100,000. It is rare, and rare diseases are underfunded relative to their severity. The two FDA-approved ALS medications, riluzole and edaravone, extend median survival by months, not years. The incentive to test unpatentable natural compounds is low when pharmaceutical companies need patentable returns on clinical trial investments.

The ALSUntangled framework exists precisely because ALS patients and caregivers are searching for options outside the standard of care, and are exposed to a supplement market that has no incentive to be accurate. For the mushroom research gap, the honest framing is this: the absence of ALS-specific data reflects funding and patent constraints, not negative results.

For anyone currently on riluzole, the safety profile of dietary mushroom consumption is well-established in healthy populations. No documented drug interactions between riluzole and mushroom compounds have been published. The evidence base for interaction data is limited, which means the absence of interaction reports is not the same as confirmed safety. It reflects limited investigation.

For the mechanistic map of mushroom compounds across all five ALS pathological pathways, see Mushroom Neuroprotection in ALS: Targeting Motor Neuron Degeneration. For the broader neurodegeneration research context, the Mushrooms and Parkinson's Disease research covers ergothioneine in a condition where it has been more extensively studied.

The Bottom Line

No mushroom compound has been tested in ALS. The ALSUntangled 2024 review confirmed zero ALS studies for lion's mane, while acknowledging the theoretical relevance of its neuroprotective mechanisms. The most directly relevant motor neuron disease data is a 2025 ergothioneine study in SMA mice, which found approximately 30% survival improvement via mitophagy stimulation, NRF2 activation, and GPX upregulation. Erinacines from lion's mane mycelium activate BDNF, NGF, and NT-3, all neurotrophins critical for motor neuron survival, in preclinical models. The research gap reflects funding and patent constraints, not failed experiments. The mechanistic rationale for future ALS testing is coherent and specific.

Frequently Asked Questions

Can mushrooms help with ALS?

No mushroom has been tested in ALS clinical trials or ALS animal models. The ALSUntangled 2024 medical review found zero ALS-specific studies for lion's mane and concluded the mechanisms are theoretically plausible but unproven.^[1] The most relevant motor neuron disease data involves ergothioneine, a mushroom compound, which extended survival approximately 30% in spinal muscular atrophy mice in a 2025 study.^[2] SMA and ALS share motor neuron vulnerability. The connection is mechanistically coherent but not directly tested in ALS.

Is there any natural treatment for ALS?

No natural compound has demonstrated efficacy in ALS clinical trials. The only FDA-approved ALS medications are riluzole and edaravone, both of which extend median survival by months. Several natural compounds, including ergothioneine and lion's mane erinacines, have mechanisms relevant to ALS pathology in other models, but none has been tested specifically in ALS. The research gap is real and documented.

What neuroprotective compounds are in mushrooms?

The leading candidates with documented mechanisms relevant to motor neuron protection are: ergothioneine (found in highest concentrations in oyster and king oyster mushrooms, with direct motor neuron disease data from a 2025 SMA mouse study^[2]); erinacines from lion's mane mycelium (activates BDNF, NGF, and neurotrophin-3^[5]); hericenones from lion's mane fruiting body (NGF stimulation, anti-inflammatory); and beta-glucan polysaccharides across species (general anti-neuroinflammatory effects).

Has lion's mane been studied for ALS?

No. The ALSUntangled 2024 systematic review, published in the leading ALS specialty journal, confirmed that no studies of lion's mane have been conducted in ALS cell models, ALS animal models, or ALS clinical trials.^[1] Lion's mane has documented neuroprotective mechanisms in other conditions, including Alzheimer's models, peripheral nerve injury, and Parkinson's, but ALS-specific testing has not been done. The ALSUntangled team concluded it appears safe and the mechanisms are theoretically plausible.

What mushroom compound protects motor neurons?

The most direct motor neuron disease evidence exists for ergothioneine. A 2025 study in spinal muscular atrophy mice found approximately 30% survival improvement, with ergothioneine stimulating mitophagy, NRF2 signaling, and GPX antioxidant enzyme activity: three pathways directly relevant to ALS motor neuron degeneration.^[2] Erinacines from lion's mane mycelium activate BDNF, NGF, and neurotrophin-3 in preclinical models, all of which support motor neuron survival.^[5] Neither compound has been tested specifically in ALS models.

Sources & References

1. 1RTHM-00896·Muhanna, Maya et al. (2024). “ALSUntangled #73: Lion's Mane..” Amyotrophic lateral sclerosis & frontotemporal degeneration.Study breakdown →PubMed →↩
2. 2RTHM-02062·Cadile, Francesca et al. (2025). “Ergothioneine supplementation improves pup phenotype and survival in a murine model of spinal muscular atrophy..” FEBS letters.Study breakdown →PubMed →↩
3. 3. Source details for this reference are not yet available.
4. 4RTHM-01798·Szućko-Kociuba, Izabela et al. (2023). “Neurotrophic and Neuroprotective Effects of Hericium erinaceus..” International journal of molecular sciences.Study breakdown →PubMed →↩
5. 5RTHM-02184·Spangenberg, E T et al. (2025). “Unveiling the role of erinacines in the neuroprotective effects of Hericium erinaceus: a systematic review in preclinical models..” Frontiers in pharmacology.Study breakdown →PubMed →↩