Hericenones and NGF: The Lion's Mane Nerve Growth Mechanism

Lion's Mane & Nerve Growth Factor

60.6% more neurite growth

When trace NGF was combined with lion's mane fruiting body extract, neurite outgrowth increased 60.6% beyond NGF alone, demonstrating hericenones' synergistic action on nerve growth.

Lai et al., International Journal of Medicinal Mushrooms, 2013

6 variants

hericenones C, D, E, F, G, H isolated from Hericium erinaceus fruiting bodies

JNK + ERK1/2

two distinct neurotrophic signaling pathways activated by hericenone compounds

Fruiting body

hericenones are exclusive to the fruiting body, not the mycelium

Lai et al., International Journal of Medicinal Mushrooms, 2013

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For thirty years, the story of how lion's mane mushroom affects the brain has been told as one mechanism: the fruiting body contains compounds called hericenones that trigger the production of nerve growth factor (NGF), a protein that neurons need to survive and grow. That story is accurate. It is also incomplete.

In 2023, Martínez-Mármol and colleagues published research in the Journal of Neurochemistry showing that hericerin derivatives from lion's mane activate a neurotrophic pathway that is independent of NGF entirely.^[5] The mechanism runs through ERK1/2 signaling (a pair of enzymes that regulate cell growth and survival) and does not require the receptor that NGF and BDNF normally use to communicate with neurons. Mice given hericene A, one of these compounds, showed enhanced spatial memory. This finding changes the mechanistic picture considerably: hericenones don't just help build nerve growth factor production. They also activate a separate neurotrophic pathway that operates alongside it.

This article explains the full mechanism: what hericenones are chemically, how they stimulate NGF through the established JNK pathway, what the 60.6% synergistic enhancement finding means, why these compounds work differently from the erinacines found in lion's mane mycelium, and what the 2023 ERK1/2 discovery adds to the picture. For a broader overview of lion's mane biology, see the complete lion's mane guide.

The Compound Chemistry: What Hericenones Are and Where They Come From

Hericenones are aromatic (benzene ring-containing) small molecules found in the fruiting body of Hericium erinaceus. The earliest identification of their NGF-stimulating activity came from Kawagishi's laboratory in Japan in the early 1990s, with hericenones C, D, and E being the original compounds characterized. Friedman's 2015 comprehensive chemistry review established the full current catalog: six hericenones (designated C through H) alongside related aromatic compounds including hericene A, NDPIH, and other derivatives.^[1]

Their structure matters for understanding why they work differently from the erinacines. Hericenones have a relatively moderate molecular size and a polarity that affects how readily they move through biological membranes. This structural profile influences their pharmacokinetics, specifically how well they cross the blood-brain barrier (the tightly controlled membrane separating blood from brain tissue) after oral ingestion. The erinacines found in lion's mane mycelium have a different structural profile: smaller and more lipophilic (fat-soluble), which gives them better BBB penetration. Friedman's review makes this structural distinction clearly, establishing why fruiting body and mycelium preparations of lion's mane should not be assumed to have equivalent effects on the brain.^[1]

Critically, hericenones are exclusive to the fruiting body. A lion's mane supplement made from mycelium will not contain meaningful concentrations of hericenones. Conversely, a supplement made from fruiting body will not contain the erinacines that are central to the mycelium's neuroprotective effects. This is the foundational distinction that affects how different lion's mane products can be expected to work, and it is absent from most consumer-facing discussions of lion's mane supplements.

How Hericenones Activate NGF: The JNK Signaling Pathway

The core mechanistic work on how hericenones actually stimulate NGF production in brain cells was done by Mori and colleagues in 2008.^[2] Their experiments used 1321N1 cells, a human astrocytoma (brain support cell) line, and measured what happened at the gene expression level when H. erinaceus extracts were applied.

The mechanism works through a signaling cascade: a chain of molecular events where one protein activates the next. Hericenones activate JNK (a kinase, meaning a protein that activates other proteins by adding phosphate groups to them). Activated JNK then activates its target protein, c-Jun. Activated c-Jun, together with a related protein called c-Fos, forms a transcription factor complex called AP-1 that enters the cell nucleus and switches on the gene for NGF production. More NGF protein is then synthesized and released by the cell.

The Thumb Test version: hericenones flip a switch (JNK), which flips a second switch (c-Jun/c-Fos), which tells the cell's DNA to produce NGF. The practical result is that cells exposed to hericenones make more NGF than cells that aren't.

This is distinct from simply providing NGF externally (which would work locally but cannot reach the brain via oral supplementation) or from receptor-blocking drugs that prevent NGF breakdown. Hericenones act at the gene expression level, telling the cells themselves to produce more NGF. That is a pharmacologically meaningful distinction: the effect is driven by the cell's own production machinery, not by an external supply.

Mori's research also confirmed that this mechanism operates in human brain cells specifically, not just generic cell lines, an important confirmation given that most early supplement research uses non-neurological cell types.^[2]

The Synergy Effect: What Happens When Trace NGF Is Already Present

One of the most practically relevant findings in hericenone research comes from Lai and colleagues in 2013.^[3] Their study used NG108-15 cells (a widely-used neuronal cell line for studying NGF responses) and measured neurite outgrowth, the sprouting of extensions from nerve cell bodies that represents a functional proxy for nerve growth and connectivity.

The experimental design tested H. erinaceus fruiting body extract alone, NGF alone at a subthreshold concentration (too low to produce a measurable effect by itself), and the combination of the two together. The key result: the aqueous fruiting body extract induced NGF synthesis and promoted neurite outgrowth on its own. But when combined with the subthreshold concentration of NGF, the response was 60.6% greater than NGF alone could produce.

This is a synergistic effect, not simply an additive one. Two weak signals combined produced a stronger result than either would have produced separately. The biological interpretation: at the very low NGF concentrations that might exist in aging neurons or early-stage neurodegeneration, hericenones could amplify the signal from whatever endogenous NGF remains present, potentially producing meaningful effects in conditions where NGF is modestly depleted rather than entirely absent.

This synergy finding matters for understanding how lion's mane might be relevant to conditions like mild cognitive impairment (MCI), where NGF signaling is thought to be reduced but not eliminated. The Lion's Mane and Nerve Growth Factor guide covers the clinical evidence for that specific application.

The BBB Constraint: Why Hericenones and Erinacines Produce Different Effects

A critical piece of the hericenone story that consumer content almost always omits is the blood-brain barrier (BBB) question. The BBB is the highly selective membrane surrounding brain capillaries that controls what gets from the bloodstream into brain tissue. Small, lipophilic (fat-soluble) molecules tend to cross it more readily. Larger or more polar (water-soluble) molecules are largely blocked.

Hericenones are polar enough and large enough that their ability to cross the BBB after oral ingestion is limited. Li and colleagues' 2018 systematic review of erinacine-enriched mycelium preparations directly addresses this distinction.^[4] The erinacines, particularly erinacine A, B, and C, have a more favorable structural profile for BBB crossing. Their review documents erinacine-driven NGF stimulation specifically in central nervous system structures like the hippocampus and locus coeruleus, based on animal studies where erinacine A reached brain tissue and produced detectable NGF elevation there.

The practical implication: hericenones in the fruiting body can stimulate NGF production in cells they reach after absorption, but their direct impact on brain NGF levels (via the central nervous system pathway) is likely more limited than erinacines. Hericenones may act peripherally (in the gut, peripheral nervous system, and perhaps via indirect signaling) while erinacines act more directly centrally. This distinction does not make hericenones irrelevant. The 60.6% synergistic neurite outgrowth finding is real, and hericenones may have peripheral nerve effects and indirect brain-relevant mechanisms. But it does mean that fruiting body and mycelium preparations should not be treated as interchangeable for conditions specifically involving the central nervous system.

For more on the erinacines specifically, see Erinacines: The Compounds That Cross the Blood-Brain Barrier.

The 2023 Breakthrough: A Second Neurotrophic Pathway Independent of NGF

The most significant recent development in hericenone research is the Martínez-Mármol et al. 2023 paper in the Journal of Neurochemistry, which has not appeared in any consumer content on lion's mane despite being published in one of the highest-impact journals in the field.^[5]

The researchers studied two hericerin derivatives, NDPIH and hericene A, in hippocampal neurons (the brain cells most associated with learning and memory formation). They found these compounds activated a neurotrophic pathway via the ERK1/2 signaling molecules (a pair of enzymes that regulate neuronal growth and survival). This is mechanistically distinct from the established hericenone story in an important way.

The canonical neurotrophic pathway works like this: NGF binds to its receptor TrkA, which activates downstream signaling including ERK1/2. BDNF binds to TrkB, also activating ERK1/2. The cell grows or survives because of this receptor-signal cascade. What Martínez-Mármol found was that NDPIH and hericene A activated ERK1/2 without going through TrkB (the receptor for both BDNF and a related neurotrophin). This is a "pan-neurotrophic" pathway activation that is receptor-independent.

The ERK1/2 pathway in hippocampal neurons is directly connected to the molecular changes that underlie memory formation and synaptic plasticity (the brain's ability to strengthen or weaken connections between neurons based on experience). The mice in this study that received hericene A showed measurably enhanced spatial memory performance, providing in vivo confirmation that the mechanism has functional consequences.

The practical meaning for understanding lion's mane: NGF stimulation was always the primary proposed mechanism for hericenones' effects. This research shows that at least some hericenones also activate a separate pathway that enhances hippocampal function independently of whether NGF levels change at all. This could explain why some studies show lion's mane effects that seem larger or broader than simple NGF elevation alone would predict.

For more on how this connects to progranulin and other emerging neurotrophic pathways, see Lion's Mane and Progranulin: A Second Neurotrophic Pathway Beyond NGF.

What the Updated Evidence Means for Understanding Lion's Mane

Spangenberg and colleagues' 2025 systematic review of all preclinical erinacine research provides the most comprehensive current synthesis of lion's mane's neurotrophic mechanisms.^[6] While focused primarily on erinacines, the review situates them within the full mechanistic picture: lion's mane compounds act through NGF stimulation, BDNF stimulation, and the TrkB-independent ERK1/2 pathway that Martínez-Mármol identified. The convergence of multiple neurotrophic pathways may explain the compound effect seen in the Lai 2013 synergistic data.

The honest summary of the hericenone research: the JNK-mediated NGF synthesis mechanism (Mori 2008) is well-established in cell culture. The synergistic 60.6% enhancement at low NGF concentrations (Lai 2013) is a meaningful preclinical finding. The 2023 ERK1/2 pan-neurotrophic pathway (Martínez-Mármol 2023) is a genuine scientific advance, confirmed in hippocampal neurons with functional behavioral outcomes in mice.

What remains limited: there are no human trials specifically measuring whether oral hericenone-rich fruiting body extracts raise blood or brain NGF levels, at what doses, or over what time periods. The mechanistic evidence from cell culture and animal studies is strong. The translation to human dosing for specific clinical outcomes is not yet established with the kind of controlled trial evidence that would permit confident dosing recommendations.

The framing that best fits the evidence: hericenones are the best-characterized fruiting-body mechanism for how lion's mane interacts with neural growth pathways. They work through at least two distinct mechanisms, one involving NGF production and one involving direct ERK1/2 activation in hippocampal neurons. The preclinical evidence for their activity is solid; the clinical translation to specific human outcomes and doses is an active area of research. For the clinical human trial data on lion's mane and cognitive outcomes, see NGF Deficiency and Neurological Disease: Can Lion's Mane Help? and the pharmacology overview.

The Bottom Line

Hericenones are fruiting-body-specific aromatic compounds that stimulate NGF production in brain cells via JNK/c-Jun signaling, with 60.6% synergistic enhancement of neurite outgrowth when combined with low NGF concentrations. Distinct from the mycelium-derived erinacines, hericenones have more limited blood-brain barrier penetration. The significant 2023 finding: hericerin derivatives (NDPIH, hericene A) activate hippocampal ERK1/2 signaling independently of the TrkB receptor, representing a pan-neurotrophic pathway separate from NGF, with functional spatial memory enhancement in mice. The mechanistic picture is stronger than NGF stimulation alone accounts for; human dose-finding and clinical translation remain ongoing areas of research.

Frequently Asked Questions

What do hericenones do in the brain?

Hericenones primarily stimulate the production of nerve growth factor (NGF), a protein that neurons need to survive and extend growth. They do this by activating the JNK signaling molecule in brain support cells (astrocytes), which triggers NGF gene expression. A 2023 study also found that specific hericenone-related compounds (hericene A, NDPIH) activate a second neurotrophic pathway via ERK1/2 signaling in hippocampal neurons, independently of NGF, and that this activation improved spatial memory in mice.

How do hericenones stimulate nerve growth factor?

The molecular mechanism identified by Mori et al. 2008 runs through a signaling chain: hericenones activate JNK (a kinase enzyme), which activates c-Jun, which forms a transcription factor complex (AP-1) that switches on the NGF gene in cells. More NGF is then produced and released. This is different from providing NGF externally (which can't reach the brain via oral supplementation) or from preventing NGF breakdown. Hericenones trigger the cell's own production system.

Are hericenones found in the fruiting body or mycelium?

Hericenones are found exclusively in the fruiting body (the white, shaggy, visible mushroom), not in the mycelium (the root-like network). The mycelium contains a different compound class called erinacines. These two compound classes have different chemical structures, different pharmacokinetic profiles, and different primary mechanisms. A lion's mane supplement made from mycelium does not contain meaningful hericenone concentrations, and one made from fruiting body does not contain erinacines.

Do hericenones cross the blood-brain barrier?

Hericenones have limited blood-brain barrier (BBB) penetration compared to the erinacines from lion's mane mycelium. The BBB preferentially allows small, lipophilic (fat-soluble) molecules to cross. Hericenones are more polar than erinacines, making direct central nervous system access less efficient. This means hericenones likely exert more of their effects peripherally or via indirect mechanisms, while erinacines, confirmed in multiple studies including pig pharmacokinetics research, more reliably reach brain tissue after oral ingestion.

What is the difference between hericenones and erinacines?

Both are bioactive compounds from Hericium erinaceus, but they come from different parts of the mushroom and work through different mechanisms. Hericenones (C, D, E, F, G, H) are aromatic compounds from the fruiting body that stimulate NGF via JNK signaling and activate ERK1/2 via a TrkB-independent pathway. Erinacines (A, B, C, and others) are diterpene compounds from the mycelium that more readily cross the blood-brain barrier and directly stimulate central NGF and BDNF production in the hippocampus and cerebral cortex. For the erinacines specifically, see the dedicated article on their BBB properties and central nervous system effects.

Sources & References

1. 1RTHM-00371·Friedman, Mendel (2015). “Chemistry, Nutrition, and Health-Promoting Properties of Hericium erinaceus (Lion's Mane) Mushroom Fruiting Bodies and Mycelia and Their Bioactive Compounds..” Journal of agricultural and food chemistry.Study breakdown →PubMed →↩
2. 2RTHM-00268·Mori, Koichiro et al. (2008). “Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells..” Biological & pharmaceutical bulletin.Study breakdown →PubMed →↩
3. 3RTHM-00295·Lai, Puei-Lene et al. (2013). “Neurotrophic properties of the Lion's mane medicinal mushroom, Hericium erinaceus (Higher Basidiomycetes) from Malaysia..” International journal of medicinal mushrooms.Study breakdown →PubMed →↩
4. 4RTHM-00973·Li, I-Chen et al. (2018). “Neurohealth Properties of Hericium erinaceus Mycelia Enriched with Erinacines..” Behavioural neurology.Study breakdown →PubMed →↩
5. 5RTHM-01746·Martínez-Mármol, Ramón et al. (2023). “Hericerin derivatives activates a pan-neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory..” Journal of neurochemistry.Study breakdown →PubMed →↩
6. 6RTHM-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 →↩