Mushrooms and the Brain: Neuronal Activity, Neuroplasticity, and Cognitive Effects

By James Aspinwall, co-written by Alfred Pennyworth (my trusted AI) — February 27, 2026, 09:00

Mushrooms have been used in traditional medicine for centuries. Modern neuroscience is now catching up, revealing that several fungal species contain bioactive compounds capable of crossing the blood-brain barrier, stimulating nerve growth, and rewiring neural circuits. The evidence ranges from robust preclinical findings to emerging clinical trials — and the mechanisms are more diverse than most people realize.

This article surveys the current state of research across four domains: culinary/medicinal mushrooms, the amino acid ergothioneine, Lion’s Mane as a neurotrophin stimulator, and psilocybin as a neuroplasticity agent.

1. The Shared Biology: How Mushrooms Affect Neurons

Despite their diversity, mushroom-derived compounds converge on a handful of neural pathways:

Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) — proteins essential for neuronal survival, growth, and synaptic plasticity
Nrf2/ARE pathway — the master antioxidant switch that protects neurons from oxidative damage
Microglial modulation — reducing chronic neuroinflammation, a driver of cognitive decline
Default Mode Network (DMN) disruption — relevant to psilocybin, which temporarily breaks rigid neural patterns

The key insight is that different mushroom species target different parts of this machinery, which is why combination approaches and dietary variety may matter more than any single supplement.

2. Ergothioneine: The Longevity Amino Acid

Ergothioneine (EGT) is a sulfur-containing amino acid found almost exclusively in mushrooms. Humans cannot synthesize it — we absorb it through a dedicated transporter (OCTN1), which concentrates it in tissues with high oxidative demand, including the brain.

What the Evidence Shows

Low blood EGT levels correlate with cognitive decline and dementia, supporting its classification as a conditionally essential micronutrient for healthy aging.
EGT scavenges reactive oxygen species, suppresses neuroinflammatory cytokines (TNF-α, IL-1β, IL-6), activates Nrf2 antioxidant pathways, and preserves mitochondrial integrity.
2025 research demonstrates that EGT significantly increases BDNF expression in nerve cells — a direct mechanism for supporting neuronal health.
In a pilot trial, older adults with mild cognitive impairment who received EGT supplementation showed modest cognitive improvements and stabilization of plasma neurofilament light chain (a biomarker of neuronal damage).
Clinical studies suggest benefits for learning performance and sleep quality in healthy adults at doses of 8–20 mg/day.

Dietary Sources

Among 14 evaluated species, shiitake mushrooms contain the highest ergothioneine content. King oyster, oyster, and maitake mushrooms are also significant sources. Cooking does not destroy EGT — it is heat-stable.

3. Lion’s Mane: Stimulating Nerve Growth From Within

Hericium erinaceus (Lion’s Mane) is the most studied mushroom for direct neurotrophin stimulation. Its mechanism is unique among natural compounds.

The Mechanism

Lion’s Mane contains two classes of terpenoids — hericenones (from the fruiting body) and erinacines (from the mycelium) — that stimulate NGF synthesis in the brain. Critically, erinacines can cross the blood-brain barrier, a property that most neurotrophin-promoting compounds lack.

Using super-resolution microscopy, researchers at the University of Queensland demonstrated that Lion’s Mane extract and its active components significantly increase the size of neuronal growth cones — the sensory tips of developing axons that guide new connections between brain cells.

In animal models of Alzheimer’s disease, Lion’s Mane treatment:

Increased neurogenesis in the hippocampus
Improved the NGF/pro-NGF ratio (shifting toward the protective form)
Reduced astrogliosis and microgliosis (markers of chronic brain inflammation)

Hericerin derivatives activate a pan-neurotrophic pathway in hippocampal neurons converging on ERK1/2 signaling, a cascade that enhances spatial memory.

Human Clinical Evidence

Study	Participants	Dose	Duration	Outcome
Mori et al. (2009)	50–80 year olds with MCI	3 g/day fruiting body	16 weeks	Significant improvement in cognitive function scores
2025 RCT (healthy adults 18–45)	28-day trial	Standardized extract	28 days	Trend toward reduced subjective stress; no significant global cognitive change
Acute dose study (2025)	18 healthy young adults	Single dose	Acute	No significant effect on cognition or mood vs. placebo

The pattern is telling: Lion’s Mane appears most effective in populations with existing cognitive impairment or age-related decline, where the neurotrophin deficit is greatest. Healthy young adults — who already have robust NGF/BDNF signaling — show minimal acute effects.

4. Psilocybin: Rewiring Neural Circuits

Psilocybin (from Psilocybe mushrooms) operates through an entirely different mechanism than culinary or medicinal mushrooms. It is a serotonin 2A receptor agonist that triggers profound and measurable changes in brain connectivity.

Neuroplasticity Effects

A single dose of psilocybin induces approximately a 10% increase in dendritic spine density — the structural basis of synaptic connections.
Psilocybin directly binds to TrkB (BDNF receptors), leading to robust spinogenesis and dendritogenesis independent of serotonin receptor activation.
It increases expression of plasticity-related genes including c-Fos, BDNF, and mTOR, and enhances dendritic spine density in both the hippocampus and frontal cortex.

Brain Connectivity Changes

A landmark 2024 study in Nature found that psilocybin massively disrupted functional connectivity across cortex and subcortex — causing more than threefold greater change in brain connectivity than methylphenidate (Ritalin). This isn’t damage; it’s a temporary desynchronization that allows rigid neural patterns to reorganize.

A 2025 study published in Cell demonstrated that psilocybin triggers activity-dependent rewiring of large-scale cortical networks — meaning the brain doesn’t just become more random under psilocybin; it actively rebuilds connections based on which circuits are engaged during the experience.

Neuroimaging consistently shows that psilocybin:

Reduces Default Mode Network (DMN) activity — the network associated with self-referential thinking and rumination
Increases global brain integration, particularly across higher-order cognitive systems
Enhances hippocampal-cortical connectivity, relevant to memory and fear extinction

Cognitive and Therapeutic Evidence

A 2024 systematic review in Psychiatry and Clinical Neurosciences found emerging evidence that psilocybin may benefit cognitive flexibility, emotional processing, and creative thinking. Its therapeutic applications now include clinical trials for major depressive disorder, treatment-resistant depression, anxiety, alcohol use disorder, and cancer-related distress.

The cognitive mechanism may involve temporarily disrupting the DMN — breaking entrenched thought patterns — while simultaneously promoting the growth of new neural connections and pruning less efficient ones.

Important Context

Psilocybin is a controlled substance in most jurisdictions. The research cited here was conducted in clinical settings with medical supervision. The neuroplasticity effects, while remarkable, occur in a dose-dependent manner, and unsupervised use carries psychological risks.

5. Other Species: Reishi, Cordyceps, and Chaga

These species have demonstrated neuroprotective properties in preclinical research, though human clinical evidence remains limited.

Reishi (Ganoderma lucidum): Triterpenes and polysaccharides reduce neuroinflammation and oxidative stress. Animal studies show reduced amyloid-beta accumulation. No robust human cognitive trials exist.

Cordyceps: Cordycepin (its primary bioactive compound) enhances cerebral circulation and reduces fatigue. Animal studies suggest improved mental performance and concentration. Human evidence is preliminary.

Chaga (Inonotus obliquus): Among the highest ORAC (antioxidant capacity) values of any mushroom. May protect brain cells from oxidative damage and support acetylcholine signaling — the neurotransmitter most critical for memory. Human evidence is preclinical only.

6. The Evidence Landscape

Mushroom/Compound	Mechanism	Human Evidence	Best Evidence For
Ergothioneine	Antioxidant, anti-inflammatory, BDNF expression	Moderate (pilot trials, epidemiological)	Neuroprotection in aging
Lion’s Mane	NGF/BDNF stimulation, neurogenesis	Moderate (RCTs in MCI populations)	Mild cognitive impairment in older adults
Psilocybin	Dendritic spine growth, network rewiring, TrkB binding	Strong (RCTs, neuroimaging)	Depression, neuroplasticity, cognitive flexibility
Reishi	Anti-inflammatory, amyloid-beta reduction	Weak (preclinical only)	Neuroinflammation (theoretical)
Cordyceps	Cerebral circulation, fatigue reduction	Weak (preclinical + preliminary)	Mental fatigue, endurance
Chaga	Antioxidant, acetylcholine support	Weak (preclinical only)	Oxidative stress protection (theoretical)

7. Practical Takeaways

Dietary mushroom consumption matters. Epidemiological data from the EPIC-Norfolk cohort shows that higher mushroom intake is associated with better cognitive performance across word recall, executive function, and prospective memory — and with lower risk of incident dementia. This is likely mediated by ergothioneine and other bioactive compounds.

Supplementation evidence is strongest for Lion’s Mane in older adults with existing cognitive concerns. The effective dose in clinical trials was 3 g/day of dried fruiting body over 16 weeks.

Psilocybin represents a fundamentally different intervention — not a daily supplement but a supervised clinical experience that triggers structural brain changes. The neuroplasticity evidence is among the most striking in modern neuroscience, but it requires clinical context.

Combination is plausible but unproven. No study has examined whether combining ergothioneine-rich dietary mushrooms, Lion’s Mane supplementation, and other neuroprotective interventions produces additive or synergistic effects. The non-overlapping mechanisms suggest it could, but the trial hasn’t been done.

The research gap remains significant. Most mushroom neuroscience is preclinical. The compounds that work in cell cultures and animal models need larger, longer, well-controlled human trials before clinical recommendations can be made with confidence. The exception is psilocybin, where human neuroimaging and RCT data are now substantial.