Neurological Activity of Lion’s Mane ( Hericium erinaceus )

Abstract

Hericium erinaceus, most commonly known as lion’s mane, is an edible fungus, with a long history of use in Traditional Chinese Medicine. The mushroom is abundant in bioactive compounds including β-glucan polysaccharides; hericenones and erinacine terpenoids; isoindolinones; sterols; and myconutrients, which potentially have neuroprotective and neuroregenerative properties. Because of its anti-inflammatory properties and promotion of nerve growth factor gene expression and neurite (axon or dendrite) outgrowth, H. erinaceus mycelium shows great promise for the treatment of Alzheimer’s and Parkinson’s diseases. The fungus was well tolerated in two clinical studies, with few adverse events reported.

Full text

Journal of Restorative Medicine 2017; 6: page 19
Neurological Activity of Lion’s Mane (Hericium erinaceus)
Kevin Spelman, PhD, MCPPa
Elizabeth Sutherland, NDb
Aravind Bagade, MDc
©2017, Kevin Spelman, PhD, MCPP
Journal Compilation ©2017, AARM
DOI 10.14200/jrm.2017.6.0108
ABSTRACT
Hericium erinaceus, most commonly known as lion’s mane, is an edible fungus, with
a long history of use in Traditional Chinese Medicine. The mushroom is abundant in
bioactive compounds including β-glucan polysaccharides; hericenones and erinacine
terpenoids; isoindolinones; sterols; and myconutrients, which potentially have
neuroprotective and neuroregenerative properties. Because of its anti-inflammatory
properties and promotion of nerve growth factor gene expression and neurite
(axon or dendrite) outgrowth, H. erinaceus mycelium shows great promise for the
treatment of Alzheimer’s and Parkinson’s diseases. The fungus was well tolerated in
two clinical studies, with few adverse events reported.
Keywords: Lion’s mane; Neuroregeneration; Neurodegeneration; Neuroprotection;
Neurotropins; Neurotrophic; Alzheimer’s disease; Parkinson’s disease; Multiple
Sclerosis; Nerve growth factor
aCorresponding author: Health, Education & Research, POB 599, Ashland, OR 97520, USA,
Tel.: +1-541-708-3002; E-mail: phytochemks@gmail.com
bAdjunct faculty National University of Natural Medicine, Portland, OR, USA
cExecutive Secretary and Researcher, Ayurveda Interdisciplinary Research Minds Association, Mysore, India

Journal of Restorative Medicine 2017; 6: page 20
Lion’s Mane Neurological Activity
INTRODUCTION
Ancient, traditional, and modern cultures around
the world have known about the nutritive and
medicinal properties of mushrooms for centu-
ries. As early as 450 BCE, the Greek physician
Hippocrates identified mushrooms as potent
anti-inflammatory agents, useful for cauterizing
wounds. In the East, reverence for fungi is evident
in the Chinese description of ling zhi (Ganoderma
lucidum), as the “spirit plant,” believed to provide
longevity and spiritual potency.
Modern medicine has been slower to catch on to
the immense potential of fungi. Despite Fleming’s
1929 discovery of penicillin,1 and the subsequent
implementation of the fungi-chemical as a block-
buster pharmaceutical in the 1940s,2 it is only
in the last few decades that medical science has
looked beyond the antimicrobial and cholesterol-
lowering properties of fungi for other potential
applications.
Clinicians now have greater access to myce-
lium extracts, which are used clinically for their
cytotoxic, antineoplastic, cardiovascular, anti-
inflammatory, and immune-modulating activities.3–5
Functional studies and chemical assays also support
their potential to act as analgesic, antibacterial,
antioxidant, and neuroprotective agents. A number
of mushrooms, including Sarcodon scabrosus,
Ganoderma lucidum, Grifola frondosa, and
Hericium erinaceus are reported to have activi-
ties related to nerve and brain health.6 Hericium
erinaceus, a member of the Herinaceae family, is a
culinary and medicinal mushroom. Both the myce-
lium and fruiting bodies of H. erinaceus have been
shown to have therapeutic potential for brain and
nerve health.7 The unique neurological activities of
this fungus are the subject of this review.
TRADITIONAL USE OF LION’S
MANE (H. ERINACEUS)
Hericium erinaceus (lion’s mane, yamabushi-
take, or bearded tooth carpophore) grows on old
or dead broadleaf trees, and is used as both food
and medicine in parts of Asia. The fruiting body
is called hóu tóu gū (“monkey head mushroom”)
in Chinese8 and yamabushitake (“mountain monk
mushroom”) in Japanese. In Chinese and Japanese
medical systems, it has traditionally been used to
fortify the spleen, nourish the gut, and also as an
anticancer drug.9 Lion’s mane is said to be nutri-
tive to the five internal organs (liver, lung, spleen,
heart, and kidney), and promotes good digestion,
general vigor, and strength. It is also recommended
for gastric and duodenal ulcers, as well as chronic
gastritis (in prepared tablet form).10 The mushroom
is also known for its effects on the central nervous
system, and is used for insomnia, vacuity (weak-
ness), and hypodynamia, which are characteristic
symptoms of Qi deficiency in Traditional Chinese
medicine (TCM).
CHEMISTRY
The bioactive metabolites of H. erinaceus can be
classified into high molecular weight compounds,
such as polysaccharides, and low molecular
weight compounds, such as polyketides and
terpenoids.10,11
POLYSACCHARIDES
Fungal polysaccharides are found mainly in cell
walls, and are present in large quantities in both
fruiting bodies and cultured mycelium. Hericium
erinaceus fruiting bodies (HEFB) contain immu-
noactive β-glucan polysaccharides, as well as
α-glucans and glucan-protein complexes.12 A total
of more than 35 H. erinaceus polysaccharides
(HEP) have been extracted to date from cultured,
wild-growing, or fermentative mycelia and fresh/
dried fruiting bodies. Of these β-glucans represent
the main polysaccharides. HEP are composed of
xylose (7.8%), ribose (2.7%), glucose (68.4%),
arabinose (11.3%), galactose (2.5%), and mannose
(5.2%).4 Four different polysaccharides isolated
from the H. erinaceus sporocarp show antitumor
activity: xylans, glucoxylans, heteroxyloglucans,
and galactoxyloglucans.5 Chemical analysis shows
that the total content of HEP found in fruiting bod-
ies is higher than that in mycelium. Table 1 lists the

Journal of Restorative Medicine 2017; 6: page 21
Lion’s Mane Neurological Activity
polysaccharides along with their source and chemi-
cal composition.
Studies of the polysaccharides found in
H. erinaceus reveal a number of activities. For
example, extracellular and intracellular polysac-
charides showed a protective effect on oxidative
hepatotoxicity in mice.11 Neuroprotective effects of
HEPs were observed in an in vitro model of cells
that were toxic from amyloid β plaque formation.
In this model, HEPs decreased the production of
reactive oxygen species from 80% to 58% in a dose-
dependent manner, and increased the efficacy of free
radical scavenging. HEPs also promoted cell viabil-
ity and protected cells against apoptosis induced
by amyloid β plaque formation.13 HEPs decreased
blood lactic acid, serum urea nitrogen, tissue glyco-
gen, and malondialdehyde, further supporting the
beneficial role of HEPs on oxidative stress.14
TERPENOIDS: SESTERPENES, AND
DITERPENOIDS
Terpenoids are a class of naturally occurring
hydrocarbons that consist of terpenes attached to an
oxygen containing group. Terpenoids make up over
60% of products in the natural world.15,16
A variety of diterpenes and sesterpenes are found
in the fruiting body and fermenting mycelium of
H. erinaceus.17 Of particular pharmacological inter-
est are two classes of terpenoid compounds thus far
known to occur only in Hericium spp.: hericenones
(C–H), a group of aromatic compounds isolated
from the fruiting body; and erinacines (A–I), a
group of cyathane-type diterpenoids found in the
mycelium.18 Both groups of substances easily cross
the blood-brain barrier, and have been found to have
neurotrophic and in some cases neuroprotective
effects.19 Erinacines (A–I) have demonstrated induc-
tion of nerve growth factor (NGF) synthesis.20 Table
2 lists the terpenoids, sesterpenes, and diterpenoids
along with their source and chemical composition.
STEROLS
Ten erinarols, described as erinarol A–J, five
ergostane-type sterol fatty acid esters, and ten
ergostane-type sterols have been identified in the
fruiting body of H. erinaceus.21 Sterols, such as
Table 1: Polysaccharides: source and composition.
Polysaccharides No. Isolated from Composition
(FI0-a, FI0-a-α, FI0-a-β, FI0-b,
FII-1, FIII-2b)
6Fresh fruiting bodies of H.
erinaceus
Xylans, glucoxylans,
heteroxyloglucans, and
galactoxyloglucans
AF2S-2, BF2S-2 2 Fresh fruiting bodies Backbone of β-(l→6)-linked
D-glucopyranosyl residues,
and had β-(1→3) and
β-(l→6) glucosidic linkages
Heteropolysaccharides (HEPA1,
HEPA4, HEPB2)
3 Mycelium Glucose
Water extractable polysaccharides
(HPA and HPB)
2 Aqueous extract Glucose and galactose
Water soluble polysaccharide
(HPI)
1H. caput-medusae Glucose and galactose
Neutral heteropolysaccharides
(HEP-1 and HEP-4)
2 Fruiting bodies Glucose
Glucans HEP-3 (β-glucan) and
HEP-5 (α glucan)
2 Fruiting bodies Glucose
Acidic polysaccharide (HEP-2) 1 Fruiting bodies Uronic acid
Heteropolysaccharide (HPB-3) 1 The maturating-stage IV,
V, and VI fruiting body
I-fucose, d-galactose and
d-glucose
Homopolysaccharides, a neutral
glucan (HPP)
1 Fermentative mycelia Glucose

Journal of Restorative Medicine 2017; 6: page 22
Lion’s Mane Neurological Activity
ergosterol confer antioxidative properties.21,22
Hericium erinaceus has been found to be the most
potent in vitro inhibitor of both low-density lipo-
protein (LDL) oxidation and HMG Co-A reductase
activity, suggesting therapeutic potential for the
prevention of oxidative stress-mediated vascular
diseases.23
NEUROLOGICAL ACTIVITY
NEUROPROTECTION
Hericenones and erinacines isolated from
H. erinaceus have demonstrated neuroprotective
properties.24 Hericium erinaceus mycelia (HEM),
and its isolated diterpenoid derivative, erinacine A,
reduced infarction by 22% at 50 mg/kg and 44% at
300 mg/kg in an animal model of global ischemic
stroke. This effect was thought to be partially medi-
ated by its ability to reduce cytokine levels.25
A purified polysaccharide from the liquid culture
broth of HEM was also found to possess neuro-
protective activity in an in vitro model through a
dramatic delay of apoptosis, which was 20%–50%
greater than that seen in the control sample. The
same study showed HEM to be more effective than
control, NGF, or brain-derived neurotrophic fac-
tor (BDNF) alone in enhancing the growth of rat
adrenal nerve cells and neurite (axon or dendrite)
extension.26 However, in a model of NG108-15
neuroblastoma cells subjected to H2O2 oxidative
stress in pre-treatment and co-treatment, the aque-
ous extract of H. erinaceus (as opposed to a purified
polysaccharide), failed to show a protective effect.27
Although it is challenging to draw clinically rele-
vant conclusions from in vitro studies, this suggests
that water extracts would not have a neuroprotec-
tive effect without one particular polysaccharide
being highly concentrated.
NEUROTROPHIC ACTIVITY AND
MYELINATION
The addition of an ethanol extract of HEFB resulted
in NGF gene expression in human astrocytoma
cells, in a concentration-dependent manner. Neurite
outgrowth was also improved. The same investi-
gators also observed that mice fed 5% HEFB dry
powder for 7 days, showed an increase in the level
of NGF mRNA expression in the hippocampus.28
Another study showed that an aqueous extract of
HEFB increased secretion of extracellular NGF
and neurite outgrowth activity. These researchers
also observed a synergistic interaction between
H. erinaceus aqueous extract and exogenous
NGF on neurite outgrowth stimulation of neuro-
blastoma-glioma cells at physiologically relevant
concentrations (1 μg/mL HEFB extract +10 ng/mL
NGF).21 Myelin sheath formation in the presence
of H. erinaceus extract proceeded at a higher rate
and was completed by day 26, as compared to day
31 in controls. No toxic effects of the extracts were
observed in this model.30
COGNITIVE FUNCTION
In a behavior test on wild-type mice, oral
supplementation with H. erinaceus induced a
Table 2: Sesterpenes and diterpenoids: source and composition.
Terpenoids Isolated from Composition
Hericenones
Erinacines
Fresh fruiting bodies of H. erinaceus
Mycelia
Erinacerins C–L together with
(E)-5- (3,7- methylocta-2,6-dien-
1-yl)-4-hydroxy-6-methoxy-2-
phenethylisoindolin-1-one
Diterpenoids Fresh fruiting bodies of H. erinaceusErinacines A–I
Isoindolinones Fresh fruiting bodies of H. erinaceusErinaceolactams A–E, hericenone
A, hericenone J, N-De
phenylethylisohericerin, erinacerin A,
and hericerin

Journal of Restorative Medicine 2017; 6: page 23
Lion’s Mane Neurological Activity
statistically significant improvement in spatial
short-term and visual recognition memory.31 In a
double-blind placebo-controlled clinical trial of
50–80-year-old Japanese adults (n=30) diagnosed
with mild cognitive impairment, oral intake of
H. erinaceus 250 mg tablets (96% dry powder)
three times a day for 16 weeks was associ-
ated with marked improvement in the revised
Hasegawa Dementia Scale (HDS-R) as compared
to controls. Scores on the HDS-R decreased,
however, by 4 weeks after cessation of the
intervention.28
ALZHEIMER’S DISEASE
In a mouse model of Alzheimer’s disease, oral
administration of HEFB increased expression of
NGF mRNA in the hippocampus, and prevented
impairments of spatial, short-term, and visual
recognition memory induced by amyloid β plaque
that were observed in non-treated mice.28 In another
study using an Alzheimer’s model of mice that
develop amyloid plaque deposits by 6 months of
age, a 30-day oral administration of HEM resulted
in fewer plaque deposits in microglia and astro-
cytes in the cerebral cortex and hippocampus.32
In an aluminum chloride induced animal model
of Alzheimer’s disease, HEM increased serum
and hypothalamic concentrations of acetylcholine
and choline acetyltransferase in a dose-dependent
manner.29 Figure 1 illustrates the apparent mecha-
nisms of action for the effects that H. erinaceus
may have in Alzheimer’s disease.
PARKINSON’S DISEASE
Oral administration of low-dose HEM (10.76
or 21.52 mg/day) used in an animal model of
Parkinson’s disease led to significant improve-
ment in oxidative stress and dopaminergic lesions
in the striatum and substantia nigra after 25
days.33
PERIPHERAL NERVE INJURY
An aqueous extract of HEFB that was admin-
istered to animals at a dose of 10 mL/kg for
14 days following crush injury improved nerve
regeneration and increased the rate of motor
functional recovery. The animals treated with
HEFB recovered 4–7 days earlier than animals in
the control group, as assessed by walking track
analysis. Normal toe spreading, a measure of
reinnervation, was achieved 5–10 days earlier
in the aqueous extract group than in the control
group. Based on functional evaluation and the
morphological examination of regenerated nerves,
ipsilateral dorsal root ganglia, and target extensor
digitorum longus muscles, researchers concluded
that HEFB aqueous extract promoted peripheral
Figure 1: Mechanism of action of Hericium erinaceus in Alzheimer’s disease.

Journal of Restorative Medicine 2017; 6: page 24
Lion’s Mane Neurological Activity
nerve regeneration with significant functional
recovery.33
CLINICAL TRIALS
As previously described under Cognitive
Function, a double-blind placebo-controlled study
of 50–80-year-old Japanese men and women
(n=30) diagnosed with mild cognitive impair-
ment showed marked improvement in cognitive
function, as measured by the revised Hasegawa
Dementia Scale (HDS-R), when compared to
controls, following oral intake of H. erinaceus
250 mg tablets (96% dry powder) three times
a day for 16 weeks. Scores on the HDS-R
decreased, however, by 4 weeks after cessation of
the intervention.28
In another clinical trial, administration of HEFB
at 2.0 g/day (in cookies) over 4 weeks showed a
reduction in some symptoms of anxiety and depres-
sion in menopausal women (n=30). The Indefinite
Complaints Index categories for Palpitation
and Incentive showed a statistically significant
improvement in women taking HEFB compared to
those taking placebo. The categories of Irritating,
Anxious, and Concentration indicated a trend in the
direction of improvement with HEFB as compared
to placebo.29 Table 3 summarizes the two clinical
trials reported on in this paper.
POSOLOGY
COGNITION AND NGF PRODUCTION
The recommended dose of H. erinaceus dried
fruiting body for increasing NGF production is
3–5 g per day.34 Hericium erinaceus dosed at
250 mg tablets (96% dry powder) three times a
day for 16 weeks was associated with signifi-
cant improvement on a dementia rating scale in
subjects with mild cognitive impairment.28 The
dose utilized in the study of menopausal women
that showed reduction in symptoms of depression
and anxiety was 2.0 g/day of HEFB (in cookies)
for 4 weeks.29
TOXICOLOGY
In an in vitro model, HEFB aqueous extract
demonstrated a remarkable lack of cytotoxicity.31
Toxicology studies of H. erinaceus in rats suggest
that mycelia enriched with 5 mg/g erinacine A at
doses of up to 5 g/kg bodyweight/day are safe. No
toxicity was found in the two clinical trials reported
on here.28,29
REPORTED ADVERSE EVENTS
No adverse clinical or biochemical events were
reported in the clinical trial of subjects with
mild cognitive impairment.28 In the study of
Table 3: Outcomes of clinical trials of H. erinaceus.
Trial Parameter
assessed/Scale
Results Adverse events Dose Citation
Double-blind,
parallel-group,
placebo-controlled
trial
Mild cognitive
impairment/Revised
Hasegawa Dementia
Scale (HDS-R)
Significant
improvement
in cognitive
function scale
None 250 mg tid×16 weeks Mori et al., 200928
Randomized
placebo-controlled
trial
Anxiety and
depression/Center
for Epidemiologic
Studies Depression
Scale (CES-D)
and Indefinite
Complaints Index
(ICI)
Significant
improvement in
some anxiety and
depression scores
None 2 g/day×4 weeks Nagano et al., 201029

Journal of Restorative Medicine 2017; 6: page 25
Lion’s Mane Neurological Activity
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menorrhea (18 days menorrhea/month). However,
whether or not supplementation with H. eri-
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inconclusive.29
Allergies and sensitivities to mushrooms are not
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composition suggest that using the whole fungus may
be most advantageous clinically. More clinical studies
are needed to corroborate these conclusions.
COMPETING INTERESTS
The authors declare they have no competing interests.

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