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Mushrooms magnify memory by boosting nerve growth

Researchers from The University of Queensland have discovered the active compound from an edible mushroom that boosts nerve growth and enhances memory.

Professor Frederic Meunier from the Queensland Brain Institute said the team had identified new active compounds from the mushroom, Hericium erinaceus.

“Extracts from these so-called ‘lion’s mane’ mushrooms have been used in traditional medicine in Asian countries for centuries, but we wanted to scientifically determine their potential effect on brain cells,” Professor Meunier said.

“Pre-clinical testing found the lion’s mane mushroom had a significant impact on the growth of brain cells and improving memory.

“Laboratory tests measured the neurotrophic effects of compounds isolated from Hericium erinaceus on cultured brain cells, and surprisingly we found that the active compounds promote neuron projections, extending and connecting to other neurons.

“Using super-resolution microscopy, we found the mushroom extract and its active components largely increase the size of growth cones, which are particularly important for brain cells to sense their environment and establish new connections with other neurons in the brain.”

Co-author, UQ’s Dr Ramon Martinez-Marmol said the discovery had applications that could treat and protect against neurodegenerative cognitive disorders such as Alzheimer’s disease.

“Our idea was to identify bioactive compounds from natural sources that could reach the brain and regulate the growth of neurons, resulting in improved memory formation,” Dr Martinez-Marmol said.

Dr Dae Hee Lee from CNGBio Co, which has supported and collaborated on the research project, said the properties of lion’s mane mushrooms had been used to treat ailments and maintain health in traditional Chinese medicine since antiquity.

“This important research is unravelling the molecular mechanism of lion’s mane mushroom compounds and their effects on brain function, particularly memory,” Dr Lee said.

The study was published in the Journal of Neurochemistry .

UQ acknowledges the collaborative efforts of researchers from the Republic of Korea’s Gachon University and Chungbuk National University.

Media: QBI Communications, [email protected] u , Elaine Pye +61 415 222 606, Merrett Pye +61 422 096 049.

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Mushrooms Magnify Memory by Boosting Nerve Growth

Summary: Active compounds in the edible Lion’s Mane mushroom can help promote neurogenesis and enhance memory, a new study reports. Preclinical trials report the compound had a significant impact on neural growth and improved memory formation. Researchers say the compound could have clinical applications in treating and preventing neurodegenerative disorders such as Alzheimer’s disease.

Source: University of Queensland

Researchers from The University of Queensland have discovered the active compound from an edible mushroom that boosts nerve growth and enhances memory.

Professor Frederic Meunier from the Queensland Brain Institute said the team had identified new active compounds from the mushroom, Hericium erinaceus.

“Extracts from these so-called ‘lion’s mane’ mushrooms have been used in traditional medicine in Asian countries for centuries, but we wanted to scientifically determine their potential effect on brain cells,” Professor Meunier said. “Pre-clinical testing found the lion’s mane mushroom had a significant impact on the growth of brain cells and improving memory. “Laboratory tests measured the neurotrophic effects of compounds isolated from Hericium erinaceus on cultured brain cells, and surprisingly we found that the active compounds promote neuron projections, extending and connecting to other neurons. “Using super-resolution microscopy, we found the mushroom extract and its active components largely increase the size of growth cones, which are particularly important for brain cells to sense their environment and establish new connections with other neurons in the brain.”

Co-author, UQ’s Dr Ramon Martinez-Marmol said the discovery had applications that could treat and protect against neurodegenerative cognitive disorders such as Alzheimer’s disease. “Our idea was to identify bioactive compounds from natural sources that could reach the brain and regulate the growth of neurons, resulting in improved memory formation,” Dr Martinez-Marmol said. Dr Dae Hee Lee from CNGBio Co, which has supported and collaborated on the research project, said the properties of lion’s mane mushrooms had been used to treat ailments and maintain health in traditional Chinese medicine since antiquity. “This important research is unravelling the molecular mechanism of lion’s mane mushroom compounds and their effects on brain function, particularly memory,” Dr Lee said. The study was published in the  Journal of Neurochemistry . UQ acknowledges the collaborative efforts of researchers from the Republic of Korea’s Gachon University and Chungbuk National University.

About this neurogenesis and memory research news

Author: Elaine Pye Source: University of Queensland Contact: Elaine Pye – University of Queensland Image: The image is in the public domain

Original Research: Open access. “ Hericerin derivatives activates a pan-neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory ” by Frederic Meunier et al. Journal of Neurochemistry

Hericerin derivatives activates a pan-neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory

The traditional medicinal mushroom  Hericium erinaceus  is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity.

Here, we purified and identified biologically new active compounds from  H. erinaceus , based on their ability to promote neurite outgrowth in hippocampal neurons.  N -de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity.

Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA-12 only partly prevented the NDPIH-induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK-293T cells, an effect that was not sensitive to ANA-12 in the presence of TrkB.

Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with  H. erinaceus  crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory.

Hericene A therefore acts through a novel pan-neurotrophic signaling pathway ,  leading to improved cognitive performance.

Is it better to eat lion mane cooked or pill form I love mushrooms

It’ll be very good too, for TBI and aphasia cuz I have that now.

I wonder if using the term neurogenesis in this context is misleading. This supplement would seem to stimulate connectivity between existing neurons; not to create new ones. Be that as it may, enhanced connectivity can be beneficial. The danger, of course, is increased stimulation can negatively impact established pathways and over-stimulation can actually disrupt them to the point of neurosis.

A study sponsored by a company that sells the product being tested is bad enough, but the study is admittedly “sub-clinical” – there is no testing nor proof mentioned that the compounds/chemicals producing these study results would have any effect on human brains following digestion, either as fresh produce or as a powder or pills. By extension, there’s no indication how much of these chemicals would have to be consumed to have a similar positive effect, and what the possible negative effects of that level of consumption might be. And do the same chemicals also promote accelerated growth of tumor cells? The headline here and in multiple sites picking up this story is misleading at best, but will generate revenue for the sponsoring company as well as the ad revenue for the clickbait. If there is a website that lists these studies and has a yes/no column indicating financial interest/sponsorship, I’d appreciate someone posting the link.

There are other studies that say the same things. Perhaps you could read some before telling people it’s bunk when you clearly don’t know anything at all about the muschrooms.

I have tried dozens of supplements to help me continue to play bullet chess online (each side has 1 minute total for all their moves), even though I am too old for it (54). Lion’s Mane is one of my keepers. I have been taking it for about 2 years. I was never stronger before the last 2 years. And I have been very active playing bullet chess for around 16 years (well over 200,000 games). Lion’s Mane Mushroom extract, Salmon oil, Nicotinamide Riboside, PQQ, Lecithin, B-2, L-Carnosine, Choline Bitartrate, and DMAE appear to be effective for me. And raspberry Ice Tea or Hibiscus Tea.

Thanks, Noodle -Naut! Any particular brand of Lion’s Mane extract?

from where do you get these supplements?

RealMushrooms.com is the best source

So Noodle … are you going to share a Brand Name and where we might find it available?

That’s a lot of information with no payoff so far.

Please construct this eb page so that I can forward it to my wife ‘ just love mushrooms!

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The acute and chronic effects of lion’s mane mushroom supplementation on cognitive function, stress and mood in young adults: a double-blind, parallel groups, pilot study.

1. Introduction

2. materials and methods, 2.1. study design and participants, 2.2. treatments, 2.3. cognitive and mood assessments, 2.4. procedure, 2.5. statistics, 3.1. the acute effects of lion’s mane after a single dose (day 1), 3.2. the chronic effects of lion’s mane 28-day treatment, 4. discussion, 5. conclusions, supplementary materials, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Share and Cite

Docherty, S.; Doughty, F.L.; Smith, E.F. The Acute and Chronic Effects of Lion’s Mane Mushroom Supplementation on Cognitive Function, Stress and Mood in Young Adults: A Double-Blind, Parallel Groups, Pilot Study. Nutrients 2023 , 15 , 4842. https://doi.org/10.3390/nu15224842

Docherty S, Doughty FL, Smith EF. The Acute and Chronic Effects of Lion’s Mane Mushroom Supplementation on Cognitive Function, Stress and Mood in Young Adults: A Double-Blind, Parallel Groups, Pilot Study. Nutrients . 2023; 15(22):4842. https://doi.org/10.3390/nu15224842

Docherty, Sarah, Faye L. Doughty, and Ellen F. Smith. 2023. "The Acute and Chronic Effects of Lion’s Mane Mushroom Supplementation on Cognitive Function, Stress and Mood in Young Adults: A Double-Blind, Parallel Groups, Pilot Study" Nutrients 15, no. 22: 4842. https://doi.org/10.3390/nu15224842

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• Dean Ornish 1 , 2 ,
• Catherine Madison 1 , 3 ,
• Miia Kivipelto 4 , 5 , 6 , 7 ,
• Colleen Kemp 8 ,
• Charles E. McCulloch 9 ,
• Douglas Galasko 10 ,
• Jon Artz 11 , 12 ,
• Dorene Rentz 13 , 14 , 15 ,
• Jue Lin 16 ,
• Kim Norman 17 ,
• Anne Ornish 1 ,
• Sarah Tranter 8 ,
• Nancy DeLamarter 1 ,
• Noel Wingers 1 ,
• Carra Richling 1 ,
• Rima Kaddurah-Daouk 18 ,
• Rob Knight 19 ,
• Daniel McDonald 20 ,
• Lucas Patel 21 ,
• Eric Verdin 22 , 23 ,
• Rudolph E. Tanzi 13 , 24 , 25 , 26 &
• Steven E. Arnold 13 , 27  

Alzheimer's Research & Therapy volume  16 , Article number:  122 ( 2024 ) Cite this article

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Evidence links lifestyle factors with Alzheimer’s disease (AD). We report the first randomized, controlled clinical trial to determine if intensive lifestyle changes may beneficially affect the progression of mild cognitive impairment (MCI) or early dementia due to AD.

A 1:1 multicenter randomized controlled phase 2 trial, ages 45-90 with MCI or early dementia due to AD and a Montreal Cognitive Assessment (MoCA) score of 18 or higher. The primary outcome measures were changes in cognition and function tests: Clinical Global Impression of Change (CGIC), Alzheimer’s Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating–Sum of Boxes (CDR-SB), and Clinical Dementia Rating Global (CDR-G) after 20 weeks of an intensive multidomain lifestyle intervention compared to a wait-list usual care control group. ADAS-Cog, CDR-SB, and CDR-Global scales were compared using a Mann-Whitney-Wilcoxon rank-sum test, and CGIC was compared using Fisher’s exact test. Secondary outcomes included plasma Aβ42/40 ratio, other biomarkers, and correlating lifestyle with the degree of change in these measures.

Fifty-one AD patients enrolled, mean age 73.5. No significant differences in any measures at baseline. Only two patients withdrew. All patients had plasma Aβ42/40 ratios <0.0672 at baseline, strongly supporting AD diagnosis. After 20 weeks, significant between-group differences in the CGIC ( p = 0.001), CDR-SB ( p = 0.032), and CDR Global ( p = 0.037) tests and borderline significance in the ADAS-Cog test ( p = 0.053). CGIC, CDR Global, and ADAS-Cog showed improvement in cognition and function and CDR-SB showed significantly less progression, compared to the control group which worsened in all four measures. Aβ42/40 ratio increased in the intervention group and decreased in the control group ( p = 0.003). There was a significant correlation between lifestyle and both cognitive function and the plasma Aβ42/40 ratio. The microbiome improved only in the intervention group ( p <0.0001).

Conclusions

Comprehensive lifestyle changes may significantly improve cognition and function after 20 weeks in many patients with MCI or early dementia due to AD.

Trial registration

Approved by Western Institutional Review Board on 12/31/2017 (#20172897) and by Institutional Review Boards of all sites. This study was registered retrospectively with clinicaltrials.gov on October 8, 2020 (NCT04606420, ID: 20172897).

Increasing evidence links lifestyle factors with the onset and progression of dementia, including AD. These include unhealthful diets, being sedentary, emotional stress, and social isolation.

For example, a Lancet commission on dementia prevention, intervention, and care listed 12 potentially modifiable risk factors that together account for an estimated 40% of the global burden of dementia [ 1 ]. Many of these factors (e.g., hypertension, smoking, depression, type 2 diabetes, obesity, physical inactivity, and social isolation) are also risk factors for coronary heart disease and other chronic illnesses because they share many of the same underlying biological mechanisms. These include chronic inflammation, oxidative stress, insulin resistance, telomere shortening, sympathetic nervous system hyperactivity, and others [ 2 ]. A recent study reported that the association of lifestyle with cognition is mostly independent of brain pathology, though a part, estimated to be only 12%, was through β-amyloid [ 3 ].

In one large prospective study of adults 65 or older in Chicago, the risk of developing AD was 38% lower in those eating high vs low amounts of vegetables and 60% lower in those consuming omega-3 fatty acids at least once/week, [ 4 ] whereas consuming saturated fat and trans fats more than doubled the risk of developing AD [ 5 ].A systematic review and meta-analysis of 243 observational prospective studies and 153 randomized controlled trials found a similar relationship between these and similar risk factors and the onset of AD [ 6 ].

The multifactorial etiology and heterogeneity of AD suggest that multidomain lifestyle interventions may be more effective than single-domain ones for reducing the risk of dementia, and that more intensive multimodal lifestyle interventions may be more efficacious than moderate ones at preventing dementia [ 7 ].

For example, in the Finnish Geriatric Intervention Study (FINGER) study, a RCT of men and women 60-77 in age with Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk scores of at least 6 points and cognition at mean or slightly lower, a multimodal intervention of diet, exercise, cognitive training, vascular risk monitoring maintained cognitive function after 2 years in older adults at increased risk of dementia [ 8 ]. After 24 months, global cognition in the FINGER intervention group was 25% higher than in the control group which declined. Moreover, the FINGER intervention was equally beneficial regardless of several demographic and socioeconomic risk factors [ 9 ] and apolipoprotein E (APOE) ε4 status [ 10 ].

The FINGER lifestyle intervention also resulted in a 13-20% reduction in rates of cardiovascular disease events (stroke, transient ischemic attack, or coronary), providing more evidence that “what’s good for the heart is good for the brain”(and vice versa) [ 11 ]. Other large-scale multidomain intervention studies to determine if this intervention can help prevent dementia are being conducted or planned in over 60 countries worldwide, as part of the World-Wide FINGERS network, including the POINTER study in the U.S. [ 12 , 13 ].

More recently, a similar dementia prevention-oriented RCT showed that a 2-year personalized multidomain intervention led to modest improvements in cognition and dementia risk factors in those at risk for (but not diagnosed with) dementia and AD [ 14 ].

All these studies showed that lifestyle changes may help prevent dementia. The study we are reporting here is the first randomized, controlled clinical trial to test whether intensive lifestyle changes may beneficially affect those already diagnosed with mild cognitive impairment (MCI) or early dementia due to AD.

In two earlier RCTs, we found that the same multimodal lifestyle intervention described in this article resulted in regression of coronary atherosclerosis as measured by quantitative coronary arteriography [ 15 ] and ventricular function, [ 16 ] improvements in myocardial perfusion as measured by cardiac PET scans, and 2.5 times fewer cardiac events after five years, all of which were statistically significant [ 17 ]. Until then, it was believed that coronary heart disease progression could only be slowed, not stopped or reversed, similar to how MCI or early dementia due to AD are viewed today.

Since AD and coronary heart disease share many of the same risk factors and biological mechanisms, and since moderate multimodal lifestyle changes may help prevent AD, [ 18 ] we hypothesized that a more intensive multimodal intervention proven to often reverse the progression of coronary heart disease and some other chronic diseases may also beneficially affect the progression of MCI or early dementia due to AD.

We report here results of a randomized controlled trial to determine if the progression of MCI or early dementia due to AD may be slowed, stopped, or perhaps even reversed by a comprehensive, multimodal, intensive lifestyle intervention after 20 weeks when compared to a usual-care randomized control group. This lifestyle intervention includes (1) a whole foods, minimally processed plant-based diet low in harmful fats and low in refined carbohydrates and sweeteners with selected supplements; (2) moderate exercise; (3) stress management techniques; and (4) support groups.

This intensive multimodal lifestyle modification RCT sought to address the following questions:

Can the specified multimodal intensive lifestyle changes beneficially affect the progression of MCI or early dementia due to AD as measured by the AD Assessment Scale–Cognitive Subscale (ADAS-Cog), CGIC (Clinical Global Impression of Change), CDR-SB (Clinical Dementia Rating Sum of Boxes), and CDR-G (Clinical Dementia Rating Global) testing?

Is there a significant correlation between the degree of lifestyle change and the degree of change in these measures of cognition and function?

Is there a significant correlation between the degree of lifestyle change and the degree of change in selected biomarkers (e.g., the plasma Aβ42/40 ratio)?

Participants and methods

This study was a 1:1 multi-center RCT during the first 20 weeks of the study, and these findings are reported here. Patients who met the clinical trial inclusion criteria were enrolled between September 2018 and June 2022.

Participants were enrolled who met the following inclusion criteria:

Male or female, ages 45 to 90

Current diagnosis of MCI or early dementia due to AD process, with a MoCA score of 18 or higher (National Institute on Aging–Alzheimer’s Association McKhann and Albert 2011 criteria) [ 19 , 20 ]

Physician shared this diagnosis with the patient and approved their participation in this clinical trial

Willingness and ability to participate in all aspects of the intervention

Availability of spouse or caregiver to provide collateral information and assist with study adherence

Patients were excluded if they had any of the following:

Moderate or severe dementia

Physical disability that precludes regular exercise

Evidence for other primary causes of neurodegeneration or dementia, e.g., significant cerebrovascular disease (whose primary cause of dementia was vascular in origin), Lewy Body disease, Parkinson's disease, FTD

Significant ongoing psychiatric or substance abuse problems

Fifty-one participants with MCI or early-stage dementia due to AD who met these inclusion criteria were enrolled between September 2018 and June 2022 and underwent baseline testing. 26 of the enrolled participants were randomly assigned to an intervention group that received the multimodal lifestyle intervention for 20 weeks and 25 participants were randomly assigned to a usual habits and care control group that was asked not to make any lifestyle changes for 20 weeks, after which they would be offered the intervention. Patients in both groups received standard of care treatment managed by their own neurologist.

The intervention group received the lifestyle program for 20 weeks (initially in person, then via synchronous Zoom after March 2020 due to COVID-19). Two participants who did not want to continue these lifestyle changes withdrew during this time, both in the intervention group (one male, one female). Participants in both groups completed a follow-up visit at 20 weeks, where clinical and cognitive assessments were completed. Data were analyzed comparing the baseline and 20 week assessments between the groups.

In a drug trial, access to an investigational new drug can be restricted from participants in a randomized control group. However, we learned in our prior clinical trials of this lifestyle intervention with other diseases that it is often difficult to persuade participants who are randomly assigned to a usual-care control group to refrain from making these lifestyle changes for more than 20 weeks, which is why this time duration was chosen. If participants in both groups made similar lifestyle changes, then it would not be possible to show differences between the groups. Therefore, to encourage participants randomly assigned to the control group not to make lifestyle changes during the first 20 weeks, we offered to provide them the same lifestyle program at no cost to them for 20 weeks after being in the usual-care control group and tested after 20 weeks.

We initially planned to enroll 100 patients into this study based on power calculations of possible differences between groups in cognition and function after 20 weeks. However, due to challenges in recruiting patients, especially with the COVID-19 emergency and that many pharma trials began recruiting patients with similar criteria, it took longer to enroll patients than initially planned [ 21 ]. Because of this, we terminated recruitment after 51 patients were enrolled. This decision was based only on recruitment issues and limited funding, without reviewing the data at that time.

Patients were recruited from advertisements, presentations at neurology meetings, referrals from diverse groups of neurologists and other physicians, and a search of an online database of patients at UCSF. We put a special emphasis on recruiting diverse patients, although we were less successful in doing so than we hoped (Table 1 ).

This clinical trial was approved by the Western Institutional Review Board on 12/31/2017 (approval number: 20172897) and all participants and their study partners provided written informed consent. The trial protocol was also approved by the appropriate Institutional Review Board of all participating sites, and all subjects provided informed consent. Due to the COVID-19 emergency, planned MRI and amyloid PET scans were no longer feasible, and the number of cognition and function tests was decreased. An initial inclusion criterion of “current diagnosis of mild to moderate dementia due to AD (McKhann et al., 2011)” was further clarified to include a MoCA score of 18 or higher. This study was registered with clinicaltrials.gov on October 8, 2020 (NCT04606420, Unique Protocol ID: 20172897) retrospectively due to an administrative error. None of the sponsors who provided funding for this study participated in its design, conduct, management, or reporting of the results. Those providing the lifestyle intervention were separate from those performing testing and from those collecting and analyzing the data, who were blinded to group assignment. All authors contributed to manuscript draft revisions, provided critical comment, and approved submission for publication.

Any modifications in the protocol were approved in advance and in writing by the senior biostatistician (Charles McCulloch PhD) or the senior expert neuropsychologist (Dorene Rentz PsyD), and subsequently approved by the WIRB.

Patients were initially recruited only from the San Francisco Bay area beginning October 2018 and met in person until February 2020 when the COVID-19 pandemic began. Subsequently, this multimodal lifestyle intervention was offered to patients at home in real time via Zoom.

Offering this intervention virtually provided an opportunity to recruit patients from multiple sites, including the Massachusetts General Hospital/Harvard Medical School, Boston, MA; the University of California, San Diego; and Renown Regional Medical Center, Reno, NV, as well as with neurologists in the San Francisco Bay Area. These participants were recruited and tested locally at each site and the intervention was provided via Zoom and foods were sent directly to their home.

Patient recruitment

This is described in the Supplemental Materials section.

Intensive multimodal lifestyle intervention

Each patient received a copy of a book which describes this lifestyle medicine intervention for other chronic diseases. [ 2 ]

A whole foods minimally-processed plant-based (vegan) diet, high in complex carbohydrates (predominantly fruits, vegetables, whole grains, legumes, soy products, seeds and nuts) and especially low in harmful fats, sweeteners and refined carbohydrates. It was approximately 14-18% of calories as total fat, 16-18% protein, and 63-68% mostly complex carbohydrates. Calories were unrestricted. Those with higher caloric needs were given extra portions.

To assure the high adherence and standardization required to adequately test the hypothesis, 21 meals/week and snacks plus the daily supplements listed below were provided throughout the 40 weeks of this intervention to each study participant and his or her spouse or study partner at no cost to them. Twice/week, we overnight shipped to each patient as well as to their spouse or study partner three meals plus two snacks per day that met the nutritional guidelines as well as the prescribed nutritional supplements.

We asked participants to consume only the food and nutritional supplements we sent to them and no other foods. We reasoned that if adherence to the diet and lifestyle intervention was high, whatever outcomes we measured would be of interest. That is, if patients in the intervention group were adherent but showed no significant benefits, that would be a disappointing but an important finding. If they showed improvement, that would also be an important finding. But if they did not follow the lifestyle intervention sufficiently, then we would not have been able to adequately test the hypotheses.

Aerobic (e.g., walking) at least 30 minutes/day and mild strength training exercises at least three times per week from an exercise physiologist in person or with virtual sessions. Patients were given a personalized exercise prescription based on age and fitness level. All sessions were overseen by a registered nurse.

• Stress management

Meditation, gentle yoga-based poses, stretching, progressive relaxation, breathing exercises, and imagery for a total of one hour per day, supervised by a certified stress management specialist. The purpose of each technique was to increase the patient’s sense of relaxation, concentration, and awareness. They were also given access to online meditations. Patients had the option of using flashing-light glasses at a theta frequency of 7.83 Hz plus soothing music as an aid to meditation and insomnia [ 22 ]. They were also encouraged to get adequate sleep.

Group support

Participants and their spouses/study partners participated in a support group one hour/session, three days/week, supervised by a licensed mental health professional in a supportive, safe environment to increase emotional support and community as well as communication skills and strategies for maintaining adherence to the program. They also received a book with memory exercises used periodically during group sessions [ 23 ].

To reinforce this lifestyle intervention, each patient and their spouse or study partner met three times/week, four hours/session via Zoom: 2

one hour of supervised exercise (aerobic + strength training)

one hour of stress management practices (stretching, breathing, meditation, imagery)

one hour of a support group

one hour lecture on lifestyle

Additional optional exercise and stress management classes were provided.

Supplements

Omega-3 fatty acids with Curcumin (1680 mg omega-3 & 800 mg Curcumin, Nordic Naturals ProOmega CRP, 4 capsules/day). Omega-3 fatty acids: In those age 65 or older, those consuming omega-3 fatty acids once/week or more had a 60% lower risk of developing AD, and total intake of n-3 polyunsaturated fatty acids was associated with reduced risk of Alzheimer disease [ 24 ]. Curcumin targets inflammatory and antioxidant pathways as well as (directly) amyloid aggregation, [ 25 ] although there may be problems with bioavailability and crossing the blood-brain barrier [ 26 ].

Multivitamin and Minerals (Solgar VM-75 without iron, 1 tablet/day). Combinatorial formulations demonstrate improvement in cognitive performance and the behavioral difficulties that accompany AD [ 27 ].

Coenzyme Q10 (200 mg, Nordic Naturals, 2 soft gels/day). CoQ10. May reduce mitochondrial impairment in AD [ 28 ].

Vitamin C (1 gram, Solgar, 1 tablet/day): Maintaining healthy vitamin C levels may have a protective function against age-related cognitive decline and AD [ 29 ].

Vitamin B12 (500 mcg, Solgar, 1 tablet/day): B12 hypovitaminosis is linked to the development of AD pathology [ 30 ].

Magnesium L-Threonate (Mg) (144 mg, Magtein, 2 tablets/day). A meta-analysis found that Mg deficiency may be a risk factor of AD and Mg supplementation may be an adjunctive treatment for AD [ 31 ].

Hericium erinaceus (Lion’s Mane, Stamets Host Defense, 2 grams/day): Lion’s mane may produce significant improvements in cognition and function in healthy people over 50 [ 32 ] and in MCI patients compared to placebo [ 33 ].

Super Bifido Plus Probiotic (Flora, 1 tablet/day). A meta-analysis suggests that probiotics may benefit AD patients [ 34 ].

Primary outcome measures: cognition and function testing

Four tests were used to assess changes in cognition and function in these patients. These are standard measures of cognition and function included in many FDA drug trials: ADAS-Cog; Clinical Global Impression of Change (CGIC); Clinical Dementia Rating Sum of Boxes (CDR-SB); Clinical Dementia Rating Global (CDR Global). All cognition and function raters were trained psychometrists with experience in administering these tests in clinical trials. Efforts were made to have the same person perform cognitive testing at each visit to reduce inter-observer variability. Those doing ADAS-Cog assessments were certified raters and tested patients in person. The CGIC and CDR tests were administered for all patients via Zoom by different raters than the ADAS-cog. Also, raters were blind to treatment arm to the degree possible.

Secondary outcome measures: biomarkers and microbiome

These are described in the Supplemental Materials section. These include blood-based biomarkers (such as the plasma Aβ42/40 ratio) and microbiome taxa (organisms).

Statistical methods

These are described in the Supplemental Materials section.

The recruitment effort for this trial lasted from 01/23/2018 to 6/16/2022. The most effective recruitment method was referral from the subjects’ physician or healthcare provider. Additional recruitment efforts included advertising in print and digital media; speaking to community groups; mentioning the study during podcast and radio interviews; collaborating with research institutions that provide dementia diagnosis and treatment; and contracting a clinical trials recruitment service (Linea). A total of 1585 people contacted us; of these, 1300 did not meet the inclusion criteria, 102 declined participation, and 132 were screening incomplete when enrollment closed, resulting in the enrollment of 51 participants (Fig. 1 ).

CONSORT flowchart: patients, demographics, and enrollment

The remaining 51 patients were randomized to an intervention group (26 patients) that received the lifestyle intervention for 20 weeks or to a usual-care control group (25 patients) that was asked not to make any lifestyle changes. Two patients in the intervention group withdrew during the intervention because they did not want to continue the diet and lifestyle changes. No patients in the control group withdrew prior to 20-week testing. Analyses were performed on the remaining 49 patients. No patients were lost to follow-up.

All of these 49 patients had plasma Aβ42/40 ratios <0.089 (all were <0.0672), strongly supporting the diagnosis of Alzheimer’s disease [ 35 ].

At baseline, there were no statistically significant differences between the intervention group and the randomized control group in any measures, including demographic characteristics, cognitive function measures, or biomarkers (Table 1  and Table 2 ).

Cognition and function testing: primary analysis

Results after 20 weeks of a multimodal intensive lifestyle intervention in all patients showed overall statistically significant differences between the intervention group and the randomized control group in cognition and function in the CGIC ( p = 0.001), CDR-SB ( p = 0.032), and CDR Global ( p = 0.037) tests and of borderline significance in the ADAS-Cog test ( p = 0.053, Table 3 ). Three of these measures (CGIC, CDR Global, ADAS-Cog) showed improvement in cognition and function in the intervention group and worsening in the control group, and one test (CDR-SB) showed significantly less progression when compared to the randomized control group, which worsened in all four of these measures.

PRIMARY ANALYSIS (with outlier included), Table 3 :

CGIC (Clinical Global Impression of Change)

These scores improved in the intervention group and worsened in the control group.

(Fisher’s exact p -value = 0.001). 10 people in the intervention group showed improvement compared to none in the control group. 7 people in the intervention group and 8 people in the control group were unchanged. 7 people in the intervention group showed minimal worsening compared to 14 in the control group. None in the intervention group showed moderate worsening compared to 3 in the control group.

CDR-Global (Clinical Dementia Rating-Global)

These scores improved in the intervention group (from 0.69 to 0.65) and worsened in the randomized control group (from 0.66 to 0.74), mean difference = 0.12, p = 0.037 (Table 3 and Fig. 2 ).

Changes in CDR-Global (lower = improved)

ADAS-Cog (Alzheimer’s Disease Assessment Scale)

These scores improved in the intervention group (from 21.551 to 20.536) and worsened in the randomized control group (from 21.252 to 22.160), mean group difference of change = 1.923 points, p = 0.053 (Table 3 and Fig. 3 ). (ADAS-Cog testing in one intervention group patient was not administered properly so it was excluded.)

Changes in ADAS-Cog (lower = improved)

CDR-SB (Clinical Dementia Rating Sum of Boxes)

These scores worsened significantly more in the control group (from 3.34 to 3.86) than in the intervention group (from 3.27 to 3.35), mean group difference = 0.44, p = 0.032 (Table 3 and Fig. 4 ).

Changes in CDR-SB (lower = improved)

There were no significant differences in depression scores as measured by PHQ-9 between the intervention and control groups.

Secondary sensitivity analyses

One patient in the intervention group was a clear statistical outlier in his cognitive function testing based on standard mathematical definitions (none was an outlier in the control group) [ 36 ]. Therefore, this patient’s data were excluded in a secondary sensitivity analysis. These results showed statistically significant differences in all four of these measures of cognition and function (Table 4 ). Three measures (ADAS-Cog, CGIC, and CDR Global) showed significant improvement in cognition and function and one (CDR-SB) showed significantly less worsening when compared to the randomized control group, which worsened in all four of these measures.

Sensitivity analysis (with outlier excluded)

There were no significant differences in depression scores as measured by PHQ-9 between the intervention and control groups in either analysis.

A reason why this patient might have been a statistical outlier is that he reported intense situational stress before his testing. As a second sensitivity analysis, this same outlier patient was retested when he was calmer, and all four measures (ADAS-Cog, CGIC, CDR Global, and CDR-SB) showed significant improvement in cognition and function, whereas the randomized control group worsened in all four of these measures.

Biomarker results

We selected biomarkers that have a known role in the pathophysiology of AD (Table 5 ). Of note is that the plasma Aβ42/40 ratio increased in the intervention group but decreased in the randomized control group ( p = 0.003, two-tailed).

Correlation of lifestyle index and cognitive function

In the current clinical trial, despite the inherent limitations of self-reported data, we found statistically significant correlations between the degree of lifestyle change (from baseline to 20 weeks) and the degree of change in three of four measures of cognition and function as well as correlations between the adherence to desired lifestyle changes at just the 20-week timepoint and the degree of change in two of the four measures of cognition and function and borderline significance in the fourth measure.

Correlation with lifestyle at 20 weeks: p = 0.052; correlation: 0.241

Correlation with degree of change in lifestyle: p = 0.015; correlation: 0.317

Correlation with lifestyle at 20 weeks: p = 0.043; correlation: 0.251

Correlation with degree of change in lifestyle: p = 0.081; correlation: 0.205

Correlation with lifestyle at 20 weeks: p = 0.065; correlation: 0.221

Correlation with degree of change in lifestyle: p = 0.024; correlation: 0.286

Correlation with lifestyle at 20 weeks: p = 0.002

Correlation with degree of change in lifestyle: p = 0.0005

(CGIC tests are non-parametric analyses, so standard effect size calculations are not included for this measure.)

Also, we also found a significant correlation between dietary total fat intake and changes in the CGIC measure ( p = 0.001), but this was not significant for the other three measures.

Correlation of lifestyle index and biomarker data

In the current clinical trial, despite the inherent limitations of self-reported data, we found statistically significant correlations between the degree of lifestyle change (from baseline to 20 weeks) and the degree of change in many of the key biomarkers, as well as correlations between the degree of lifestyle change at 20 weeks and the degree of change in these biomarkers:

Plasma Aβ42/40 ratio

Correlation with lifestyle at 20 weeks: p = 0.035; correlation: 0.306

Correlation with degree of change in lifestyle: p = 0.068; correlation: 0.266

Correlation with lifestyle at 20 weeks: p = 0.011; correlation: 0.363

Correlation with degree of change in lifestyle: p = 0.007; correlation: 0.383

LDL-cholesterol

Correlation with lifestyle at 20 weeks: p < 0.0001; correlation: 0.678

Correlation with degree of change in lifestyle: p < 0.0001; correlation: 0.628

Beta-Hydroxybutyrate (ketones)

Correlation with lifestyle at 20 weeks: p = 0.013; correlation: 0.372

Correlation with degree of change in lifestyle: p = 0.034; correlation: 0.320

Correlation with lifestyle at 20 weeks: p = 0.228; correlation: 0.177

Correlation with degree of change in lifestyle: p = 0.135; correlation: 0.219

GFAP/glial fibrillary acidic protein

Correlation with lifestyle at 20 weeks: p = 0.096; correlation: 0.243

Correlation with degree of change in lifestyle: p =0.351; correlation: 0.138

What degree of lifestyle change is correlated with improvement in cognitive function tests?

What degree of lifestyle is needed to stop or improve the worsening of MCI or early dementia due to AD? In other words, what % of adherence to the lifestyle intervention was correlated with no change in MCI or dementia across both groups? Higher adherence than this degree of lifestyle change was associated with improvement in MCI or dementia.

Correlation with lifestyle at 20 weeks: 71.4% adherence

Correlation with lifestyle at 20 weeks: 120.6% adherence

CDR-Global:

Correlation with lifestyle at 20 weeks: 95.6%

Microbiome results

There was a significant and beneficial change in the microbiome configuration in the intervention group but not in the control group.

Several taxa (groups of microorganisms) that increased only in the intervention group were consistent with those involved in reduced AD risk in other studies. For example, Blautia, which increased during the intervention in the intervention group, has previously been associated with a lower risk of AD, potentially due to its involvement in increasing γ-aminobutyric acid (GABA) production [ 37 ].  Eubacterium also increased during the intervention in the intervention group, and prior studies have identified Eubacterium genera (namely Eubacterium fissicatena) as a protective factor in AD [ 38 ].

Also, there was a decrease in relative abundance of taxa involved in increased AD risk in the intervention group, e.g., Prevotella and Turicibacter , the latter of which has been associated with relevant biological processes such as 5-HT production. Prevotella and Turicibacter have previously been shown to increase with disease progression, [ 39 ] and these taxa decreased over the course of the intervention.

These results support the hypothesis that the lifestyle intervention may beneficially modify specific microbial groups in the microbiome: increasing those that lower the risk of AD and decreasing those that increase the risk of AD. (Please see Supplement for more detailed information.)

We report the first randomized, controlled trial showing that an intensive multimodal lifestyle intervention may significantly improve cognition and function and may allay biological features in many patients with MCI or early dementia due to AD after 20 weeks.

After 20 weeks of a multimodal intensive lifestyle intervention, results of the primary analysis when all patients were included showed overall statistically significant differences between the intervention group and the randomized control group in cognition and function as measured by the CGIC ( p = 0.001), CDR-SB ( p = 0.032), and CDR Global ( p = 0.037) tests and of borderline significance in the ADAS-Cog test ( p = 0.053).

Three of these measures (CGIC, CDR Global, ADAS-Cog) showed improvement in cognition and function in the intervention group and worsening in the randomized control group, and one test (CDR-SB) showed less progression in the intervention group when compared to the control group which worsened in all four of these measures.

These differences were even clearer in a secondary sensitivity analysis when a mathematical outlier was excluded. These results showed statistically significant differences between groups in all four of these measures of cognition and function. Three of these measures showed improvement in cognition and function and one (CDR-SB) showed less deterioration when compared to the randomized control group, which worsened in all four of these measures.

The validity of these changes in cognition and function and possible biological mechanisms of improvement is supported by the observed changes in several clinically relevant biomarkers that showed statistically significant differences in a beneficial direction after 20 weeks when compared to the randomized control group.

One of the most clinically relevant biomarkers is the plasma Aβ42/40 ratio, which increased by 6.4% in the intervention group and decreased by 8.3% in the randomized control group after 20 weeks, and these differences were statistically significant ( p = 0.003, two-tailed).

In the lecanemab trial, plasma levels of the Aβ42/40 biomarker increased in the intervention group over 18 months with the presumption that this reflected amyloid moving from the brain to the plasma [ 40 ]. We found similar results in the direction of change in the plasma Aβ42/40 ratio from this lifestyle intervention but in only 20 weeks. Conversely, this biomarker decreased in the control group (as in the lecanemab trial), which may indicate increased cerebral uptake of amyloid.

Other clinically relevant biomarkers also showed statistically significant differences (two-tailed) in a beneficial direction after 20 weeks when compared to the randomized control group. These include hemoglobin A1c, insulin, glycoprotein acetyls (GlycA), LDL-cholesterol, and β-Hydroxybutyrate (ketone bodies).

Improvement in these biomarkers provides more biological plausibility for the observed improvements in cognition and function as well as more insight into the possible mechanisms of improvement. This information may also help in predicting which patients are more likely to show improvements in cognition and function by making these intensive lifestyle changes.

Other relevant biomarkers were in a beneficial direction of change in the intervention group compared with the randomized control group after 20 weeks. These include pTau181, GFAP, CRP, SAA, and C-peptide. Telomere length increased in the intervention group and was essentially unchanged in the control group. These differences were not statistically significant even when there was an order of magnitude difference between groups (as with GFAP and pTau181) or an almost four-fold difference (as with CRP), but these changes were in a beneficial direction. At least in part, these findings may be due to a relatively small sample size and/or a short duration of only 20 weeks.

We found a statistically significant dose-response correlation between the degree of lifestyle changes in both groups (“lifestyle index”) and the degree of change in many of these biomarkers. This correlation was found in both the degree of change in lifestyle from baseline to 20 weeks as well as the lifestyle measured at 20 weeks. These correlations also add to the biological plausibility of these findings.

We also found a statistically significant dose-response correlation between the degree of lifestyle changes in both groups (“lifestyle index”) and changes in most measures of cognition and function testing. In short, the more these AD patients changed their lifestyle in the prescribed ways, the greater was the beneficial impact on their cognition and function. These correlations also add to the biological plausibility of these findings. This variation in adherence helps to explain in part why some patients in the intervention group improved and others did not, but there are likely other mechanisms that we do not fully understand that may play a role. These statistically significant correlations are especially meaningful given the greater variability of self-reported data, the relatively small sample size, and the short duration of the intervention.

These findings are consistent with earlier clinical trials in which we used this same lifestyle intervention and the same measure of lifestyle index and found significant dose-response correlations between this lifestyle index (i.e., the degree of lifestyle changes) and changes in the degree of coronary atherosclerosis (percent diameter stenosis) in coronary heart disease; [ 41 , 45 ] changes in PSA levels and LNCaP cell growth in men with prostate cancer; [ 42 ] and changes in telomere length [ 43 ].

We also found significant differences between the intervention and control groups in several taxa (groups of micro-organisms) in the microbiome which may be beneficial.

There were no significant differences in depression scores as measured by PHQ-9 between the intervention and control groups. Therefore, reduction in depression is unlikely to account for the overall improvements in cognition and function seen in the intervention group patients.

We also found that substantial lifestyle changes were required to stop the progression of MCI in these patients. In the primary analysis, this ranged from 71.4% adherence for ADAS-Cog to 95.6% adherence for CDR-Global to 120.6% adherence for CDR-SB. In other words, extensive lifestyle changes were required to stop or improve cognition and function in these patients. This helps to explain why other studies of less-intensive lifestyle interventions may not have been sufficient to stop deterioration or improve cognition and function.

For example, comparing these results to those of the MIND-AD clinical trial provides more biological plausibility for both studies [ 44 ]. That is, more moderate multimodal lifestyle changes may slow the rate of worsening of cognition and function in MCI or early dementia due to early-stage AD, whereas more intensive multimodal lifestyle changes may result in overall average improvements in many measures of cognition and function when compared to a randomized usual-care control group in both clinical trials.

Lifestyle changes may provide additional benefits to patients on drug therapy. Anti-amyloid antibodies have shown modest effects on slowing progression, but they are expensive, have potential for adverse events, are not yet widely available, and do not result in overall cognitive improvement [ 40 ]. Perhaps there may be synergy from doing both.

Limitations

This study has several limitations. Only 51 patients were enrolled and randomized in our study, and two of these patients (both in the intervention group) withdrew during the trial. Showing statistically significant differences across different tests of cognition and function and other measures despite the relatively small sample size suggests that the lifestyle intervention may be especially effective and has strong internal validity.

However, the smaller sample size limits generalizability, especially since there was much less racial and ethnic diversity in this sample than we strived to achieve. Also, we measured these differences despite the relative insensitivity of these measures, which might have increased the likelihood of a type II error.

Raters were blinded to the group assignment of the participants. However, unlike a double-blind placebo-controlled drug trial, it is not possible to blind subjects in a lifestyle intervention about whether or not they are receiving the intervention. This might have affected outcome measures, although to reduce positive expectations and because it was true, patients were told during the study that we did not know whether or not this lifestyle intervention would be beneficial, and we said that whatever we showed would be useful.

Also, 20 weeks is a relatively short time for any intervention with MCI or early dementia due to AD. We did not include direct measures of brain structure in this trial, so we cannot determine whether there were direct impacts on markers of brain pathology relevant to AD. However, surrogate markers such as the plasma Aβ42/40 ratio are becoming more widely accepted.

Not all patients in the intervention group improved. Of the 24 patients in the intervention group, 10 showed improvement as measured by the CGIC test, 7 were unchanged, and 7 worsened. In the control group, none improved, 8 were unchanged, and 17 worsened. In part, this may be explained by variations in adherence to the lifestyle intervention, as there was a significant relationship between the degree of lifestyle change and the degree of change in cognition and function across both groups. We hope that further research may further clarify other factors and mechanisms to help explain why cognition and function improved in some patients but not in others.

The findings on the degree of lifestyle change required to stop the worsening or improve cognition and function need to be interpreted with caution. Since data from both groups were combined, it was no longer a randomized trial for this specific analysis, so there could be unknown confounding influences. Also, it is possible that those with improved changes in cognition were better able to adhere to the intervention and thus have higher lifestyle indices.

In summary, in persons with mild cognitive impairment or early dementia due to Alzheimer’s disease, comprehensive lifestyle changes may improve cognition and function in several standard measures after 20 weeks. In contrast, patients in the randomized control group showed overall worsening in all four measures of cognition and function during this time.

The validity of these findings was supported by the observed changes in plasma biomarkers and microbiome; the dose-response correlation of the degree of lifestyle change with the degree of improvement in all four measures of cognition and function; and the correlation between the degree of lifestyle change and the degree of changes in the Aβ42/40 ratio and the changes in some other relevant biomarkers in a beneficial direction.

Our findings also have implications for helping to prevent AD. Newer technologies, some aided by artificial intelligence, enable the probable diagnosis of AD years before it becomes clinically apparent. However, many people do not want to know if they are likely to get AD if they do not believe they can do anything about it. If intensive lifestyle changes may cause improvement in cognition and function in MCI or early dementia due to AD, then it is reasonable to think that these lifestyle changes may also help to prevent MCI or early dementia due to AD. Also, it may take less-extensive lifestyle changes to help prevent AD than to treat it. Other studies cited earlier on the effects of these lifestyle changes on diseases such as coronary heart disease support this conclusion. Clearly, intensive lifestyle changes rather than moderate ones seem to be required to improve cognition and function in those suffering from early-stage AD.

These findings support longer follow-up and larger clinical trials to determine the longer-term outcomes of this intensive lifestyle medicine intervention in larger groups of more diverse AD populations; why some patients beneficially respond to a lifestyle intervention better than others besides differences in adherence; as well as the potential synergy of these lifestyle changes and some drug therapies.

Availability of data and materials

The datasets used and/or analyzed during the current study may be available from the corresponding author on reasonable request. Requesters will be asked to submit a study protocol, including the research question, planned analysis, and data required. The authors will evaluate this plan (i.e., relevance of the research question, suitability of the data, quality of the proposed analysis, planned or ongoing analysis, and other matters) on a case-by-case basis.

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Acknowledgements

We are grateful to each of the following people who made this study possible. Paramount among these are all of the study participants and their spouse or support person. Their commitment was inspiring, and without them this study would not have been possible. Each of the staff who provided and supported this program is exceptionally caring and competent, and includes: Heather Amador, who coordinated and administered all grants and infrastructure; Tandis Alizadeh, who is chief of staff; as well as Lynn Sievers, Nikki Liversedge, Pamela Kimmel, Stacie Dooreck, Antonella Dewell, Stacey Dunn-Emke, Marie Goodell, Emily Dougherty, Kamala Berrio, Kristin Gottesman, Katie Mayers, Dennis Malone, Sarah & Mary Barber, Steven Singleton, Kevin Lane, Laurie Case, Amber O’Neill, Annie DiRocco, Alison Eastwood, Sara Henley, Sousha Naghshineh, Sarah Reinhard, Laura Kandell, Alison Haag, Sinead Lafferty, Haley Perkins, Chase Delaney, Danielle Marquez, Ava Hoffman, Sienna Lopez, and Sophia Gnuse. Dr. Caitlin Moore conducted much of the cognition and function testing along with Dr. Catherine Madison, Trevor Ragas, Andrea Espinosa, Lorraine Martinez, Davor Zink, Jeff Webb, Griffin Duffy, Lauren Sather, and others. Dr. Cecily Jenkins trained the ADAS-Cog rater. Dr. Jan Krumsiek and Dr. Richa Batra performed important analyses in Dr. Rima Kaddurah-Daouk’s lab. Dr. Pia Kivisåkk oversaw biomarker assays in Dr. Steven Arnold's lab. We are grateful to all of the referring neurologists. Board members of the nonprofit Preventive Medicine Research Institute provided invaluable oversight and support, including Henry Groppe, Jenard & Gail Gross, Ken Hubbard, Brock Leach, and Lee Stein, as well as Joel Goldman.

Author’s information

DO is the corresponding author. RT contributed as the senior author.

We are very grateful to Leonard A. Lauder & Judith Glickman Lauder; Gary & Laura Lauder; Howard Fillit and Mark Roithmayr of The Alzheimer’s Drug Discovery Foundation; Mary & Patrick Scanlan of the Mary Bucksbaum Scanlan Family Foundation; Laurene Powell Jobs/Silicon Valley Community Foundation; Pierre & Pamela Omidyar Fund/Silicon Valley Community Foundation (Pat Christen and Jeff Alvord); George Vradenburg Foundation/Us Against Alzheimer’s; American Endowment Foundation (Anna & James McKelvey); Arthur M. Blank Family Foundation/Around the Table Foundation (Elizabeth Brown, Natalie Gilbert, Christian Amica); John Paul & Eloise DeJoria Peace Love & Happiness Foundation (Constance Dykhuizen); Maria Shriver/Women’s Alzheimer’s Movement (Sandy Gleysteen, Laurel Ann Gonsecki, Erin Stein); Mark Pincus Family Fund/Silicon Valley Community Foundation; Christy Walton/Walton Family Foundation; Milken Family Foundation; The Cleveland Clinic Lou Ruvo Center for Brain Health (Larry Ruvo); Jim Greenbaum Foundation; R. Martin Chavez; Wonderful Company Foundation (Stewart & Lynda Resnick); Daniel Socolow; Anthony J. Robbins/Tony Robbins Foundation; John Mackey; John & Lisa Pritzker and the Lisa Stone Pritzker Family Foundation; Ken Hubbard; Greater Houston Community Foundation (Jenard & Gail Gross); Henry Groppe; Brock & Julie Leach Family Charitable Foundation; Bucksbaum/Baum Foundation (Glenn Bucksbaum & April Minnich); YPO Gold Los Angeles; Lisa Holland/Betty Robertson; the Each Foundation (Lionel Shaw); Moby Charitable Fund; California Relief Program; Gary & Lisa Schildhorn; McNabb Foundation (Ricky Rafner); Renaissance Charitable Foumdation (Stephen & Karen Slinkard); Network for Good; Ken & Kim Raisler Foundation; Miner Foundation; Craiglist Charitable Fund (Jim Buckmaster and Annika Joy Quist); Gaurav Kapadia; Healing Works Foundation/Wayne Jonas; and the Center for Innovative Medicine (CIMED) at the Karolinska Institutet, Hjärnfonden, Stockholms Sjukhem, Research Council for Health Working Life and Welfare (FORTE). In-kind donations were received from Alan & Rob Gore of Body Craft Recreation Supply (exercise equipment), Dr. Andrew Abraham of Orgain, Paul Stamets of Fungi Perfecta ( Host Defense Lion’s Mane), Nordic Naturals, and Flora. Dr. Rima Kaddurah-Daouk at Duke is PI of the Alzheimer Gut Microbiome Project (funded by NIA U19AG063744). She also received additional funding from NIA that has enabled her research (U01AG061359 & R01AG081322).

The funders had no role in the conceptualization; study design; data collection; analysis; and interpretation; writing of the report; or the decision to submit for publication.

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Authors and affiliations.

Preventive Medicine Research Institute, 900 Bridgeway, Sausalito, CA, USA

Dean Ornish, Catherine Madison, Anne Ornish, Nancy DeLamarter, Noel Wingers & Carra Richling

University of California, San Francisco and University of California, San Diego, USA

Dean Ornish

Ray Dolby Brain Health Center, California Pacific Medical Center, San Francisco, CA, USA

Catherine Madison

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska vägen 37 A, SE-171 64, Solna, Sweden

Miia Kivipelto

Theme Inflammation and Aging, Karolinska University Hospital, Karolinska vägen 37 A, SE-171 64, Stockholm, Solna, Sweden

The Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, St Mary’s Hospital, Norfolk Place, London, W2 1PG, United Kingdom

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Yliopistonranta 8, 70210, Kuopio, Finland

Clinical Services, Preventive Medicine Research Institute, Bridgeway, Sausalito, CA, 900, USA

Colleen Kemp & Sarah Tranter

Division of Biostatistics, Department of Epidemiology & Biostatistics, UCSF, San Francisco, CA, USA

Charles E. McCulloch

Neurosciences, University of California, San Diego, CA, USA

Douglas Galasko

Clinical Neurology, School of Medicine, University of Nevada, Reno, USA

Renown Health Institute of Neurosciences, Reno, NV, USA

Harvard Medical School, Boston, MA, USA

Dorene Rentz, Rudolph E. Tanzi & Steven E. Arnold

Center for Alzheimer Research and Treatment, Boston, MA, USA

Dorene Rentz

Mass General Brigham Alzheimer Disease Research Center, Boston, MA, USA

Elizabeth Blackburn Lab, UCSF, San Francisco, CA, USA

UCSF, San Francisco, CA, USA

Departments of Medicine and Psychiatry, Duke University Medical Center and Member, Duke Institute of Brain Sciences, Durham, NC, USA

Rima Kaddurah-Daouk

Department of Pediatrics; Department of Computer Science & Engineering; Department of Bioengineering; Center for Microbiome Innovation, Halıcıoğlu Data Science Institute, University of California, San Diego, La Jolla, CA, USA

Department of Pediatrics and Scientific Director, American Gut Project and The Microsetta Initiative, University of California San Diego, La Jolla, CA, USA

Daniel McDonald

Bioinformatics and Systems Biology Program; Rob Knight Lab; Medical Scientist Training Program, University of California, San Diego, La Jolla, CA, USA

Lucas Patel

Buck Institute for Research on Aging, San Francisco, CA, USA

Eric Verdin

University of California, San Francisco, CA, USA

Genetics and Aging Research Unit, Boston, MA, USA

Rudolph E. Tanzi

McCance Center for Brain Health, Boston, MA, USA

Massachusetts General Hospital, Boston, MA, USA

Interdisciplinary Brain Center, Massachusetts General Hospital, Boston, MA, USA

Steven E. Arnold

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Contributions

DO, CM, MK, CK, DG, JA, DR, CEM, JL, KN, AO, ST, ND, NW, CR, RKD, RK, EV, RT, and SEA were involved in the study design and conduct. DO conceptualized the study hypotheses (building on the work of MK), obtained funding, prepared the first draft of the manuscript, and is the principal investigator. CEM oversaw the statistical analyses and interpretation, and DR oversaw the cognition and function testing and interpretation. CK and ST oversaw all clinical operations and patient recruitment, including the IRB. JL conducted the telomere analyses. CM oversaw patient selection. AO developed the learning management system and community platform for patients and providers. KN managed an IRB. ND co-led most of the support groups, and CR oversaw all aspects involving nutrition. All authors participated in writing the manuscript. NW and ST oversaw data collection and prepared the databases other than the microbiome databases which were overseen by RK and prepared by DM and LP who helped design this part of the study. CM, CK, JL, RKD, RK, DM, and LP were involved in the acquisition of data. SA, RT, and RKD did biomarker analyses. All authors contributed to critical review of the manuscript and approved the final manuscript.

Corresponding author

Correspondence to Dean Ornish .

Ethics declarations

Competing interests.

MK is one of the Editors-in-Chief of this journal and has no relevant competing interests and recused herself from the review process. RKD is an inventor on key patents in the field of metabolomics and holds equity in Metabolon, a biotech company in North Carolina. In addition, she holds patents licensed to Chymia LLC and PsyProtix with royalties and ownership. DO and AO have consulted for Sharecare and have received book royalties and lecture honoraria and, with CK, have received equity in Ornish Lifestyle Medicine. RK is a scientific advisory board member and consultant for BiomeSense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant and scientific advisory board member for DayTwo, and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a cofounder of Micronoma, and has equity and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. DM is a consultant for BiomeSense. RT is a co-founder and equity holder in Hyperion Rx, which produces the flashing-light glasses at a theta frequency of 7.83 Hz used as an optional aid to meditation. The rest of the authors declare that they have no competing interests.

Ethics approval and consent to participate

This clinical trial was approved by the Western Institutional Review Board on 12/31/2017 (approval number: 20172897) and all participants and their study partners provided written informed consent. The trial protocol was also approved by the appropriate Institutional Review Board of all participating sites; and all subjects provided informed consent.

Consent for publication

Informed consent was received from all patients. All data from research participants described in this paper is de-identified.

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Ornish, D., Madison, C., Kivipelto, M. et al. Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease: a randomized, controlled clinical trial. Alz Res Therapy 16 , 122 (2024). https://doi.org/10.1186/s13195-024-01482-z

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Health Benefits Of Lion’s Mane

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Table of Contents

What is lion’s mane mushroom, lion’s mane health benefits, may benefit brain health, does lion’s mane have side effects, how to use lion’s mane, what to look for when purchasing lion’s mane.

If you’ve ever noticed pom-pom-shaped growths on the trunks of broadleaf trees like beech or oak, it might have been a lion’s mane mushroom (hericium erinaceus). Lion’s mane mushroom grows in forests across North America, Asia and Europe.

Lion’s mane is an herb that has been used for centuries for its many medicinal purposes, says Trista Best, a registered dietician, environmental health specialist and consultant with Balance One Supplements.

Continue reading to learn more about lion’s mane mushroom, including its history of traditional use in Chinese medicine, as well as potential health benefits that encompass supporting cognition and mood and reducing anxiety and inflammation.

• Contains 1000mg of Organic Lion's Mane in every serving
• Formulated with organic reishi, lion’s mane, and Cordyceps sinensis
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Lion’s mane is a mushroom with a history of both medicinal and culinary uses in Asia and Europe. Medicinal mushroom use dates back to 450 BCE when Greek physician Hippocrates discovered the potential anti-inflammatory properties of fungi as well as its role in wound cauterization, according to a 2017 study in the Journal of Restorative Medicine [1] Spelman K, Sutherland E, Bagade A. Neurological Activity of Lion’s Mane (Hericium erinaceus) . Journal of Restorative Medicine. 2017;6(1)19-26. .

Lion’s mane grows on old or dead broadleaf tree trunks. Broadleaf trees shed their leaves seasonally and spread their seeds using a vessel, such as fruit.

Lion’s mane is composed of two parts: the visible fruiting body (the mushroom) and the mycelium, which is the bottom structure that resembles roots. Both the fruiting body and the root-like mycelium contain compounds that offer potential health benefits.

The potential benefits of lion’s mane mushroom are numerous and span physical, cognitive and mental health [2] Ghosh S, Nandi S, et alBanerjee A, Sarkar S, Chakraborty N. Prospecting Medicinal Properties of Lion’s Mane Mushroom . Journal of Food Biochemistry. 2021;45(8). . The mushroom is a source of natural bioactive compounds, which are health-promoting chemicals found in certain foods and plants. As a result, it exhibits disease-fighting properties, including anti-cancer, anti-microbial and antioxidant activity.

Research also suggests that lion’s mane may protect nerves from disease or decline, according to a 2015 abstract in the Journal of Agricultural and Food Chemistry . The same study concludes the mushroom displays additional health-promoting benefits, such as:

• Regulates blood sugar
• Reduces high blood pressure
• Promotes healthy energy levels and combats fatigue
• Helps to prevent excess blood lipid accumulation
• Protects heart health
• Slows biological aging
• Protects liver health
• Protects kidney health

Potential Alternative Treatment for Depression

Lion’s mane mushroom may be a potential alternative treatment for depression, according to a 2020 abstract in the Journal of Molecular Science . The abstract highlights three ways in which lion’s mane may ease depression symptoms:

• Helping ensure the presence of sufficient neurotransmitters
• Reducing the loss of nerve growth brought about by stressful situations
• Minimizing inflammation linked to depression [3] Chong PS, Fung ML, Wong KH, Lim LW. Therapeutic Potential of Hericium erinaceus for Depressive Disorder . International Journal of Molecular Sciences. 2020;21(1):163. .

Furthermore, research shows that people living with major depressive disorder may have lower nerve growth factor than non-depressed people, according to a 2015 meta-analysis in Neuropsychiatric Disease and Treatment [4] Chen YW, Lin PY, et al. Significantly Lower Nerve Growth Factor Levels in Patients with Major Depressive Disorder than in Healthy Subjects: A Meta-Analysis and Systematic Review . Neuropsychiatric Disease and Treatment. 2015;11:925-933. .  Nerve growth factor helps nerve cells specialize, grow and remain healthy, which are important aspects of mood regulation.

A number of studies demonstrate that lion’s mane increases nerve growth factor, according to Lexi Watson, a doctor of pharmacology, functional medicine practitioner and founder of Oakley Wellness, a practice that specializes in brain health and optimal aging.

Lion’s mane’s effect on nerve growth factor levels may enable it to help protect against disorders like Alzheimer’s disease that feature cognitive impairment.

Lion’s mane is a type of nootropic, meaning it contains compounds that improve brain health and function, according to Best.

“Some research has shown a benefit on certain measures of memory and cognitive function,” says Tod Cooperman, M.D., a dietary supplement researcher and president and founder of ConsumerLab.com, a health and nutrition product testing company. “But results have been inconsistent, and most improvements have been modest at best,” he adds.

For example, lion’s mane may be effective at improving symptoms of mild cognitive impairment, according to a placebo-controlled trial in Phytotherapy Research. In the trial, adults ages 50 to 80 took four 250-milligram powdered lion’s mane tablets three times daily for 16 weeks. Cognitive function scale testing showed that participants taking lion’s mane scored higher than the placebo group, and their cognitive ability improved with the duration of supplementation. Four weeks after discontinuing lion’s mane, their cognitive test scores decreased [5] Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial . Phytotherapy Research. 2009;23(3):367-72. .

• Science-backed formulas, clinically effective dosages
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Promotes Brain Injury Recovery

A 2021 study in Antioxidants offers some promising research of lion’s mane for people who’ve experienced traumatic brain injury (TBI). The study found that both lion’s mane mushroom and coriolus versicolor (another type of mushroom also known as turkey tail) exhibit neuroprotective effects against the inflammation and oxidative stress often associated with TBI [6] D’Amico R, Salinaro AT, et al. Hericium erinaceus and Coriolus versicolor Modulate Molecular and Biochemical Changes after Traumatic Brain Injury . Antioxidants. 2021;10(6):898. .

The neurodegeneration, or progressive breakdown of nerve cells, caused by TBI can lead to further conditions like Parkinson’s disease . Treatment with lion’s mane may reduce the impact of brain trauma and TBI complications like Parkinson’s disease.

Reduces Anxiety and Stress

Lion’s mane may help ease stress, according to Best, and a 2010 study in Biomedical Research provides some evidence to support this theory. The study examines the effects of lion’s mane on brain function and concludes that participants who ate cookies containing 0.5 grams of powdered lion’s mane (specifically the mushroom or fruiting body) for four weeks reported less anxiety than those who ate placebo cookies. The study authors theorize that the nerve growth effect of lion’s mane mushroom contributes to its anti-anxiety action.

Supports Gastrointestinal Health

Lion’s mane mushroom exhibits ulcer-inhibiting action, which research suggests may stem from its  effect on the helicobacter pylori (H. pylori) bacteria. H. pylori can cause stomach issues including ulcers, according to a study in the Journal of Ethnopharmacology [7] Wang M, Konishi T, Gao Y, Xu D, Gao Q. Anti-Gastric Ulcer Activity of Polysaccharide Fraction Isolated from Mycelium Culture of Lion’s Mane Medicinal Mushroom, Hericium erinaceus (Higher Basidiomycetes) . International Journal of Medicinal Mushrooms. 2015;17(11):1055-60Wang M, Konishi T, Gao Y, Xu D, Gao Q. .

If you have a medical condition or a history of asthma or allergies, consult your doctor before you try lion’s mane.

“Lion’s mane is generally well tolerated, but the most common side effects include gastrointestinal discomfort, nausea and a skin rash,” says Dr. Watson.

If you experience side effects, discontinue lion’s mane consumption until you’ve spoken with a health care provider. Hives, swelling, diarrhea and abdominal pain were symptoms of a potentially serious allergic reaction to lion’s mane mushroom, according to a 2022 case study in Annals of Allergy, Asthma & Immunology .

Lion’s mane mushroom can be taken as a supplement form, such as in capsules or a powder, or used fresh as a culinary ingredient. When used for culinary purposes, lion’s mane mushroom has a mild flavor that allows it to blend with a variety of meals and may be used as a plant-based meat substitute or a supplemental powder stirred into coffee or tea.

Lion’s mane powder is also used in savory dishes like stew, or sweet beverages like hot chocolate. It can also be made into a tea by adding hot water to mushroom pieces or powder.

Lion’s Mane Dosage

As with any supplement, it’s important to take lion’s mane as directed by the manufacturer’s instructions and not to exceed the recommended dose unless directed to do so by a health care provider.

“Most studies have provided [participants with] about 1 gram of dried mushroom (although some have used mycelium [root-like structure] or a combination of the two [mycelium and fruiting body]) given three times daily,” says Dr. Cooperman

Dr. Watson takes a more conservative approach, recommending 250 to 500 milligrams up to three times a day with or without food. The brand she recommends, Om Organic Mushroom Nutrition, contains both mycelial biomass and the fruit body.

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When purchasing lion’s mane, Dr. Cooperman recommends reading labels carefully. “Be aware that most research has focused on the portion of lion’s mane that grows above ground (the mushroom) as opposed to the part underground (the mycelium),” he says. “In our tests, we found that two out of eight lion’s mane products claim to be [made from the] mushroom but are actually mycelium, as confirmed in our testing. So a consumer needs to be sure they are getting a product that contains what they are expecting.”

Unlock The Benefits of Medicinal Mushrooms

The mushrooms in Transparent Labs's Mushroom Stack are packed with bioactive constituents that promote overall health and longevity through diverse mechanisms across multiple body systems, especially the immune, gastrointestinal, and nervous systems.

• Spelman K, Sutherland E, Bagade A. Neurological Activity of Lion’s Mane (Hericium erinaceus). Journal of Restorative Medicine. 2017;6(1)19-26.
• Ghosh S, Nandi S, et alBanerjee A, Sarkar S, Chakraborty N. Prospecting Medicinal Properties of Lion’s Mane Mushroom. Journal of Food Biochemistry. 2021;45(8).
• Chong PS, Fung ML, Wong KH, Lim LW. Therapeutic Potential of Hericium erinaceus for Depressive Disorder. International Journal of Molecular Sciences. 2020;21(1):163.
• Chen YW, Lin PY, et al. Significantly Lower Nerve Growth Factor Levels in Patients with Major Depressive Disorder than in Healthy Subjects: A Meta-Analysis and Systematic Review. Neuropsychiatric Disease and Treatment. 2015;11:925-933.
• Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial. Phytotherapy Research. 2009;23(3):367-72.
• D’Amico R, Salinaro AT, et al. Hericium erinaceus and Coriolus versicolor Modulate Molecular and Biochemical Changes after Traumatic Brain Injury. Antioxidants. 2021;10(6):898.
• Wang M, Konishi T, Gao Y, Xu D, Gao Q. Anti-Gastric Ulcer Activity of Polysaccharide Fraction Isolated from Mycelium Culture of Lion’s Mane Medicinal Mushroom, Hericium erinaceus (Higher Basidiomycetes). International Journal of Medicinal Mushrooms. 2015;17(11):1055-60Wang M, Konishi T, Gao Y, Xu D, Gao Q.
• Boddy L, Crockatt ME, Ainsworth AM. Ecology of Hericium cirrhatum, H. coralloides and H. erinaceus in the UK. Fungal Ecology. 2011;4(2): 163-173.
• Kunca V, Ciliak M. Habitat preferences of Hericium erinaceus in Slovakia. Fungal Ecology. 2017;27(B): 189-192.
• Friedman M. 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. 2015;63,32,7108-7123.
• Choi WS, Kim YS, Park BS, Kim JE, Lee SE. Hypolipidaemic Effect of Hericium erinaceum Grown in Artemisia capillaris on Obese Rats. Mycobiology. 2013;41(2): 94–99.
• Mori K, Kikuchi H, Obara Y, Iwashita M, Azumi Y, Kinugasa S, Inatomi S, Oshima Y, Nakahata N. Inhibitory Effect of Hericenone B from Hericium erinaceus on Collagen-Induced Platelet Aggregation. Phytomedicine. 2010;17(14):1082-5.
• Lion’s Mane Supplement: What’s the Best Way to Take Lion’s Mane?. Erbology. Accessed 11/1/2022.
• Lion’s Mane Mushroom. Drugs.com. Accessed 11/1/2022.
• Bioactive Compound. Cancer.gov. Accessed 11/20/2022.
• Identify a Broadleaf Tree. Natural Resources Canada. Accessed 11/20/2022.
• Nagano N, Shimizu K, Kondo R, Hayashi C, Sato D, Kitagawa K, Ohnuki K. Reduction of Depression and Anxiety by 4 Weeks Hericium erinaceus Intake. Biomedical Research. 2010;31(4):231-237.
• Rogers RD. Neurodegeneration and Medicinal Mushrooms. Fungi. 2017;10(3):36-40.
• Watson C, Kobernick A. Dangers at the Dinner Table - A Report of Anaphylaxis to Lion’s Mane Mushroom. Annals of Allergy, Asthma & Immunology. 2022;129(5):S147.
• Nkodo A. A Systematic Review of in-vivo Studies on Dietary Mushroom Supplementation of Cognitive Impairment. Current Developments in Nutrition. 2019;3(1):14-021-19.
• Liu JH, Li L, Shang XD, Zhang JL, Tan Q. Anti-Helicobacter Pylori Activity of Bioactive Components Isolated from Hericium Erinaceus. Journal of Ethnopharmacology. 2016;183:54-58.
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The Health Benefits of Lion's Mane

Benefits, Side Effects, Dosage, and Interactions

NomadicImagery / Getty Images

• Potential Benefits
• Side Effects
• How to Take Lion's Mane
• Precautions and Interactions
• What to Look For
• Where to Find Lion's Mane
• Consult your doctor before consuming lion's mane or any other supplement.
• Call 911 immediately if you have problems breathing, throat inflammation, or other allergy symptoms.
• Use caution if you are taking diabetes or anticoagulant/antiplatelet medications.

Lion's mane ( Hericium erinaceus ) is a type of medicinal mushroom long used in traditional Chinese medicine that's widely available fresh, dried, and as a supplement. This article discusses the potential health benefits of lion's mane.

Potential Health Benefits of Lion's Mane

So far, scientific exploration of lion's mane and its effects is limited primarily to animal-based research, test-tube studies, and small clinical trials. More research is needed to understand its potential positive and negative effects and mechanisms of action in the body. Some research, however, points to possible benefits.

Brain Function

Lion's mane has shown promise in the realm of cognitive function. For example, it had positive effects in the brains of mice in a 2023 study, enhancing memory and brain cell growth. Likewise, a small study of the mushroom's impact on cognitive function and moods in young adults hinted at faster processing times and decreased stress levels. Many other studies support the idea that lion's mane might augment the brain's performance.

Likewise, lion's mane may benefit older adults with mild cognitive impairment, according to a small 2009 study. Researchers assigned 30 older adults with mild cognitive impairment to take lion's mane extract or a placebo every day for 16 weeks. In cognitive tests at weeks eight, 12, and 16 of the study, members of the lion's mane group showed significantly greater improvements in function than members of the placebo group.

In a 2011 study, scientists examined the effects of lion's mane on brain function in mice. Results revealed that lion's mane helped protect against memory problems caused by the buildup of amyloid beta (a substance that forms the brain plaques associated with Alzheimer's disease ). Studies have also shown a possible neuroprotective effect against ischemic stroke.

Depression and Anxiety

Research to date suggests that lion's mane may help alleviate depression and anxiety. For example, a 2020 review of the literature called lion's mane "a potential alternative medicine for the treatment of depression."

Likewise, a 2021 research review detailed several studies that showed significant anti-anxiety effects. Lion's mane appears to offer "neuroprotective functions, cytotoxicity, anticarcinogenic, antidiabetic, antimicrobial, and herbicidal activities," as well.

Due to a lack of supporting research, it's too soon to recommend lion's mane for any specific health condition. If you're considering the use of lion's mane for a chronic condition, make sure to consult your physician before starting your supplement regimen. Self-treating a chronic condition with lion's mane and avoiding or delaying standard care may have serious consequences.

Possible Side Effects of Lion's Mane

Little is known about the safety of long-term use and side effects of lion's mane supplements. However, there's some concern that lion's mane may aggravate symptoms in people with allergies and asthma. Therefore, it's important to consult your physician prior to using lion's mane or any other supplement, especially if you have a history of allergies, asthma, and/or any other medical condition.

Studies on the potential benefits of lion's mane in humans have shown promise, but more research is necessary. Always consult your healthcare provider before ingesting lion's mane or any other supplement.

How to Take Lion's Mane

Lion's mane hasn't been studied enough to establish standard dosages and preparation. General guidelines follow, but always heed your physician's specific advice regarding medicines and supplements.

Lion's mane is commonly consumed in many Asian countries for medicinal and culinary purposes, but there are no consistent formulations or dosage recommendations. Follow the instructions on your package of lion's mane closely.

Always consult your doctor for specific advice on how much you should take each day.

Lion's Mane Precautions and Interactions

Avoid using lion's mane mushroom products if you're pregnant. Not enough research has been done to determine if any dosage is safe during pregnancy.

If you take diabetes medications, be aware that Lion's mane mushroom can lower your blood glucose levels too much. Keep a close eye on your readings.

Likewise, taking lion's mane along with anticoagulant/antiplatelet drugs can cause blood clotting difficulties that can result in bleeding or bruising.

Some people are allergic to lion's mane. Seek medical help immediately if you notice throat swelling, breathing trouble, or other signs and symptoms after taking lion's mane.

What to Look For When Buying Lion's Mane

Some lion's mane supplements are marketed with unsupported claims, such as weight loss, brain health improvement, and heart disease prevention. Remember that these claims have not been proven definitively, Ask your healthcare provider about lion's mane before taking it for any reason.

For example, in 2019, the Food and Drug Administration (FDA) sent a warning letter to Pure Nootropics, LLC, for making unsubstantiated claims about some of their products, including their lion's mane powder. The company was marketing the supplement as "great for brain injury recovery" and to "reduce symptoms of anxiety and depression." Since then, the company has replaced this language with the claim that the product "supports overall cognitive health," with the disclaimer that the FDA has not evaluated it and it's not intended to prevent or treat any condition or disease.

Where to Find Lion's Mane

Lion's mane is widely available in big-box stores, groceries, drugstores, and online stores. Its many forms include fresh, dried, and powdered, in capsules, teas, and more. In nature, lion's mane mushrooms grow in logs, decaying wood, and tree wounds.

Martínez‐Mármol R, Chai Y, Conroy JN, et al. H ericerin derivatives activates a pan‐neurotrophic pathway in central hippocampal neurons converging to ERK1 /2 signaling enhancing spatial memory .  Journal of Neurochemistry . 2023;165(6):791-808. doi:10.1111/jnc.15767

Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: A double-blind placebo-controlled clinical trial . Phytother Res. 2009;23(3):367-72. doi:10.1002/ptr.2634

Mori K, Obara Y, Moriya T, Inatomi S, Nakahata N. Effects of Hericium erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in mice . Biomed Res. 2011;32(1):67-72.

I-Chen Li, et al. Neurohealth Properties of  Hericium erinaceus  Mycelia Enriched with Erinacines . Neurol . 2018; 2018. doi:10.1155/2018/5802634

Chong PS, Fung ML, Wong KH, Lim LW. Therapeutic potential of hericium erinaceus for depressive disorder .  IJMS . 2019;21(1):163. doi:10.3390/ijms21010163

Hericium erinaceus - A rich source of diverse bioactive metabolites .  FunBiotec . 2021;1(2):10-38. doi:10.5943/FunBiotec/1/2/2

Sabaratnam V, Kah-hui W, Naidu M, Rosie David P. Neuronal health - Can culinary and medicinal mushrooms help? . J Tradit Complement Med . 2013;3(1):62-8. doi:10.4103/2225-4110.106549

Lion's Mane Mushroom - Uses, Side Effects, and More . WebMD. Updated June 28, 2021.

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The lion’s mane has long been an iconic symbol, yet there has been no clear answer as to why lions have manes, or what function they serve. Charles Darwin was the first to suggest that the mane may be a result of sexual selection, meaning that the mane increases reproductive success. The mane may protect a male’s neck during a fight with another male, or it might signal physical condition, allowing males to assess each other’s fighting ability and females to choose superior mates.

If the mane primarily serves as a shield, the neck should be a special target of attacks or wounds to the neck should be particularly dangerous. However, wounds in adult males and in females and sub-adult males (whose neck areas are bare) were no more common on the neck than on other parts of the body nor were wounds to the neck more likely to be fatal.

So what information is conveyed by the length and coloration of the lion’s mane? And if longer, darker manes are more intimidating/attractive, why don’t all male lions have extravagant manes?

Our longterm records show that males with shorter manes had often been recently injured or sick, suggesting that mane length indicates current fighting ability. Males with darker manes had higher testosterone levels, were more likely to recover from injury, spent more time resident with prides, and had higher offspring survival. Thus, mane color appears to convey information about male aggressiveness and potential reproductive success.

Variation in a sexually selected trait generally results from the inherent costs of expressing such an elaborate physical characteristic. For example, the peacock’s tail makes the male more vulnerable to predation, and only the highest-quality males can evade predators while carrying such exaggerated tails. To determine the costs of growing a large mane, we used an infrared camera to measure the surface temperatures of male and female lions. Maned males, but not those with abbreviated manes, were hotter than females, suggesting that the mane imposes a general increase in heat sensitivity. Furthermore, males with darker manes were hotter than males with blond manes. Referring again to our longterm records, we determined that males with darker manes had higher proportions of defective sperm, and ate relatively small meals in hotter weather (increasing the ratio of foraging time to food consumption). These costs are most likely heat-related and they are burdens that only superior males can bear; for inferior males, a dark mane would inflict physiological costs that outweighed the reproductive benefits.

Thus the lion’s mane appears to be a sexually selected signal by which a male advertises his quality to other lions. Our study also highlights the importance of temperature to lion ecology and behavior—which will become increasingly relevant in the face of global climate change: the Serengeti lions are already developing lighter and shorter manes than in the past. These findings were presented by Science magazine in a paper entitled “Sexual Selection, Temperature and the Lion’s Mane” by Peyton West and Craig Packer.

FURTHER READING

• The lion’s mane
• Maneless in Tsavo
• Sexual selection, temperature, and the lions’ mane
• Sexual selection, temperature, and the lions’ mane: Supporting materials and methods
• Wounding, mortality and mane morphology in African lions

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The Science Behind 10 Lion's Mane Mushroom Benefits, From Heart to Gut Health

Are lion’s mane mushrooms healthy or overhyped? Let's dig into the research.

Haley is a Wisconsin-based creative freelancer and recent graduate. She has worked as an editor, fact checker, and copywriter for various digital and print publications. Her most recent position was in academic publishing as a publicity and marketing assistant for the University of Wisconsin Press

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Lion's mane mushroom benefits have been creating quite a buzz—and with a regal name like lion’s mane, how could they not? Whether or not you’ve heard of them, when it comes to adaptogenic, functional mushrooms , lion’s mane tops the list as one of the most popular and well-studied. 

But what exactly do “adaptogenic” and “functional” mean in the context of edible fungi? The benefits touted by lion's mane mushrooms are immune support, boosting brain, heart, and gut health, and more. But are the benefits completely woo-woo, or based in actual science? Here’s what to know about the benefits of lion’s mane mushrooms, both nutritional and beyond.

What exactly are lion’s mane mushrooms?

Also known as the hedgehog mushroom, or by its scientific name Hericium erinaceus , the lion’s mane mushroom has a rich history. As a centuries-old cornerstone of traditional Chinese medicine, it was used to improve overall health and longevity. Meanwhile, in Japan, Buddhist monks used the powder of this mushroom to enhance focus during meditation. Evidence dating back to as early as 450 B.C. to ancient Greece suggests lion’s mane was utilized for its anti-inflammatory and wound-healing properties.

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Maybe one of the most compelling benefits associated with lion's mane is that it’s considered to be a functional and adaptogenic food. Adaptogenic foods help the body to adapt to stress of any kind: physical, biological, or chemical.

Lion’s Mane Mushroom Benefits

With all of the names this mushroom has accumulated comes an even larger number of health benefits. Here are some of the top evidence-based health benefits of lion’s mane mushrooms that give it such a high reputation in the health and wellness world.

Lion's Mane Can Improve Immune Health

Speaking of immune health , hedgehog mushrooms are effective at keeping our immune systems strong and functioning optimally. This is due, in part, to their bioactive plant compounds and zinc , both of which are antioxidants that help reduce inflammation in the body and fight off disease-causing free radicals. When it comes to lion’s mane, its protein and carbohydrate content also amplifies its immune-boosting powers. One animal study found that one type of protein extracted from lion's mane was associated with modulation of the immune system through regulation of the gut microbiome in mice. While another found that certain carbs in this mushroom also stimulated our intestinal bacteria, helping to enhance the body’s cellular immune system pathways.

While more human studies are needed to confirm, emerging research also suggests that these nutritional components add up when it comes to fighting off some of the scariest of illnesses, like cancer. One in vitro and animal study, for example, found lion’s mane extract to be effective against liver, colon, and even gastric cancer cells. Further studies and reviews echo these findings when it comes to this fungus’ potential to stand up to cancer.

Lion’s Mane Helps Boost and Protect Brain Health

Where these mushrooms really shine, and what they’re most known for, is their ability to positively impact our brain health. This is primarily due to the neurotrophic factors and bioactive compounds found in this functional fungus. Neurotrophic factors are biomolecules made of protein that promote the growth and differentiation of neurons, the nerve cells in the brain that send and receive information. Lion's mane has also been associated with reduced brain inflammation, offering neuroprotective benefits. Some of these benefits include symptom improvement of sleep disorders, Alzheimer’s, and Parkinson’s disease. One animal study even found lion’s mane to assist in neurotransmission and recognition memory.

Lion’s Mane Supports Gut Health

As already mentioned above, this edible fungi is also a champion for gut health. Many of the functional mushrooms, including lion’s mane, are excellent sources of beta-glucan, a kind of soluble fiber that benefits our health in a number of ways beyond just gut health, including immune, heart, and metabolic health. It also has a prebiotic effect in the microbiome, serving as food for our healthy gut bacteria. Beyond its beta-glucan content, animal studies suggest lion’s mane may potentially be beneficial in treating inflammatory bowel disease and ulcerative colitis.

Lion’s Mane Promotes Heart Health

Lion’s mane mushrooms can even help support heart health . Similar to other soluble fibers, their beta-glucans also bind to cholesterol in the small intestine and move it through the rest of the digestive tract for disposal. This means that cholesterol literally goes down the drain instead of being absorbed into your blood. Beta-glucans are also associated with reduced blood pressure levels and together, cholesterol and blood pressure make up some of the key conditions needed for heart disease to arise. Various studies reiterate these impacts, with one in vitro showing lion’s mane’s ability to help reduce bad cholesterol (or low-density lipoprotein, LDL) levels. While another review found edible plants, including lion’s mane (though it’s technically a fungus), to help promote healthy blood clotting in humans, another contributor to heart disease if functioning improperly.

Lion’s Mane Provides Important Vitamins and Minerals

Additionally, these fungi offer quite a few vitamins and minerals including potassium, iron, and B vitamins. These nutrients combine to support healthy fluid balance, immune function, red blood cell formation, and energy metabolism.

Lion’s Mane May Help Regulate Blood Sugars

These fungi also impact metabolic health, including the ability to regulate blood sugars. While this makes sense given this mushroom’s fiber content, there’s budding research to back it up. In one animal study, lion’s mane was found to help reduce blood sugars to normal levels while also providing a protective effect on the pancreas, liver, and kidneys. Another found this mushroom to help relieve diabetic nerve pain in animal subjects.

That said, more research on human subjects is required to say definitively its ability to help people with (and without) diabetes manage their blood sugar levels and aid diabetes-related nerve pain.

Lion's Mane May Alleviate Anxiety and Depression

Early research indicates that several of the chemicals in lion's mane mushrooms boost the regeneration of brain cells and improve the performance of the hippocampus, the part of the brain that regulates emotional response.

Studies also show that individuals with depression and anxiety have lower nerve growth factor (NGF). NGF helps nerve cells regenerate and remain healthy, which are factors in mood regulation. Lion's mane mushrooms promote these factors, which indicates that it could be a potential alternative medication for depression in the future.

Lion's Mane Can Help Nervous System Recovery

Individuals who have had an injury to the brain, spinal cord, or nervous system may benefit from lion's mane mushrooms. Lion's mane has the ability to aid in the regeneration of peripheral nerves. Because of these properties, scientists are looking into using lion's mane to treat a number of illnesses and injuries, including traumatic brain injuries, stroke, multiple sclerosis, and Creutzfeldt-Jakob disease, among others.

Lion's Mane Guards Against Stomach Ulcers

As mentioned earlier, lion's mane can help with gut health and certain intestinal disorders. But it also fights against stomach ulcers through a couple of mechanisms of action. Ulcers are usually caused by one of two things: first, by overuse of NSAIDs like ibuprofen, which eat away at the mucus lining of the stomach; second, through the presence of a bacteria called H. pylori . Lion's mane has been shown to thicken the mucosal lining of the stomach, fighting against ulcers caused by NSAIDs and slowing the growth of H. pylori .

Lion's Mane Reduces Inflammation

According to the NIH, chronic inflammatory diseases are the leading cause of death worldwide. Chronic inflammation is associated with diabetes, cardiovascular disease, arthritis, allergies, COPD, autoimmune disorders, and more. Studies have shown that lion's mane mushrooms contain anti-inflammatory compounds that can lessen the impact of these conditions.

How to Take Lion’s Mane 

Acknowledging that several of the studies examined above were conducted in animals, there’s enough human evidence for researchers to conclude that lion’s mane is a bonafide superfood. But how can you include it in your cooking and daily routine?

Lion’s mane is one of the few functional mushrooms that you can find in its whole form relatively readily these days, especially in specialty food stores and from local producers. You can whip up any of your favorite mushroom recipes , adding it to pastas, soups, eggs, and rice dishes. However, many feature lion’s mane in vegan “seafood” recipes as it can offer a flavor and texture reminiscent of lobster, shrimp, or crab. These mushrooms can even be steeped in hot water to make a deliciously earthy tea loaded with health benefits.

Lion’s mane can also be powdered and added to stews, soups, and gravies, not only as a way to boost the recipe’s healthfulness, but to add umami flavor. However, it can just as easily be added to smoothies, coffees, teas, and oatmeal in smaller amounts without compromising the overall flavor. There are also a variety of mushroom coffee and tea alternative brands that feature this fungus including MUD/WTR , Rasa , Ryze , and Four Sigmatic .

Supplement Safety and Tips

Otherwise, there are a number of supplements available that feature lion’s mane, including pills, powders, and tinctures. When buying supplements, however, it’s extremely important to know that while the U.S. Food and Drug Administration (FDA) monitors supplements in the country, it does not test or regulate each one for safety or purity. This means that products that are not reliable or safe are as readily available on the market for purchase, ultimately placing that risk and responsibility on the consumer.

That means it's (unfortunately) our job as consumers to do our research before buying supplements to ensure their safety and purity. There are a few organizations conducting third-party verifications to help in that process including NSF and U.S. Pharmacopeia (USP). Look for their seal of approval on any products you're considering

Side Effects and Risks of Taking Lion's Mane

Scientists are still researching the side effects and possible risks of taking lion's mane supplements. No human trials have been conducted to determine the risks and significant side effects. However, no adverse effects were observed in animal trials, even at higher doses.

If you are allergic or sensitive to mushrooms, however, you should avoid taking lion's mane. Allergic reactions can present in rashes and difficulty breathing; as a general rule, you should always speak with your doctor before adding any supplements to your diet.

Frequently Asked Questions

Yes, you can; just watch your daily intake. The recommended dosage varies by individual based on weight, metabolism, and tolerance. Supplements range widely in dosage from 250 to 2,500 mg per day, so it's crucial to consult your physician before starting a regimen.

In short, it depends on who you ask. Some supplement companies state that you'll begin to see effects within two to five days. Others say it can take up to six months to see an impact. The effects will likely depend on your metabolism and the dose that you've chosen.

Adaptogenic mushroom use has become quite popular, and as a result, there are a good amount of options to choose from. The benefits vary from species to species, so pick one based on the effects you're hoping to see. In addition to lion's mane, reishi and cordyceps are also commonly used supplements. Some supplements mix different types of mushrooms in each formulation.

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• lion's mane mushroom

LION'S MANE MUSHROOM - Uses, Side Effects, and More

Side effects.

• Precautions
• Interactions
• Reviews (27)

Uses & Effectiveness ?

We currently have no information for LION'S MANE MUSHROOM overview .

Special Precautions and Warnings

Interactions , moderate interaction.

Be cautious with this combination

Medications for diabetes (Antidiabetes drugs) interacts with LION'S MANE MUSHROOM

Lion's mane mushroom might lower blood sugar levels. Taking lion's mane mushroom along with diabetes medications might cause blood sugar to drop too low. Monitor your blood sugar closely.

Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs) interacts with LION'S MANE MUSHROOM

Lion's mane mushroom might slow blood clotting. Taking lion's mane mushroom along with medications that also slow blood clotting might increase the risk of bruising and bleeding.

Medications that decrease the immune system (Immunosuppressants) interacts with LION'S MANE MUSHROOM

Lion's mane mushroom can increase the activity of the immune system. Some medications, such as those used after a transplant, decrease the activity of the immune system. Taking lion's mane mushroom along with these medications might decrease the effects of these medications.

Abdulla MA, Fard AA, Sabaratnam V, et al. Potential activity of aqueous extract of culinary-medicinal Lion's Mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) in accelerating wound healing in rats. Int J Med Mushrooms. 2011;13(1):33-9. View abstract.

Abdullah N, Ismail SM, Aminudin N, Shuib AS, Lau BF. Evaluation of Selected Culinary-Medicinal Mushrooms for Antioxidant and ACE Inhibitory Activities. Evid Based Complement Alternat Med. 2012;2012:464238. View abstract.

Chang HC, Yang HL, Pan JH, et al. Hericium erinaceus Inhibits TNF-a-Induced Angiogenesis and ROS Generation through Suppression of MMP-9/NF-?B Signaling and Activation of Nrf2-Mediated Antioxidant Genes in Human EA.hy926 Endothelial Cells. Oxid Med Cell Longev. 2016;2016:8257238. View abstract.

Cheng JH, Tsai CL, Lien YY, Lee MS, Sheu SC. High molecular weight of polysaccharides from Hericium erinaceus against amyloid beta-induced neurotoxicity. BMC Complement Altern Med. 2016;16(1):170. View abstract.

Cui F, Gao X, Zhang J, et al. Protective Effects of Extracellular and Intracellular Polysaccharides on Hepatotoxicity by Hericium erinaceus SG-02. Curr Microbiol. 2016 Jun 4. [Epub ahead of print] View abstract.

Grozier CD, Alves VA, Killen LG, Simpson JD, O'Neal EK, Waldman HS. Four weeks of Hericium erinaceus supplementation does not impact markers of metabolic flexibility or cognition. Int J Exerc Sci 2022;15(2):1366-1380. View abstract.

Han ZH, Ye JM, Wang GF. Evaluation of in vivo antioxidant activity of Hericium erinaceus polysaccharides. Int J Biol Macromol. 2013;52:66-71. View abstract.

Hao L, Xie Y, Wu G, et al. Protective Effect of Hericium erinaceus on Alcohol Induced Hepatotoxicity in Mice. Evid Based Complement Alternat Med. 2015;2015:418023. View abstract.

Hiwatashi K, Kosaka Y, Suzuki N, et al. Yamabushitake mushroom (Hericium erinaceus) improved lipid metabolism in mice fed a high-fat diet. Biosci Biotechnol Biochem. 2010;74(7):1447-51. View abstract.

Hou Y, Ding X, Hou W. Composition and antioxidant activity of water-soluble oligosaccharides from Hericium erinaceus. Mol Med Rep. 2015;11(5):3794-9. View abstract.

Kim SP, Kang MY, Choi YH, et al. Mechanism of Hericium erinaceus (Yamabushitake) mushroom-induced apoptosis of U937 human monocytic leukemia cells. Food Funct. 2011;2(6):348-56. View abstract.

Kim SP, Kang MY, Kim JH, Nam SH, Friedman M. Composition and mechanism of antitumor effects of Hericium erinaceus mushroom extracts in tumor-bearing mice. J Agric Food Chem. 2011;59(18):9861-9. View abstract.

Kim SP, Moon E, Nam SH, Friedman M. Hericium erinaceus mushroom extracts protect infected mice against Salmonella Typhimurium-Induced liver damage and mortality by stimulation of innate immune cells. J Agric Food Chem. 2012;60(22):5590-6. View abstract.

Kim SP, Nam SH, Friedman M. Hericium erinaceus (Lion's Mane) mushroom extracts inhibit metastasis of cancer cells to the lung in CT-26 colon cancer-tansplanted mice. J Agric Food Chem. 2013;61(20):4898-904. View abstract.

Lai PL, Naidu M, Sabaratnam V, et al. Neurotrophic properties of the Lion's mane medicinal mushroom, Hericium erinaceus (Higher Basidiomycetes) from Malaysia. Int J Med Mushrooms. 2013;15(6):539-54. View abstract.

Lee JS, Hong EK. Hericium erinaceus enhances doxorubicin-induced apoptosis in human hepatocellular carcinoma cells. Cancer Lett. 2010;297(2):144-54. View abstract.

Lee JS, Min KM, Cho JY, Hong EK. Study of macrophage activation and structural characteristics of purified polysaccharides from the fruiting body of Hericium erinaceus. J Microbiol Biotechnol. 2009;19(9):951-9. View abstract.

Lee KF, Chen JH, Teng CC, et al. Protective effects of Hericium erinaceus mycelium and its isolated erinacine A against ischemia-injury-induced neuronal cell death via the inhibition of iNOS/p38 MAPK and nitrotyrosine. Int J Mol Sci. 2014;15(9):15073-89. View abstract.

Lee SR, Jung K, Noh HJ, et al. A new cerebroside from the fruiting bodies of Hericium erinaceus and its applicability to cancer treatment. Bioorg Med Chem Lett. 2015;25(24):5712-5. View abstract.

Li G, Yu K, Li F, et al. Anticancer potential of Hericium erinaceus extracts against human gastrointestinal cancers. J Ethnopharmacol. 2014;153(2):521-30. View abstract.

Li IC, Chang HH, Lin CH, et al. Prevention of early Alzheimer's disease by erinacine A-enriched Hericium erinaceus mycelia pilot double-blind placebo-controlled study. Front Aging Neurosci 2020 Jun 3;12:155. doi: 10.3389/fnagi.2020.00155. View abstract.

Liang B, Guo Z, Xie F, Zhao A. Antihyperglycemic and antihyperlipidemic activities of aqueous extract of Hericium erinaceus in experimental diabetic rats. BMC Complement Altern Med. 2013;13:253. View abstract.

Liu J, DU C, Wang Y, Yu Z. Anti-fatigue activities of polysaccharides extracted from Hericium erinaceus. Exp Ther Med. 2015;9(2):483-487. View abstract.

Liu JH, Li L, Shang XD, Zhang JL, Tan Q. Anti-Helicobacter pylori activity of bioactive components isolated from Hericium erinaceus. J Ethnopharmacol. 2016;183:54-8. View abstract.

Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial. Phytother Res. 2009;23(3):367-72. View abstract.

Mori K, Kikuchi H, Obara Y, et al. Inhibitory effect of hericenone B from Hericium erinaceus on collagen-induced platelet aggregation. Phytomedicine. 2010;17(14):1082-5. View abstract.

Mori K, Obara Y, Hirota M, et al. Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells. Biol Pharm Bull. 2008 Sep;31(9):1727-32. View abstract.

Mori K, Obara Y, Moriya T, Inatomi S, Nakahata N. Effects of Hericium erinaceus on amyloid ß(25-35) peptide-induced learning and memory deficits in mice. Biomed Res. 2011;32(1):67-72. View abstract.

Nagano M, Shimizu K, Kondo R, et al. Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res 2010;31(4):231-7. View abstract.

Phan CW, Lee GS, Hong SL, et al. Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways. View abstract.

Product information for <em>Niaspan</em>. Abbott Laboratories. North Chicago, IL 60064. April 2015.

Rahman MA, Abdullah N, Aminudin N. Inhibitory effect on in vitro LDL oxidation and HMG Co-A reductase activity of the liquid-liquid partitioned fractions of Hericium erinaceus (Bull.) Persoon (lion's mane mushroom). Biomed Res Int. 2014;2014:828149. View abstract.

Rossi P, Cesaroni V, Brandalise F, et al. Dietary supplementation of lion's mane medicinal mushroom, Hericium erinaceus (Agaricomycetes), and spatial memory in wild-type mice. Int J Med Mushrooms. 2018;20(5):485-494. View abstract.

Ryu S, Kim HG, Kim JY, Kim SY, Cho KO. Hericium erinaceus extract reduces anxiety and depressive behaviors by promoting hippocampal neurogenesis in the adult mouse brain. J Med Food. 2018;21(2):174-180. View abstract.

Saitsu Y, Nishide A, Kikushima K, Shimizu K, Ohnuki K. Improvement of cognitive functions by oral intake of Hericium erinaceus. Biomed Res. 2019;40(4):125-131. View abstract.

Samberkar S, Gandhi S, Naidu M, et al. Lion's Mane, Hericium erinaceus and Tiger Milk, Lignosus rhinocerotis (Higher Basidiomycetes) Medicinal Mushrooms Stimulate Neurite Outgrowth in Dissociated Cells of Brain, Spinal Cord, and Retina: An In Vitro Study. Int J Med Mushrooms. 2015;17(11):1047-54. View abstract.

Tian B, Liu R, Xu T, et al. Modulating effects of Hericium erinaceus polysaccharides on the immune response by regulating gut microbiota in cyclophosphamide-treated mice. J Sci Food Agric 2023;103(6):3050-3064. View abstract.

Tsai-Teng T, Chin-Chu C, Li-Ya L, et al. Erinacine A-enriched Hericium erinaceus mycelium ameliorates Alzheimer's disease-related pathologies in APPswe/PS1dE9 transgenic mice. J Biomed Sci. 2016;23(1):49. View abstract.

Tzeng TT, Chen CC, Chen CC, et al. The cyanthin diterpenoid and sesterterpene constituents of Hericium erinaceus mycelium ameliorate Alzheimer's disease-related pathologies in APP/PS1 transgenic mice. Int J Mol Sci. 2018;19(2). pii: E598. View abstract.

Wang K, Bao L, Qi Q, et al. Erinacerins C-L, isoindolin-1-ones with a-glucosidase inhibitory activity from cultures of the medicinal mushroom Hericium erinaceus. J Nat Prod. 2015;78(1):146-54. View abstract.

Wang M, Gao Y, Xu D, Gao Q. A polysaccharide from cultured mycelium of Hericium erinaceus and its anti-chronic atrophic gastritis activity. Int J Biol Macromol. 2015;81:656-61. View abstract.

Wang XL, Xu KP, Long HP, et al. New isoindolinones from the fruiting bodies of Hericium erinaceum. Fitoterapia. 2016;111:58-65. View abstract .

Wong JY, Abdulla MA, Raman J, et al. Gastroprotective Effects of Lion's Mane Mushroom Hericium erinaceus (Bull.:Fr.) Pers. (Aphyllophoromycetideae) Extract against Ethanol-Induced Ulcer in Rats. Evid Based Complement Alternat Med. 2013;2013:492976. View abstract .

Wong KH, Kanagasabapathy G, Naidu M, David P, Sabaratnam V. Hericium erinaceus (Bull.: Fr.) Pers., a medicinal mushroom, activates peripheral nerve regeneration. Chin J Integr Med. 2014 Aug 26. View abstract.

Wong KH, Naidu M, David P, et al. Peripheral Nerve Regeneration Following Crush Injury to Rat Peroneal Nerve by Aqueous Extract of Medicinal Mushroom Hericium erinaceus (Bull.: Fr) Pers. (Aphyllophoromycetideae). Evid Based Complement Alternat Med. 2011;2011:580752. View abstract.

Xie XQ, Geng Y, Guan Q, et al. Influence of short-term consumption of Hericium erinaceus on serum biochemical markers and the changes of the gut microbiota: A pilot study. Nutrients. 2021;13(3):1008. View abstract.

Xu CP, Liu WW, Liu FX, et al. A double-blind study of effectiveness of hericium erinaceus pers therapy on chronic atrophic gastritis. A preliminary report. Chin Med J (Engl). 1985;98(6):455-6. View abstract.

Yang BK, Park JB, Song CH. Hypolipidemic effect of an Exo-biopolymer produced from a submerged mycelial culture of Hericium erinaceus. Biosci Biotechnol Biochem. 2003;67(6):1292-8. View abstract.

Yi Z, Shao-Long Y, Ai-Hong W, et al. Protective Effect of Ethanol Extracts of Hericium erinaceus on Alloxan-Induced Diabetic Neuropathic Pain in Rats. Evid Based Complement Alternat Med. 2015;2015:595480. View abstract.

Zan X, Cui F, Li Y, et al. Hericium erinaceus polysaccharide-protein HEG-5 inhibits SGC-7901 cell growth via cell cycle arrest and apoptosis. Int J Biol Macromol. 2015;76:242-53. View abstract.

Zhang CC, Yin X, Cao CY, et al. Chemical constituents from Hericium erinaceus and their ability to stimulate NGF-mediated neurite outgrowth on PC12 cells. Bioorg Med Chem Lett. 2015;25(22):5078-82. View abstract.

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Lion's mane spores 450% Google search growth

07-Jun-2024 - Last updated on 09-Jun-2024 at 23:57 GMT

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The program, now in its third series, follows British celebrity car expert and presenter Jeremy Clarkson in his obstacle-laden attempt to become a successful rural farmer.

In a recent episode, first streamed in May, Clarkson cultivates hordes of lion's mane in his makeshift underground facility, and his wife suggests dehydrating and blending them into powder to sell as supplements.

She informs him: “I put it in my coffee every morning, and it’s like spearmint going through my whole head, your whole mind opens up and you’re really clear thinking and the mornings I don’t take it I really notices—it’s amazing!”

“Everyone who’s anyone takes lion's mane,” she adds. 

While they fail to make a powder that can pass health and safety regulations, they surely created awareness of the fungi after the show gained more than five million views, breaking Amazon Prime Video's UK ratings.

Online pharmacy Landys Chemist noted an immediate uptick in Google search activity following the upload of the episode to the streaming platform. It noted that during the week of May 21 to 28, Google Trends showed search volumes for the phrase 'lion's mane mushroom powder' increased by 450%.

And in the following week, Google searches for "benefits of lion's mane" increased by a further 120% while "what does lion's mane do" rose by 200%.

"We've noticed a significant increase in interest in lion's mane mushroom recently, especially after its exposure on platforms like Clarkson’s Farm and TikTok. Traditionally, athletes have been early adopters of this mushroom for its cognitive and health benefits. It's encouraging to see that the broader public is now also recognizing its value." 

The shrooming trend ​

Suppliers and brands throughout Europe have noticed this mushroom climb its way up in consumer perception.

“Lion's mane is a very trendy mushroom,” Robin Gurney, founder of Musheez, the Estonia-based organic mushroom supplement supplier, told NutraIngredients. “It’s up there with cordyceps as the two seen to be performance enhancers. Gymgoers buy into cordyceps for strength and endurance, and biohackers buy into lion’s mane for memory, cognition and focus.”

His firm, which supplies brands in countries across the continent, has witnessed 100% growth year on year for the last few years, but he has noted a distinct uptick in awareness in the last 12 months alone.

“It used to be that we were contacting brands and telling them about mushrooms and asking if these could be incorporated into their portfolio. Whereas now, brands are coming to us already knowing the benefits and wanting to add these to their range,” he added.

“I do think lion's mane is on the tip of everyone’s tongue," said Sophie Barrett, an independent medical herbalist and consultant for mushroom supplement brand Hifas de Terra. "It has taken off for us. Reishi used to be the number one best seller, and now it's concentrated extract of lion's mane.”

Barrett runs her own naturopathic clinic and hosts education sessions with health professionals for Hifas de Terra. She has witnessed the change in focus of these discussions as the fungi are taken increasingly seriously, not only by gen Zers and millennials but as a serious solution for health aging.

“It’s not just for young people who want to take it for their exams, but it’s for the elderly and those looking at preventative health solutions,” she said. “It’s something we’ve noticed at my clinic also. While we used to have a lot of mainly young females and a lot of people with autoimmune diseases, now we have more elderly patients.”

She added that there has been more interest coming from health practitioners beyond nutritionists, dietitians, herbalists and kinesiologists, with doctors and general practitioners starting to ask questions about how these ingredients can support their patients.

"It's great that they can see the benefits of adding these products to their patient care toolbox," she said.

Rhysa Phommachanh, head of digital at Landys Chemist, outlines the benefits of lion’s mane:

Cognitive Function ​

Lion’s mane mushrooms ​ contain compounds such as hericenones and erinacines, which stimulate nerve growth factor production and, in turn, support brain health, memory and focus.

Research indicates it may have neuroprotective properties ​ due to its ability to promote nerve growth and repair, which could potentially aid in the prevention or management of neurological conditions such as Alzheimer’s, dementia and Parkinson’s disease.

Mental Health support ​

Evidence suggests that consuming lion's mane mushrooms can help alleviate symptoms of  stress ​, low  mood ​ and anxiety due to their anti-inflammatory properties. This mushroom also supports the production of nerve growth factor (NGF), which may help regulate mood and promote overall mental well-being.

Immune System Boost ​

The fungi contains polysaccharides, specifically beta-glucans—compounds that can help enhance the immune system.

Anti-inflammatory and antioxidant properties ​

Rich in antioxidant and anti-inflammatory compounds, these mushrooms can help reduce oxidative stress ​ and inflammation.

Digestive health ​

Lion’s mane can promote the growth of beneficial gut bacteria and reduce inflammation ​ in the gut lining. This can potentially aid with conditions like ulcers and inflammatory bowel syndrome.

Menopausal symptom relief ​

Preliminary research has indicated that supplementing lion’s mane mushrooms could provide symptomatic relief for women going through menopause, such as sleep disturbance and mood swings. This is potentially due to its beneficial effect on NGFs and cognitive enhancement.

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Lion’s Mane ( Hericium erinaceus ) Exerts Anxiolytic Effects in the rTg4510 Tau Mouse Model

Associated data.

The data presented in this study are available upon request from the corresponding author, without undue reservation.

Alzheimer’s disease (AD) significantly impairs the life of an individual both cognitively and behaviorally. Tau and beta-amyloid (Aβ) proteins are major contributors to the etiology of AD. This study used mice modeling AD through the presence of tau pathology to assess the effects of Hericium erinaceus ( H. erinaceus ), also known as Lion’s mane, on cognitive and non-cognitive behaviors. Despite neurocognitive and neurobiological effects of H. erinaceus being seen in both healthy and transgenic mice, no research to date has explored its effects on mice with solely tau pathology. In this study, mice were placed on a diet supplemented with H. erinaceus or a standard rodent diet for 4.5 months in order to determine the effect of this medicinal mushroom on behavior. Tau mice given H. erinaceus had significantly shorter latencies to enter the center of the open field (OF) ( p < 0.05) and spent significantly more time in the open arms of the elevated zero maze (EZM) ( p < 0.001) compared to tau control mice. Mice given H. erinaceus spent significantly more time in the open arms of and made more head dips in the elevated zero maze (EZM) ( p < 0.05). While H. erinaceus had anxiolytic effects, no improvements were seen in spatial memory or activities of daily living. These findings provide additional support for the anxiolytic effects of H. erinaceus and point to its potential benefit as a therapeutic for anxiety in AD.

1. Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder that negatively affects memory, language, problem-solving, consciousness, reasoning, and everyday living. AD is characterized by the unchecked accumulation of two proteins: the microtubule-associated protein tau and beta-amyloid (Aβ). β-amyloid clumps together and forms plaques in extracellular spaces between neurons, resulting in synapse loss [ 1 ]. Tau proteins normally support a healthy neuron by stabilizing microtubules [ 2 ]. Neurofibrillary tangles, or tau tangles, begin to form from these tau proteins after they have become hyperphosphorylated and dissociate from microtubules [ 3 ]; this leads to destabilization of the microtubule network and impairs neuronal communication [ 4 ]. In the AD brain, amyloid plaques and tau tangles are strongly associated with the development and progression of AD.

Treatments for AD only provide some improvements in the life of the individual that may slow the progression of the disease but do not terminate it. Investigation into treatments that may play a potential preventative role are warranted, since no new pharmacological treatments have been approved for AD since 2003 [ 5 , 6 ]. There is an urgent need for treatment to become available; however, the lack of understanding of AD, timely clinical trials, and expensive research [ 7 ] have led to the high failure rate of candidate disease-modifying treatments (DMTs) [ 8 ]. Lifestyle factors, such as diet, are more easily managed and implemented into a daily routine by individuals compared to pharmacological treatments. Mushrooms are easily accessible and do not have adverse side effects shown by prescription drugs [ 5 ]. The medicinal mushroom, Hericium erinaceus ( H. erinaceus ), has been shown to have numerous beneficial neurocognitive effects which may play a protective role against the development of AD.

H. erinaceus is an edible mushroom that is highly valued due to its various health benefits [ 9 ]. This medicinal mushroom has been shown to have many neurocognitive and mental benefits, and leads to improvements in the immune system due to its constituents hericenones and erinacines [ 5 , 10 , 11 ]. Hericenones (aromatic compounds with molecular weights between 330.4 and 598.9 g/mol [ 12 ]) and erinacines (diterpenoids with molecular weights between 360.5 and 506.6 g/mol [ 12 ]) are compounds that can be isolated from the fruiting bodies of mushrooms and cross the blood brain barrier (BBB) [ 13 , 14 ]. Their ability to cross the BBB is what allows H. erinaceus to have a high therapeutic potential. Additional benefits of H. erinaceus include the promotion of nerve growth factor (NGF) [ 15 ], promotion of brain-derived neurotrophic factor (BDNF), improvement of cognitive function [ 11 ], promotion of anti-inflammation, reduction in astrocyte activation, hippocampal neurogenesis, glial cell activation [ 16 ], reduction in nitric oxide (NO) production in BV2 microglia, and improvements in AD-related behaviors such as burrowing and nesting in mice [ 9 ] which can be viewed as analogous to activities of daily living in humans. H. erinaceus has also been shown to lessen anxiety and depression after four weeks of consumption in human subjects [ 17 ]. This is important since the onset of AD results in non-cognitive neuropsychiatric symptoms such as anxiety and depression which negatively affect the quality of life of the individual living with AD and their caregivers [ 18 ]. Thus, H. erinaceus possesses many beneficial qualities that may help combat dementia and AD [ 15 ].

Brandalise and colleagues (2017) [ 11 ] assessed the effects of H. erinaceus in wild-type (WT) mice. This was the first study to highlight the beneficial properties of H. erinaceus on healthy non-transgenic mice. One-month-old mice were administered a diet with 5% “Micotherapy Hericium” (0.025 g/g body weight) for two months. Researchers found both behavioral and biochemical effects of H. erinaceus administration. Mice receiving H. erinaceus had improved recognition memory and exploratory behavior in the novel object recognition task; this increased exploratory behavior toward novel objects was indicative of lower levels of anxiety [ 11 ]. Electrophysiological results also showed decreases in the stimulation failure rate of mossy fiber-CA3 neurons in the hippocampus when creating excitatory currents; these neurons are targeted in the neural pathway involving the perirhinal cortex, lateral entorhinal cortex, and dentate gyrus when the mice encounter novel objects [ 11 ]. This research supports the notion that H. erinaceus has beneficial effects on cognition and brain regions implicated in AD.

Researchers have also found that H. erinaceus can reduce Aβ plaque formation in the APPswe/PS1dE9 mouse model receiving erinacine A-enriched H. erinaceus Mycelia (HE-My) for 30 days [ 16 ]. Erinacines have been shown to stimulate the production of nerve growth factor (NGF) and offer neuroprotective properties [ 5 , 19 ]. In a series of biochemical assessments, HE-My administration presented multiple benefits, including: a reduction in the non-compact structure of plaques (the soluble form of Aβ plaques), an increase in insulin-degrading enzyme (IDE—an Aβ-degrading enzyme) in the cortex, and an increase in hippocampal neurogenesis. Tsai-Teng and colleagues (2016) [ 16 ] also found that continued administration of HE-My in mice from 30 days until 81 days improved burrowing and nesting behaviors in Activities of Daily Living (ADL) assessments.

H. erinaceus has also been shown to have beneficial effects on human subjects with mild AD. Li et al. (2020) [ 5 ] conducted a 1-year human pilot study with 49 eligible participants who consumed 350 mg capsules with 5 mg/g of erinacine A three times a day. Researchers found improvements in the blood biomarkers calcium, albumin, hemoglobin (Hb), superoxide dismutase (SOD), BDNF, and homocysteine (Hcy) [ 5 ]. Participants consuming the H. erinaceus mycelium capsules also exhibited improvements in APOE4, alpha-ACT (α-ACT), reductions in β-amyloid, and significant improvements in the Mini-Mental State Examination (MMSE) and Instrumental Activities of Daily Living (IADL), representing improved cognition and higher levels of independence [ 5 ]. Additionally, H. erinaceus has been shown to reduce anxiety and depression after four weeks in healthy female human participants [ 17 ]. These participants consumed H. erinaceus cookies containing 0.5 g of powdered fruiting body from the mushroom four times a day at any time of the day [ 17 ]. Researchers saw improvements as a result of H. erinaceus with the use of two scales: the Indefinite Complaints Index (ICI), an anxiety measure and a common scale used to measure the clinical effects of treatments, and the Center for Epidemiologic Studies Depression Scale (CES-D), a scale used to measure symptoms of depression by a self-report method [ 17 ]. Given the positive effects H. erinaceus has had on both healthy and cognitively impaired individuals, more research is warranted to continue exploring these benefits.

Previous studies have only assessed H. erinaceus supplementation in amyloid mouse models rather than tau [ 15 , 16 , 20 ]. As tau is a major constituent of AD pathology along Aβ plaques, it is important to assess the effects of H. erinaceus on a mouse model solely containing tau.

In the present study, the rTg4510 tau mouse model [ 21 ] was used to study the effects of H. erinaceus administration on cognitive and non-cognitive behaviors. This specific mouse model contains the P301L tau mutation; tau expression is driven in the forebrain as a result of the CamKIIa promoter system [ 21 ]. These mice show cognitive and behavioral impairments by four months of age and over time, behavior, tau accumulation, and brain atrophy worsen. Other tau mouse models, such as the JNPL3 have the same P301L tau mutation; however, they result in motor abnormalities which can impact behavioral assessments [ 22 ]. As we were interested in assessing whether H. erinaceus administration could rescue behavioral deficits in mice containing tangle pathology, this model was selected. Four total groups were evaluated in this study: tau mice on/off H. erinaceus and WT mice on/off H. erinaceus . Mice on the mushroom diet were supplemented with H. erinaceus through wet food. Mice underwent behavioral tests assessing general locomotor activity, anxiety-like and risk-taking behavior, and spatial cognition and memory. Additionally, activities of daily living (ADL), including burrowing and nesting were measured. It was hypothesized that H. erinaceus would decrease anxiety-like behaviors, increase locomotor activity, decrease deficits in spatial memory, and improve performance in ADL measures.

2. Materials and Methods

All procedures were approved by the Angelo State University Institutional Animal Care and Use Committee (IACUC) (approved protocol #21-204) and were in accordance with the National Institutes of Health guide for the care and use of Laboratory animals.

2.1. Animals

Experimental mice were bred by pairing female Fgf14 Tg(tetO-MAPT*P301L)4510Kha (tau) mice and male Tg(Camk2a-tTA)1Mmay (CaMKIIa promoter) mice (The Jackson Laboratory, Bar Harbor, ME, USA) in 2F:1M breeding harems. Tail snips from offspring were collected between days 11 and 14 and sent to Transnetyx, Inc. (Cordova, TN, USA) to appropriately genotype each animal. Offspring were weaned between 21 and 28 days old. Mice were then housed in separate cages (Animal Care Systems, Centennial, CO, USA) based on their sex, diet condition, and genotype ( Table 1 ).

Experimental Sample Sizes (Behavioral Analysis).

2.2. Housing

Mice were housed in an Optimice® caging system (Animal Care Systems, Centennial, CO, USA); each cage contained sani-chip bedding and was equipped with a nylabone for mice to chew and a nesting square. No more than three mice were housed in any single cage. All mice were maintained on a 12-h light/dark cycle (08:00–20:00 lights on). Food and water were provided ad libitum .

2.3. Dietary Supplementation

At four weeks of age, mice in the mushroom dietary condition began to receive Lion’s Mane Mushroom Mycelium Powder that was mixed into wet food (Host Defense Mushrooms, Fungi Perfecti, LLC., Olympia, WA, USA)); this continued throughout the duration of the study for four months. Each cage in each of the groups was administered 150 g of wet food and 100 g of standard dry food pellets. Wet food was made by combining laboratory water and dry food, waiting for the dry pellets to soften, and mixing by hand. WT and tau mice supplemented with H. erinaceus received 1/3 teaspoon of powder containing 1000 mg of Lion’s Mane and approximately 550 mg of ( H. erinaceus ) mycelium polysaccharides mixed into the 150 g of wet food. WT and tau control mice received 150 g of wet food with no H. erinaceus powder. All mice were provided food ad libitum and weights of the wet food along with the dry food were taken every four days to measure average food consumption.

2.4. Measures and Behavioral Testing

2.4.1. body weights and food consumption weights.

Body weights were collected throughout the duration of the experiment every eight days (after every second food weight collection) to assess weight gain as a result of maturation and dietary condition. Food weights were collected every four days to verify that mice were consuming a sufficient amount of wet food in accordance with their experimental condition, in comparison to the dry food provided ad libitum . Due to group housing of mice, the amount of wet food and dry food consumed was calculated by weighing the amount of wet food and dry food remaining in the cage after four days, subtracting that from the original amount (150 g for wet food; 100 g for dry food), and dividing that total by the number of mice in the cage to yield an average.

2.4.2. Open Field Test (OFT)

The Open Field Test (OFT) consists of a square enclosure that is used to assess general locomotor activity in rodents, exploratory behavior, mood, and anxiety [ 23 ]. The enclosure was a white plastic box that measures 45 × 45 × 40 cm. Mice were given a single five-minute trial while an overhead camera with SMART animal behavior software (Panlab, Harvard Apparatus, Holliston, MA, USA) measured the following variables: distance traveled in the center of the OFT (cm), percent time spent in the center, and latency (s) to first enter into the center of the box. The OFT box was cleaned with 70% ethanol between mice to eliminate olfactory cues. The number of fecal boli was also counted manually at the end of each trial before cleaning.

2.4.3. Elevated Zero Maze (EZM)

The Elevated Zero Maze (EZM) is a behavioral test measuring anxiety-like behavior and approach/avoidance conflict in rodents [ 24 ]. It is elevated off the ground and consists of an elevated ‘0’ shaped platform with two enclosed arms and two open arms on opposite ends [ 25 ]. The mouse moves between the enclosed and open arms within a single five-minute trial. Mice were considered to be inside a given arm when all four paws were in that particular arm. Mice displaying higher levels of activity by exploring the open and exposed arms of the EZM are perceived as less anxious in comparison to those who spend more time in the enclosed and protected arms [ 24 ]. The following variables were measured: number of arm transitions, time spent in the open versus closed arms, and head dips assessing risk-taking behavior [ 26 ]. Between each mouse, the EZM apparatus was cleaned with 70% ethanol to eliminate olfactory cues. One mouse was removed from EZM data analysis due to falling off the maze.

2.4.4. Morris Water Maze (MWM)

The Morris Water Maze (MWM) is a behavioral test of spatial memory where rodents must use visual cues to locate a clear platform hidden just below opaque water [ 27 ]. During a five-day acquisition period, mice were run through three trials per day. Visual cues were placed onto a curtain hanging outside of the tub. These cues aid the mice in learning the location of the hidden platform which remains stationary during the test. Mice were placed into the MWM facing the wall and were given 60 s to find the hidden platform. If the mouse did not find the platform in the allotted time, the mouse was guided towards the platform and placed there for 10 s. Each day, mice were run through a different sequence of three cues; the sequence was the same for each mouse. During each trial, the following variables were measured: percent time spent in the target quadrant, latency to reach the platform (s), thigmotaxicity (time (s) spent swimming along the border of the pool), and total distance swam (cm). An overhead camera connected to SMART animal behavior tracking software (Panlab, Harvard Apparatus, Holliston, MA, USA) recorded these variables. On day six, after the five 3-trial acquisition days, each mouse underwent a single probe trial where the platform was lowered for the animals to be unable to access it. This is meant to measure long-term memory. Mice began at a novel location (between two of the previous start locations). Target crosses when the platform was submerged, time spent in the target quadrant, and thigmotaxicity were measured on this probe day.

2.4.5. Activities of Daily Living: Burrowing and Nesting

Activities of Daily Living (ADL) are common measures for studying noncognitive aspects of AD in rodents; these primarily include burrowing and nesting. These assess the tendency for mice to have normal activity levels and general animal welfare [ 28 ]. Burrowing was analyzed first. Burrowing was assessed by individually housing mice in a shoebox cage (Ancare, Bellmore, NY, USA) containing a PVC tube with one end closed, containing 250 g of pea-gravel (small rocks). The amount of removed pea gravel was measured after 2-h and the following morning. One mouse was removed from both ADL measures due to a water bottle spilling in the shoebox cage during the 2-h burrowing assessment, which could have potentially served as a stressor to the mouse and affected performance in the ADL measures.

Once the two burrowing measures were recorded, fresh sani-chip bedding was given to each cage along with 2.5 g of shredded white paper, which was sprinkled into the cage. The following morning, pictures were taken of each cage and its nest for scoring by a rater blind to condition. Two raters rated each nest on a scale of 1–5, with 1 being no nest was constructed and 5 being a complete nest was constructed [ 29 ]. After reliability in ratings was assessed, the scores were averaged and used for analysis.

2.5. Statistical Analysis

A 2 (genotype) × 2 (diet) × 2 (sex) × 5 (time) mixed ANOVA was run to assess changes in body weights overtime and a 2 (genotype) × 2 (diet) × 2 (sex) × 4 (time) mixed ANOVA was run to assess differences in the consumption of dry and wet food over the course of the experiment.

Dependent variables in the OFT, EZM, and ADL measures (burrowing and nesting) were assessed through 2 (genotype) × 2 (diet) × 2 (sex) factorial ANOVAs.

A 2 (genotype) × 2 (diet) × 2 (sex) × 5 (acquisition days of the MWM paradigm) mixed ANOVA was run for the following dependent variables in the MWM: percent time spent in the target quadrant, latency to reach the platform (s), total distance (cm) and thigmotaxicity. Target crosses on the final probe trial (when the platform was submerged), thigmotaxicity, and time spent in the target quadrant were measured with a 2 (genotype) × 2 (diet) × 2 (sex) factorial ANOVA.

Pairwise comparisons were assessed following significant main effects and simple effects analyses were run following any significant interactions with Bonferroni corrections. Greenhouse Geiser corrections were applied when sphericity was violated in mixed ANOVA analyses. p < 0.05 was considered statistically significant and p < 0.10 was considered trending. All analyses were run through SPSS v.26 (IBM Corp., Armonk, NY, USA) and graphs were made through GraphPad Prism (v.9.3.1) (San Diego, CA, USA).

3.1. Animal Body Weights

There was a significant effect of day, F (1.679, 112.507) = 161.575, p < 0.001, η p 2 = 0.707; as the experiment progressed, mice gained weight ( Figure 1 A). There was also a significant day × diet × sex × genotype interaction, F (1.679, 112.507) = 3.745, p < 0.05, η p 2 = 0.053. In male WT mice, those given the control diet (no H. erinaceus in wet food) weighed significantly more than their mushroom counterparts only at 64 days ( p < 0.05) and 96 days ( p < 0.05) ( Figure 1 B). In female tau mice, those on the control diet weighed significantly more at each weighing time (baseline: p < 0.01; 32 days: p < 0.01; 64 days: p < 0.001; 96 days: p = 0.001; 128 days: p < 0.05) than those given H. erinaceus ( Figure 1 C). Finally, in control diet mice, female tau mice weighed significantly more than female WT mice at days 64 ( p = 0.01), 96 ( p < 0.05), and 128 ( p < 0.05) ( Figure 1 D).

Weights over time. ( A ) Mice on the control diet (no H. erinaceus ) weighed significantly more than those given H. erinaceus . ( B ) Male WT mice given the control diet weighed significantly more than their H. erinaceus counterparts at 64 days and 96 days; only male mice are graphed. ( C ) Female tau mice on the control diet weighed significantly more at each weighing point than female tau mice given H. erinaceus ; only female mice are graphed. ( D ) Female tau mice weighed significantly more than female WT mice. Female tau mice weighed more than female WT mice at days 64, 96, and 128; only control diet mice are graphed. 0 = baseline; error bars represent mean ± SEM. (* p < 0.05, ** p < 0.01, *** p < 0.001).

There was a significant between-subject effect of diet, F (1, 67) = 5.833, p < 0.05, η p 2 = 0.08; control diet mice weighed more than those given H. erinaceus ( Figure 1 A). There was also a significant diet × sex × genotype interaction, F (1, 67) = 10.291, p = 0.002, η p 2 = 0.133. In male mice, WT controls weighed significantly more than WT mushroom mice, p < 0.05 ( Figure 1 B). In female mice, tau mushroom mice weighed significantly less than tau control mice ( p = 0.001) ( Figure 1 C). In control mice (no H. erinaceus ), female tau mice weighed significantly more than female WT mice, p < 0.05 ( Figure 1 D).

3.2. Wet Food Consumption

There was a significant effect of time, F (2.689, 180.133) = 11.203, p < 0.001, η p 2 = 0.143, indicating that mice ate more wet food over the course of the experiment ( Figure 2 A). There were also significant time × diet × sex, F (2.689, 180.133) = 4.511, p < 0.01, η p 2 = 0.063, and time × diet × genotype, F (2.689, 180.133) = 3.831, p < 0.05, η p 2 = 0.054 interactions. Male control diet mice ate more wet food at 64 ( p < 0.01), 96 ( p < 0.001), and 128 ( p < 0.01) days than male mushroom mice ( Figure 2 B). Female mice given H. erinaceus ate more than male mice given H. erinaceus at 64 ( p < 0.05) and 96 ( p < 0.01) days ( Figure 2 C). Tau mice given the control diet ate more than tau mice given H. erinaceus at 32 ( p < 0.05) and 128 ( p < 0.01) days ( Figure 2 D).

Wet food consumption over time. ( A ) Mice on the control diet (no H. erinaceus ) ate more food than those given H. erinaceus . ( B ) Male control diet mice ate more wet food at day 64 ( p < 0.01), 96 ( p < 0.001), and 128 ( p < 0.01) than male mushroom mice. Tau control mice ate significantly more wet food than tau mushroom mice; only male mice graphed. ( C ) Female mice ate more than male mice at 64 ( p < 0.05) and 96 ( p < 0.01) days. Female tau mice ate significantly more than male tau mice, p < 0.001. Tau female mice ate significantly more wet food than WT female mice ( p = 0.001). WT male mice ate significantly more wet food than Tau male mice, p = 0.001; only H. erinaceus diet condition graphed. ( D ) Tau control mice ate more than tau mushroom mice at day 32 ( p < 0.05) and 128 ( p < 0.01). Female mice ate significantly more than male mice, p < 0.05. Male control mice ate significantly more wet food than male mushroom mice, p < 0.001. Female mushroom mice ate significantly more wet food than male mushroom mice, p < 0.001; only tau mice graphed. Error bars represent mean ± SEM.

There were significant effects of diet, F (1, 67) = 6.251, p < 0.05, η p 2 = 0.085, and diet × sex, F (1, 67) = 8.399, p < 0.01, η p 2 = 0.111, genotype × sex, F (1, 67) = 9.179, p < 0.01, η p 2 = 0.120, and diet × sex × genotype, F (1, 67) = 13.792, p < 0.001, η p 2 = 0.171 interactions. Control mice ate significantly more wet food than those on the H. erinaceus diet, p < 0.05 ( Figure 2 A). Female mice given mushrooms ate significantly more than males given mushrooms, p < 0.05 ( Figure 2 C). Female tau mice ate significantly more than male tau mice, p < 0.05 and tau females ate significantly more wet food than WT females, p < 0.05. Male tau mice given the control diet ate significantly more than male tau mice given H. erinaceus , p < 0.001 ( Figure 2 B). Female tau mushroom mice ate significantly more than male tau mushroom mice, p < 0.001 ( Figure 2 C). Interestingly, wet food consumption in genotype was dependent on sex in the mushroom condition: tau female mushroom mice ate significantly more than WT female mushroom mice, p = 0.001 while WT male mushroom mice ate significantly more than tau male mushroom mice, p = 0.001 ( Figure 2 C).

3.3. Dry Food Consumption

There was a significant effect of time, F (1.795, 120.248) = 8.314, p = 0.001, η p 2 = 0.110; mice ate less dry food as the experiment progressed. There was a significant sex × genotype interaction, F (1, 67) = 4.497, p < 0.05, η p 2 = 0.063. Male tau mice ate significantly more dry food than male WT mice ( p < 0.05) ( Figure 3 ).

Dry food consumption over time. As the experiment progressed, mice ate less dry food, p < 0.01. Male tau mice consumed significantly more dry food than male WT mice ( p < 0.05). Error bars represent mean ± SEM.

3.4. Open Field Test

3.4.1. latency to enter the center.

There was a significant diet × genotype interaction, F (1, 67) = 7.650, p < 0.01, η p 2 = 0.102. Simple effects analysis revealed that tau control mice had significantly longer latencies to enter the center of the OF compared to tau mice given H. erinaceus ( p < 0.05) and WT control mice ( p < 0.01) ( Figure 4 A). Analysis also revealed a trending diet × sex interaction, F (1, 67) = 3.217, p = 0.077, η p 2 = 0.046. Female mushroom mice (M = 8.630 s, SD = 11.875) took less time to enter the center of the OF than female control mice (M = 17.897 s, SD = 20.574). Male mushroom mice (M = 14.813 s, SD = 19.129) took longer to enter the center of the OF than male control mice (M = 10.216 s, SD = 16.930).

Open field test measures. ( A ) Tau control mice had significantly longer latencies to enter the center compared to WT control mice. Tau mice supplemented with H. erinaceus had significantly shorter latencies in entering the center of the OF compared to tau control mice. ( B ) Male mice defecated more than females. Error bars represent mean ± SEM (* p < 0.05, ** p < 0.01).

3.4.2. Total Distance in the Center (cm)

There was a trending effect of diet, F (1, 67) = 2.873, p < 0.10, η p 2 = 0.041. Mice in the mushroom diet (M = 1033.89 cm, SD = 1534.67) traveled a greater total distance in the center of the OFT compared to mice in the control group (M = 480.23 cm, SD = 522.65).

3.4.3. Percent Time Spent in the Center

There were no significant effects of diet, F (1, 67) = 2.464, p = 0.121, η p 2 = 0.035, sex, F (1, 67) = 0.001, p = 0.979, η p 2 = 0.000, or genotype, F (1, 67) = 0.085, p = 0.771, η p 2 = 0.001 for percent time spent in the center of the OF.

3.4.4. Fecal Boli

Analysis of fecal boli revealed a significant effect of sex, F (1, 67) = 10.227, p = 0.002, η p 2 = 0.132. Males left significantly more fecal boli than females during their time in the OFT ( p < 0.01) ( Figure 4 B). There were no significant effects of genotype, F (1, 67) = 0.049, p = 0.825. There were no differences between tau mice (M = 1.181, SD = 1.929) and WT mice (M = 1.283, SD = 2.162). Additionally, there were no significant effects of diet, F (1, 67) = 0.177, p = 0.734. There were no differences between mice administered H. erinaceus (M = 1.153, SD = 1.767) and mice consuming the control diet (M = 1.311, SD = 2.311).

3.5. Elevated Zero Maze

3.5.1. head dips.

There was a significant effect of sex, F (1, 66) = 6.377, p < 0.05, η p 2 = 0.088, a significant effect of diet, F (1, 66) = 7.107, p = 0.010, η p 2 = 0.097, and a significant effect of genotype, F (1, 66) = 29.143, p < 0.001, η p 2 = 0.306. Female mice made significantly more head dips than male mice ( p < 0.05) ( Figure 5 A). Mice given H. erinaceus made significantly more head dips than control mice ( p = 0.010) ( Figure 5 B) and tau mice made significantly more head dips than WT mice ( p < 0.001) ( Figure 5 C).

Head Dips in the EZM. ( A ) Female mice made significantly more head dips than male mice. ( B ) Mice given H. erinaceus made significantly more head dips than control mice. ( C ) Tau mice made significantly more head dips than WT mice. Error bars represent mean ± SEM (* p < 0.05, ** p = 0.01, *** p < 0.001).

3.5.2. Total Transitions

There was a trending effect of sex, F (1, 66) = 3.108, p = 0.083, η p 2 = 0.045. Female mice (M = 6.259, SD = 9.918) made more transitions compared to male mice (M = 3.127, SD = 4.993).

3.5.3. Percent Time Spent in the Open Arms

There was a significant effect of diet, F (1, 66) = 4.878, p < 0.05, η p 2 = 0.069, a significant effect of genotype, F (1, 66) = 10.054, p = 0.002, η p 2 = 0.132, and a significant diet × genotype interaction, F (1, 66) = 7.099, p = 0.010, η p 2 = 0.097. Mice given H. erinaceus spent significantly more time in the open arms compared to control mice ( p < 0.05). Tau mice spent significantly more time in the open arms compared to WT mice ( p < 0.01) ( Figure 6 ). Simple effects analysis revealed that tau mice given H. erinaceus spent significantly more time in the open arms compared to tau control mice ( p = 0.001) ( Figure 6 ).

Percent time spent in the open arms of the EZM. Tau mice given H. erinaceus spent significantly more time in the open arms compared to tau control mice and tau mice spent more time in the open arms compared to WT mice. Mice given H. erinaceus spent more time in the open arms compared to control mice. Error bars represent mean ± SEM (* p < 0.05, ** p < 0.01, *** p = 0.001).

3.6. Morris Water Maze

3.6.1. latency to platform.

There was a significant effect of day, F (4, 268) = 23.470, p < 0.001, η p 2 = 0.259. As the days progressed, mice found the platform faster ( Figure 7 A). A between-subjects effect of genotype was also seen, F (1, 67) = 28.018, p < 0.001, η p 2 = 0.295. Tau mice had significantly longer latencies to find the platform compared to WT mice, p < 0.001 ( Figure 7 B).

Latency to find the platform in the MWM. ( A ) As the days progressed, mice spent less time finding the platform ( p < 0.001). ( B ) Tau mice had significantly longer latencies to find the platform compared to WT mice ( p < 0.001) Error bars represent mean ± SEM.

3.6.2. Percent Time Spent in the Target Quadrant

There was a significant effect of day, F (3.444, 230.780) = 10.059, p < 0.001, η p 2 = 0.131. As the days progressed, mice spent more time in the target quadrant ( Figure 8 A). There was also a significant day × diet × genotype × sex interaction, F (3.444, 230.780) = 2.567, p < 0.05, η p 2 = 0.037. Simple effects analysis revealed that Tau female control mice spent significantly more time in the target quadrant compared to tau male control mice on day three ( p < 0.05). A between-subjects effect of genotype was also seen, F (1, 67) = 4.926, p < 0.05, η p 2 = 0.068. WT mice spent significantly more time in the target quadrant compared to tau mice ( p = 0.03) ( Figure 8 B).

Percent time spent in the target quadrant of the MWM. ( A ) As the days progressed, mice spent more time in the target quadrant ( p < 0.001). ( B ) WT mice significantly spent more time in the target quadrant compared to tau mice ( p < 0.05). Error bars represent mean ± SEM.

3.6.3. Thigmotaxicity

There was a significant effect of day, F (3.024, 202.629) = 30.430, p < 0.001, η p 2 = 0.312. As the days progressed, mice spent less time swimming along the border of the pool. A significant day × genotype interaction was also seen, F (3.024, 202.629) = 3.651, p = 0.013, η p 2 = 0.052. Simple effects analysis revealed that WT mice spent significantly less time around the border than tau mice on days 2–4 ( p < 0.001) and 5 ( p < 0.01) ( Figure 9 ). A between-subjects effect of genotype was also seen, F (1, 67) = 17.424, p < 0.001, η p 2 = 0.206. Tau mice spent significantly more time along the border than WT mice ( p < 0.001).

MWM thigmotaxicity by genotype. As the days progressed, tau mice spent significantly more time around the border of the MWM compared to WT mice. Tau mice spent significantly more time along the border on days 2–4 and 5 compared to WT mice. Error bars represent mean ± SEM. (** p < 0.01, *** p < 0.001).

3.6.4. Total Distance

There was a significant effect of day, F (4, 268) = 9.995, p < 0.001, η p 2 = 0.130. As the days progressed, mice swam shorter total distances. There was also a significant day × sex interaction, F (4, 268) = 2.724, p < 0.05, η p 2 = 0.039. While females did not show a significant decrease in total distance swam across the acquisition days, male mice did. Males swam significantly less total distance on days 3, 4, and 5 compared to day 1 ( p < 0.001) ( Figure 10 A). There was also a significant effect of genotype, F (1, 67) = 29.733, p < 0.001, η p 2 = 0.307. Tau mice traveled a significantly greater total distance than WT mice ( p < 0.001) ( Figure 10 B).

Total distance swam in the MWM. ( A ) As the days progressed, mice swam less total distance, with male mice specifically traveling shorter distances on days 3 through 5 compared to day 1 ( p < 0.001). Female mice did not show significant differences in distances throughout the training days. ( B ) As the days progressed, tau mice traveled a significantly greater distance than WT mice ( p < 0.001). Error bars represent mean ± SEM.

3.6.5. Latency to Platform (Probe Day)

There was a significant effect of genotype, F (1, 67) = 13.264, p = 0.001, η p 2 = 0.165. Tau mice had a significantly longer latency to first reach where the platform would be than WT mice ( p = 0.001) ( Figure 11 A). There was also a significant genotype × sex interaction, F (1, 67) = 7.911, p < 0.01, η p 2 = 0.106. Female WT mice took significantly less time than female tau mice to first reach where the platform would be ( p < 0.001). Additionally, female tau mice had a longer latency in first reaching where the platform would be than male tau mice ( p < 0.01) ( Figure 11 B).

MWM probe trial latency to first cross platform. ( A ) Tau mice had a significantly longer latency to first reach where the platform would be than WT mice. ( B ) Female WT mice took significantly less time than female tau mice to first cross where the platform would be and female tau mice had a significantly longer latency to first cross where the platform would be than male tau mice. Error bars represent mean ± SEM (** p < 0.01, *** p ≤ 0.001).

3.6.6. Target Crossings (Probe Day)

There was a significant effect of genotype, F (1, 67) = 7.373, p < 0.01, η p 2 = 0.099. WT mice made significantly more crosses over the target than tau mice ( p < 0.01) ( Figure 12 A). There was also a significant genotype × sex interaction, F (1, 67) = 4.533, p < 0.05, η p 2 = 0.063. Female WT mice made significantly more target crosses than female tau mice ( p < 0.01).

Additional MWM Probe Trial measures. ( A ) WT mice crossed the target significantly more than tau mice. ( B ) WT mice spent significantly more time in the target quadrant on the probe day than tau mice. ( C ) Tau mice spent significantly more time in the border (greater thigmotaxicity) than WT mice. Error bars represent mean ± SEM (* p < 0.05, ** p < 0.01).

3.6.7. Percent Time Spent in the Target Quadrant (Probe Day)

Analysis revealed a significant effect of genotype, F (1, 67) = 5.267, p < 0.05, η p 2 = 0.073. WT mice spent significantly more time in the target quadrant on the probe day than tau mice ( p < 0.05) ( Figure 12 B). There was also a trending effect of diet, F (1, 67) = 3.616, p = 0.062, η p 2 = 0.051. Mushroom mice (M = 23.054, SD = 9.64) spent less time in the target quadrant compared to control mice (M = 26.974, SD = 8.09).

3.6.8. Thigmotaxicity (Probe Day)

There was a significant effect of genotype, F (1, 67) = 10.724, p = 0.002, η p 2 = 0.138. Tau mice spent significantly more time in the border on the probe day compared to WT mice ( p < 0.01) ( Figure 12 C).

3.7. Activities of Daily Living

3.7.1. burrowing.

Analysis of pea-gravel burrowed after 2 h revealed a significant effect of genotype, F (1, 66) = 13.805, p < 0.001, η p 2 = 0.173. WT mice burrowed significantly more pea-gravel than tau mice ( p < 0.001) ( Figure 13 A). There was also a significant diet × genotype × sex interaction, F (1, 66) = 8.512, p < 0.01, η p 2 = 0.114. Female WT mushroom mice burrowed significantly more than male WT mushroom mice ( p < 0.05). Male tau mushroom mice burrowed significantly more than female tau mushroom mice ( p = 0.020). Female WT mushroom mice burrowed more than female tau mushroom mice ( p < 0.001). Male WT control mice burrowed significantly more than male tau control mice ( p = 0.020).

Burrowing assay measures. ( A ) Two-hour burrowing assessment. WT mice burrowed significantly more pea-gravel than tau mice after 2 h. ( B ) At the overnight measure, female WT mice burrowed significantly more than female tau mice. Male tau mice burrowed significantly more than female tau mice and male WT mice burrowed significantly more than male tau mice. Error bars represent mean ± SEM (* p < 0.05, *** p ≤ 0.001).

Analysis of overnight pea-gravel burrowed revealed a significant effect of genotype, F (1, 66) = 25.586, p < 0.001, η p 2 = 0.279, a significant genotype × sex interaction, F (1, 66) = 4.475, p = 0.038, η p 2 = 0.063, and a significant diet × genotype × sex interaction, F (1, 66) = 4.626, p = 0.035, η p 2 = 0.065. Male tau mice burrowed more than female tau mice ( p < 0.05) ( Figure 13 B). Female WT mice burrowed more than female tau mice ( p < 0.001). Male WT mice burrowed more than male tau mice ( p < 0.05) ( Figure 13 B). Male tau mushroom mice burrowed significantly more than female tau mushroom mice ( p < 0.001). Female tau control mice burrowed more than female tau mushroom mice ( p = 0.013). Female WT mushroom mice burrowed more than female tau mushroom mice ( p < 0.001).

3.7.2. Nesting

Nests were scored by two raters blind to experimental conditions. There was a strong agreement between the scores of both raters, α = 0.950; analysis was conducted on the resulting average nest score. There was a significant effect of genotype, F (1, 66) = 25.222, p < 0.001, η p 2 = 0.276 ( Figure 14 A). WT mice built significantly better nests than tau mice ( p < 0.001) ( Figure 14 B).

Nesting behavior. ( A ) WT mice built significantly better nests than tau mice. ( B ) Representative nest by mushroom condition and genotype; numbers represent randomly assigned IDs for raters. Error bars represent mean ± SEM (*** p < 0.001).

4. Discussion

This study sought to assess the effects of H. erinaceus on a tauopathy mouse model. We hypothesized that H. erinaceus would decrease anxiety-like behaviors, increase locomotor activity, decrease deficits in spatial memory, and improve performance in ADL measures. Overall, results indicate that H. erinaceus had significant anxiolytic effects and increased locomotor activity, in agreement with previous literature. However, H. erinaceus led to no improvements in spatial memory or activities of daily living.

Tau mice given H. erinaceus entered the center of the OFT apparatus faster than tau mice on the control diet, signaling decreased anxiety. Additionally, mice given H. erinaceus traveled a greater distance in the center of the OFT compared to control mice. These results are consistent with studies using WT mice and the OFT to assess the effects of H. erinaceus [ 30 , 31 ]. These studies showed that mice consuming H. erinaceus spent more time in the center of the OFT. Increased locomotor activity was also seen in mice consuming H. erinaceus; tau H. erinaceus mice entered the center significantly faster than tau control mice and H. erinaceus mice traveled a greater average distance in the center. This finding of increased locomotion is consistent with recent literature which showed that WT mice consuming H. erinaceus had increased locomotor activity in the Y maze [ 32 ] and longer exploration times in the emergence test, a variant assessment to the OFT [ 11 ].

Defecation is also a variable associated with emotionality, specifically stress and anxiety [ 33 , 34 , 35 ]. In the current study, males defecated significantly more than females, indicating higher levels of anxiety in males. This is a common finding consistent with past and current literature [ 33 , 36 , 37 , 38 ]. In addition to defecation denoting stress responses, it has also been suggested that males defecate more than females as a “territory marking response” [ 33 , 36 ].

In the EZM, female mice made more head dips and total transitions than male mice. This is consistent with literature that has shown that females are typically more active than males in the EZM and elevated plus maze (EPM), a similar test to the EZM used to measure anxiety-like behaviors [ 24 , 39 ]. Head dips are typically indicative of risk-taking behavior and decreased anxiety [ 40 ], meaning that in this assessment females presented increased risk-taking behaviors than males. Overall, mice given H. erinaceus spent more time in the open arms than control mice. More importantly, tau mice given H. erinaceus spent the most time in the open arms of the EZM and made more head dips than tau control mice. This is an important finding, showing that H. erinaceus has anxiolytic effects in the rTg4510 tau mouse model. A recent study [ 30 ] also indicated that WT mice supplemented with H. erinaceus spent more time in the open arms of the EPM than control mice. Additionally, it has been shown that H. erinaceus significantly increased entries into the open arm and time spent in the open arm of the EPM in WT mice [ 41 ].

Results do not reveal significant effects of H. erinaceus during the acquisition days of the MWM. However, mice did learn as the days progressed, which is consistent with literature using the MWM and transgenic mice of AD [ 42 , 43 ] and studies specifically assessing the effects of H. erinaceus on spatial memory with the MWM on AD rodent models [ 20 , 44 ]. Past literature has consistently shown spatial memory impairments in rTg4510 mice during the MWM assessment at 2.5, 3, and 5.5 months [ 21 , 45 ], and the Barnes Maze [ 46 ], with tau mice performing worse than their non-transgenic counterparts. It is also important to note that H. erinaceus has shown no effects on spatial memory in WT mice [ 32 ], which is consistent with the effects on the transgenic and non-transgenic mice used in this study. More research is warranted on assessing the effects of H. erinaceus on spatial memory in both WT and AD mouse models. Past research implying improvements on memory as an effect of the mushroom have done this with the Novel Object Recognition (NOR) task [ 11 , 15 ] which is used as a measure for short term memory rather than MWM which typically measures long term memory.

There were no significant effects of H. erinaceus on the probe day of the MWM; only significant effects of genotype were seen. This is indicative of the dietary condition having no effect on long-term memory. This contradicts previous studies assessing the effects of H. erinaceus in AD models, which have shown mice that consuming H. erinaceus performed better than mice not consuming H. erinaceus on the probe day [ 20 , 47 ]. As this is the first study assessing the effects of H. erinaceus on spatial memory in tau mice, it can help fill the gap and push further assessment of spatial memory in this mouse model by H. erinaceus supplementation.

H. erinaceus did not lead to improvements in ADL measures; only significant effects of genotype were noted. WT mice burrowed significantly more pea-gravel and built significantly better nests than tau mice. Interactions between diet, genotype, and sex were also seen. These results reveal that female WT mushroom mice burrowed significantly more than male WT mushroom mice, and that female tau mushroom mice burrowed significantly less than male tau mushroom mice in the 2-h burrowing measure. Despite no main effects of diet being seen, it is still worth reporting as not many studies assessing the effects of H. erinaceus have investigated ADL measures. Tsai-Teng et al. (2016) [ 16 ] conducted a nesting assessment with APP/PS1 mice consuming H. erinaceus . Results showed that AD mice presented more deficits in nesting activities compared to their WT counterparts; a result consistent with this study. However, in contrast with the results of the current study, researchers found that the administration of H. erinaceus was able to alleviate deficits in APP/PS1 mice in the nesting assessment [ 16 ].

Noncognitive assessments, such as ADL measures, are important to include as they can help determine non-cognitive deterioration in AD. More importantly, previous literature has shown that H. erinaceus improves non-cognitive deficits in humans consuming the mushroom in capsules 3 times a day for 49 weeks through the Instrumental Activities of Daily Living Scale (IADL) [ 5 ]. The IADL is a test of independent living skills in humans, a construct that is parallel to the ADL measure in rodent models.

Animal weights and wet food consumption increased over the course of the experiment. Tau and WT control mice weighed more than tau and WT mice given H. erinaceus . Throughout this experiment, tau and WT control mice consumed more wet food than tau and WT mice given H. erinaceus . It has been previously shown that tau mice consume more food but weigh less [ 45 ]. However, in the current study, tau mushroom mice ate less than tau control mice, indicating that not all tau mice ate more wet food. Additionally, tau female control mice weighed significantly more than WT female control mice, a finding inconsistent with previous research [ 48 ]. Female WT mice consuming H. erinaceus weighed significantly more than female tau mice consuming H. erinaceus although tau female mice ate more wet food than WT female mice. This, again, may be due to the progression of the disease in the tau mouse model as suggested by past literature [ 48 ]. Male tau mice supplemented with H. erinaceus weighed significantly more than male WT mice consuming H. erinaceus although male mice given H. erinaceus ate less throughout the experiment. Ryu et al. (2018) [ 31 ] found that the H. erinaceus did not have effects on the natural weight gain of the mice. This could be due to differences perhaps in how the diet was given; Ryu et al. (2018) [ 31 ] administered H. erinaceus by oral gavage while mice in the current study received H. erinaceus as a powder mixed into wet food. Further research is warranted on the causes of these weight differences, as a result of H. erinaceus consumption as well as sex. Additionally, when studying the effects of dietary manipulation, including food consumption and mouse weight data can be advantageous for future researchers to consider.

The hericenones and erinacines in H. erinaceus may play a role in the neurocognitive benefits seen in this mushroom [ 11 , 15 ]. More specifically, researchers have found that erinacine A is the biggest contributor to these neurological benefits out of fifteen total erinacines (A–K, P, Q, R, S) [ 5 , 19 ]. Researchers have also found that hericenones C, D, and E contribute to the synthesis of NGF, while hericenone F can reduce inflammation [ 49 ]. Thus, these hericenones and erinacines may be responsible for the anxiolytic effects seen in this study and several others [ 11 , 17 ]. Additional research into these components of H. erinaceus is certainly warranted.

There have been multiple methods of administering H. erinaceus to WT mice. Ratto et al. (2019) [ 50 ] used 21.5-month-old male WT mice. The mushroom was administered as a drink mixed with He1 mycelium and sporophore, which were ethanol extracts able to be solubilized in water for the mixture. Mice drank this ad libitum for two months. Researchers found that H. erinaceus improved recognition memory in aging mice. Ryu et al. (2018) [ 31 ] used two-month-old male WT mice and administered either 20 or 60 mg/kg of H. erinaceus powder by oral gavage for four weeks. Mice received the powder by oral gavage four times a day. It was found that the mice receiving 60 mg/kg of H. erinaceus exhibited anxiolytic and antidepressant behaviors.

There have also been multiple methods of administering H. erinaceus to transgenic mice. Mori et al. (2011) [ 15 ] used five-week-old male ICR (Institute of Cancer Research) mice with injected amyloid peptides. Fruiting bodies of H. erinaceus were turned into powder and mixed with a standard powdered diet, allowing the concentration of H. erinaceus to be 5%. The mushroom was administered to mice ad libitum for 23 days. H. erinaceus helped to ameliorate memory deficits in mice by improving recognition memory in the NOR test but did not improve exploratory behavior or locomotor activity in the Y-maze assessment. Tzeng et al. (2018) [ 20 ] used five-month-old female APP/PS1 mice, isolating H. erinaceus mycelium erinacine A and H. erinaceus mycelium erinacine S to assess the effects of each. The mushroom was administered at 10 mg/kg and 30 mg/kg a day, respectively, to experimental condition, for 100 days by oral gavage. Results indicate that erinacine A recovered cognitive impairments in spatial memory and activities of daily living (burrowing and nesting) [ 20 ]. Tsai-Teng et al. (2016) [ 16 ] also used five-month-old female APP/PS1 mice. Researchers administered 300 mg/kg per day of the mushroom for 30 days by oral gavage, isolating H. erinaceus mycelium containing erinacine A and H. erinaceus ethanol extracts. Tsai-Teng et al. (2016) [ 16 ] found that H. erinaceus mycelium recovered behavioral deficits in transgenic mice during nesting assessments.

Discussing mushroom administration in past literature is important because numerous labs and researchers may not always use the same methods, and this may perhaps be why results differ. This is the first study to administer mushroom powder mixed into wet food ad libitum to mice, with a standard rodent diet also available for the mice to feed on ad libitum . The goal was to mimic voluntary dietary supplementation in humans and eliminate stress factors which might accompany administration through techniques such as oral gavage. In each study, different quantities of H. erinaceus mycelium and respective components of the mushroom were used. All studies showing behavioral improvements, including this study, used H. erinaceus mycelium. The results of this study indicate anxiolytic effects and increased locomotor activity, but no improvements in spatial memory and noncognitive behaviors. Thus, it is important to explore the effects of different doses, erinacines, and extracts on future models of AD, including those models solely expressing tau.

One limitation in this study was the administration of the wet food. Each cage was administered 150 g of wet food for the mice to eat ad libitum . Other studies assessing the effects of H. erinaceus on WT and AD mouse models have administered the mushroom by oral gavage [ 16 , 20 , 31 ]. However, we chose to allow mice to eat ad libitum to eliminate potential stress and more closely resemble humans’ voluntary consumption of food. Due to this type of administration, we were unable to calculate the exact amount of wet food consumed by each individual mouse. Instead, the amount of wet food consumed was calculated as an average (see Section 2.4.1 ). We also collected animals’ body weights throughout the course of the experiment every 8 days to assess maturation and whether food was being consumed.

Another limitation may be the rTg4510 mouse model itself. In this specific regulatable model, the P301L tau mutation and CaMKIIa promoter system result in progressive neurofibrillary tangle pathology within the forebrain and memory deficits over time, which can be lessened when given doxycycline [ 21 , 51 ]. However, as Gamache et al. (2019) [ 52 ] report, this phenotype may not be caused solely by the expressed tau. Gamache et al. (2019) [ 52 ] report that in this model, disruptions in genes, including fibroblast growth factor 14 (Fgf14) caused by insertion of the transgene itself may be responsible for the particular phenotypes reported. While this model still allows for researchers to assess tangle pathology and behavioral deficits as a function of age, when applying an intervention aimed at alleviating behavioral or biochemical deficits, researchers must consider other factors which may be causing the deficits in the first place, beyond simply the tau mutation.

This is the first study demonstrating that H. erinaceus has anxiolytic effects in the rTg4510 tau mouse model. Previous research has shown this in relation to amyloid and WT mouse models but has not demonstrated it in a strictly tau mouse model [ 11 , 16 , 50 , 53 ]. Many other studies have assessed the cognitive effects of H. erinaceus in other models of AD or cognitive decline/aging such as APP/swePS1dE9 [ 16 , 20 ], SAMP8 [ 54 ], ICR (Institute of Cancer Research) mice with injected amyloid peptides [ 15 ], and Sprague Dawley rats injected with d-galactose [ 44 ]. This is also one of the first studies to assess the effects of H. erinaceus on both female and male mice. Previous literature assessing the effects of H. erinaceus has only used either male [ 11 , 50 , 53 ] or female mice [ 16 ], and has not assessed both sexes, with the majority of studies primarily assessing the effects on male mice.

The effects of H. erinaceus on tau mouse models have not been as consistently analyzed as those in amyloid models. Because amyloid and tau both contribute to the development of AD, it is important to study both markers and note the behavioral differences found in each model. Research has shown that tau may be a stronger underlying factor in the development of AD than Aβ [ 55 ]. By studying the effects of H. erinaceus in this rTg4510 tau mouse model, we aim to help bridge the gap between results solely seen in amyloid models; these results provide new views on differences in behavior that can be seen when using amyloid vs. tau models.

Future biochemical assessments on the effects of H. erinaceus would be informative to help understand the mechanisms by which this mushroom improves behavior. Tsai-Teng et al. (2016) [ 16 ] assessed Insulin-degrading Enzyme (IDE), NGF, Glial Fibrillary Acidic Protein (GFAP), and APP through Western Blot analysis. Results showed that H. erinaceus increased IDE levels which ameliorated Aβ plaques, increased the ratio of NGF and proNGF, decreased levels of GFAP and, interestingly, did not affect levels of APP. Future research could use immunoblots to assess levels of tau species, SOD-1, GFAP, NGF, glucocorticoid, and BDNF in this tau mouse model. Analyzing these proteins could provide information about the mushroom’s effects on tau levels, oxidation, astrocyte activity and inflammation, fiber growth and survival, and maintenance of nerve cells. As the current study demonstrated anxiolytic effects of H. erinaceus in this tau mouse model, analyzing proteins such as glucocorticoid receptors could provide a more detailed connection between the brain and behavior.

5. Conclusions

Overall, this study demonstrated that supplementation of H. erinaceus through wet food for four months has anxiolytic effects on the rTg4510 tau mouse model but leads to no improvements in spatial memory nor activities of daily living. Although no improvements were found in spatial memory, the anxiolytic effects may serve a great benefit for caretakers or those living with AD seeking to add a supplement that can help lower anxiety.

Acknowledgments

We would like to thank the Angelo State University Psychology department and the Archer College of Health & Human Services for their support. We would also like to show our gratitude to Amy Howard who was the animal welfare/lab manager throughout this project. Additional thanks go to the third cohort of graduate students in the Experimental Psychology M.S. program (Abishag Porras, Garett Parrish, Amy Howard), Jisele Olivarez, and Psychology undergraduates (Kaitlyn Huizar, Cassidy Martin, and Danielle Mullen) who volunteered their time to assist with this research. We are additionally appreciative of Kristen Craven, who read over the manuscript prior to final submission.

Funding Statement

This research received no external funding.

Author Contributions

Conceptualization, M.N.R. and S.L.P.L.; methodology, M.N.R. and S.L.P.L.; formal analysis, M.N.R.; investigation, M.N.R.; data curation, M.N.R.; writing—original draft preparation, M.N.R.; writing—review and editing, S.L.P.L.; visualization, M.N.R. and S.L.P.L.; supervision, S.L.P.L. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

All procedures were approved by the Angelo State University Institutional Animal Care and Use Committee (IACUC) (protocol # 21-204) and were in accordance with the National Institutes of Health guide for the care and use of Laboratory animals.

Informed Consent Statement

Not applicable.

Data Availability Statement

Conflicts of interest.

The authors declare no conflict of interest.

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Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial

Affiliation.

• 1 Mushroom Laboratory, Hokuto Corporation, 800-8, Shimokomazawa, Nagano, 381-0008, Japan. [email protected]
• PMID: 18844328
• DOI: 10.1002/ptr.2634

A double-blind, parallel-group, placebo-controlled trial was performed on 50- to 80-year-old Japanese men and women diagnosed with mild cognitive impairment in order to examine the efficacy of oral administration of Yamabushitake (Hericium erinaceus), an edible mushroom, for improving cognitive impairment, using a cognitive function scale based on the Revised Hasegawa Dementia Scale (HDS-R). After 2 weeks of preliminary examination, 30 subjects were randomized into two 15-person groups, one of which was given Yamabushitake and the other given a placebo. The subjects of the Yamabushitake group took four 250 mg tablets containing 96% of Yamabushitake dry powder three times a day for 16 weeks. After termination of the intake, the subjects were observed for the next 4 weeks. At weeks 8, 12 and 16 of the trial, the Yamabushitake group showed significantly increased scores on the cognitive function scale compared with the placebo group. The Yamabushitake group's scores increased with the duration of intake, but at week 4 after the termination of the 16 weeks intake, the scores decreased significantly. Laboratory tests showed no adverse effect of Yamabushitake. The results obtained in this study suggest that Yamabushitake is effective in improving mild cognitive impairment.

(c) 2008 John Wiley & Sons, Ltd.

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News | African lion cub, Lomelok, euthanized at…

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News | African lion cub, Lomelok, euthanized at Lincoln Park Zoo after slow recovery from spinal surgery

Visitors brave the rain and dreary weather to see the three young cubs lounging with their father, Jabari, and other lions on heated rocks on, May 1, 2023, at Lincoln Park Zoo. The cubs turned 4 months old on May 9. (Brian Cassella/Chicago Tribune)

One of the young lion cubs bathes his brother Pilipili on May 1, 2023, at Lincoln Park Zoo. Cassella/Chicago Tribune)

Visitors brave the rain on a dreary spring day to see the lions, including three young cubs, lounging on heated rocks on May 1, 2023, at Lincoln Park Zoo. The cubs turned four months old on May 9. (Brian Cassella/Chicago Tribune)

Several of the lions, including the young cubs, watch visitors brave the rain and dreary weather on May 1, 2023, at Lincoln Park Zoo. (Brian Cassella/Chicago Tribune)

Shanna Madison / Chicago Tribune

Three lion cubs make their debut at the Pepper Family Wildlife Center on April 14, 2023, at the Lincoln Park Zoo in Chicago.

The first of three cubs gingerly enters the enclosure alongside its mother, Zari, for first time at the Pepper Family Wildlife Center on April 14, 2023, at the Lincoln Park Zoo. The cubs, all males, were born at the zoo Jan. 9 but have stayed behind the scenes, zoo officials said, with minimal human intervention. Three 3-month-old cubs named Pesho, Sidai and Lomelok will be on view to the public and exploring their habitat beginning April 15.

Lion cubs explore their new home at the Pepper Family Wildlife Center on April 14, 2023, at the Lincoln Park Zoo.

A child watches as three lion cubs are introduced to the Pepper Family Wildlife Center at the Lincoln Park Zoo.

Lion cubs explore their new home at the Pepper Family Wildlife Center at the Lincoln Park Zoo.

Jabari, the father of the three cubs, walks around the Pepper Family Wildlife Center on April 14, 2023, at the Lincoln Park Zoo.

People watch three lion cubs make their debut at the Pepper Family Wildlife Center on April 14, 2023, at the Lincoln Park Zoo in Chicago.

A lion cub explores its new home at the Pepper Family Wildlife Center.

Lomelok was born with a spinal defect that’s caused mobility challenges since he was a few weeks old, zoo officials said. He had an operation in March — the first of its kind on a lion cub — to reduce his pain and treat a herniated disc. 

Lomelok’s recovery from the surgery was “slow and steady,” officials said, but he wasn’t “thriving” as he should. When veterinary staff detected a gastrointestinal obstruction that would have required another intensive surgery and a lengthy recovery, they made the “difficult but responsible decision” to euthanize Lomelok on Saturday. 

“We have been overwhelmed by the support from the community for Lomelok throughout his health journey,” said Cassy Kutilek, the curator of mammals, in a Monday news release. “Lomelok’s name means ‘sweet’ in the Maa language, and that was the best way to describe him. There are no words to articulate how deeply he will be missed.”

Lomelok, who was roughly 2 pounds at birth , grew to more than 250 pounds. Zoo officials said he had started growing a thick adolescent mane. One of his favorite activities, officials said, was laying upside down and showing his white belly fur. His care team is “still processing this incredibly tough loss,” a zoo spokesperson said. 

Lomelok and his two brothers, Pesho and Sidai, were born Jan. 9, 2023, at the Pepper Family Wildlife Center. His mother, Zari, gave birth after five hours of labor, earning her the title of “rock star” among zoo staff. 

Lomelok’s family also included his older brother, Pilipili, his father, Jabari, and aunts Hasira and Cleo. Both of Zari’s pregnancies were part of the African Lions Species Survival Plan, a population management effort across accredited zoos within the Association of Zoos and Aquariums.

Zari “immediately attended to the cubs, started grooming them, and then, within hours of their birth, she started nursing them and feeding them,” the zoo’s curator of mammals and behavioral husbandry Mike Murray told the Tribune after the three cubs’ birth. 

After some private time with little human intervention, the cubs made their public debut in April 2023, with much fanfare . Pictures and videos of Lomelok’s young life, from his birth to his first playful steps in a new home to his antics with a tree , circulated across the internet. 

When Lomelok started to grow, staff were concerned about his rear limbs and lower-than-normal activity levels. He was eventually diagnosed with stenosis, which zoo officials said is the narrowing of channels that carry nerves from the spine to the legs.

“You can think of the spinal cord as a highway, carrying nerve signals from your brain out to the rest of your body,” Lomelok’s veterinarian Dr. Kate Gustavsen said in March. “Between every set of vertebrae, there are exits that the nerves leave from.”

“In Lomelok’s case, the last two exits all the way at the end of the highway have a lane closed in each direction — they’re too narrow, everybody’s irritated, the traffic is moving slowly,” she continued. “That’s causing what we see physically as his muscles not developing completely appropriately and him being clumsy in his gate, and it also causes some discomfort.”

Spinal conditions in the wild

In the wild, it’s unlikely that Lomelok would have survived very long with this condition, according to Craig Packer, a professor at the University of Minnesota and director of the Lion Research Center. 

When a lion is small, its mother carries it in its mouth with its teeth around its nape. But as the cub ages, the mother would have stopped carrying it, he said. Packer estimated that Lomelok had at least an extra year of life because of his care in captivity. 

“That cub would have been left behind. That cub would have either starved to death or been killed by a leopard or hyena or another lion from a neighboring pride,” Packer said. “So that animal had a much longer life than you ever would have seen in the wild.” 

The challenges of surviving with this condition in the wild make it hard to know how common spinal birth defects are in lions, Packer said. Mothers keep their cubs hidden for the first few weeks of their lives, and he said some research suggests they will abandon one member of their litter. 

“I’m not saying they are deliberately leaving behind disabled cubs, but I can’t say that’s impossible,” he said. “We have some evidence that they don’t always keep every single one of their cubs.” 

The opportunity to see Lomelok, or any lion cub, in a zoo is a fairly rare treat because zoos have to carefully control breeding, Packer said. 

“If you had a female lion who had the maximum number of surviving cubs, which would be four, and they can start breeding especially in captivity by the time they’re just a little over 2 years old, after about 37 years, the descendants would need to eat the population of Chicago every week,” Packer said. 

“You can’t let them breed at their maximum, so it’s a special thing in captivity,” he added.

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