What randomized studies describe clinical benefits of Lion's mane (Hericium erinaceus)?

Comment by InpharmD Researcher

Lion’s mane (Yamabushitake; Hericium erinaceus) supplementation has been studied in a plethora of clinical scenarios, including cognitive function, metabolic performance, mood disorders, and gastrointestinal issues. However, doses and durations, tested regimens, time to follow-up, and measured outcomes vary drastically, while sample sizes are small, limiting the ability to translate findings in a clinically meaningful way.

Background

A 2014 review article discusses Hericium erinaceus (HE) and its potential therapeutic effects on various physiological systems. Regarding its effects on the nervous system, it is suggested that HE operates through two primary mechanisms. Firstly, it supports the growth and development of neurons and related structures. For instance, extracts from HE have been observed to enhance neurite outgrowth in different cell cultures and promote the normal development of cerebellar cells. Additionally, HE has been noted to influence neuronal functions relevant to neurodegenerative conditions such as Alzheimer’s disease (AD), depression, anxiety, and cognitive impairment. Studies also suggest that HE may potentially mitigate impairments associated with AD and alleviate symptoms associated with mood and cognitive function. In terms of its effects on the digestive system, HE has demonstrated the potential to inhibit the growth of Helicobacter pylori, a bacterium known for causing chronic gastritis and peptic ulcers. HE extracts have been observed to protect against gastric mucosal damage and edema, and provide cytoprotection against ethanol-induced gastric ulcers in animal models. [1]

HE is also suggested to positively influence liver function by reducing hepatic triacylglycerol levels and protecting against chemically-induced liver damage. Furthermore, HE has demonstrated inhibitory effects on the proliferation of vascular smooth muscle cells, suggesting potential implications for vascular health. Regarding the immune system, it is suggested that HE exhibits antioxidant properties that address oxidative stress, enhance dendritic cell maturation, activate natural killer cells, and modulate cytokine production to manage inflammation. HE extracts have also shown promise in research related to cancer by reducing MMP-2 and MMP-9 expression, and by influencing apoptosis-related signaling pathways in cancer cells. Overall, it is suggested that HE shows potential in the treatment of various diseases affecting multiple physiological systems. [1]

Another review article, published in 2019, describes the therapeutic potential of HE specifically for depressive disorders. HE has been extensively explored in several neurological diseases; however, the authors emphasize a gap in literature on its use in mental disorders. Notably, a 2010 study (see Table 6) assessed the effects of HE on menopausal symptoms, depression, sleep quality, and general complaints in 30 female patients using cookies containing powder from HE fruiting bodies. The findings revealed alleviation of symptoms such as depression and anxiety. However, the study's focus on female patients and its small sample size may potentially limit the generalizability of its conclusions. A case report discussed improvement in neurocognitive function with HE extract Amyloban® 3399 in an elderly male patient with depressive disorder, although it was noted that concomitant antidepressant medication may have confounded the assessment of HE's direct effects. [2], [3], [4]

Additionally, a pilot study suggested HE's potential in enhancing anxiety and sleep quality among female students; however, the study's small, specific study group and situational factors may limit applicability to other patient populations. Furthermore, a study evaluating overweight or obese participants demonstrated that HE significantly reduced depression, anxiety, and sleep disorders, potentially linked to increased peripheral pro-BDNF levels; nonetheless, it remains unclear whether these results were influenced by a placebo effect from capsule consumption. Overall, research into the antidepressant effects of HE is considered to be in its early stages, and further investigation is needed to elucidate the specific mechanisms responsible for its antidepressant-like activities. [2], [3], [4], [5]

Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the clinical benefit of lion's mane?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-6 for your response.

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
Design	Double-blind, parallel groups, pilot study N= 43
Objective	To investigate the acute (60-minute dose) and chronic (28-day) cognitive and mood-enhancing effects of lion's mane mushrooms (HE) in a healthy, young adults
Study Groups	Lion's mane (n= 22) Placebo (n= 21)
Inclusion Criteria	Healthy patients aged 18-45 years
Exclusion Criteria	Current use of prescription medication; pre-existing diagnosed medical condition; diagnosed neurological condition; visual impairment that cannot be corrected with glasses or contact lenses; food allergies/intolerances/sensitivities to any ingredients in the study products; pregnant or lactation
Methods	Participants were then randomized to receive either lion's mane mushroom 1.8 g (three 600 mg capsules) or placebo (microcrystalline cellulose) administered daily after breakfast for 28 days. The first and last doses of the treatment plan were administered under laboratory supervision and the intermediate doses being self-administered at home. Participants attended four appointments as part of the study protocol: a remote screening session via telephone, a training visit, and two testing visits. Following the telephone screening, eligible participants attended a training visit where they received instruction on the cognitive tasks and mood assessment scales to ensure they understood the task instructions and test procedures.
Duration	Data collection: Between April and July 2023 Intervention: 28 days
Outcome Measures	Cognitive and mood assessments
Baseline Characteristics		Study population (N= 43)
	Age, years	26.35 ± 6.12
	Female	23 (53.5%)
	Race White Black Asian Other	29 (67.4%) 3 (6.9%) 6 (13.9%) 5 (11.6%)
	Blood pressure Systolic, mmHg Diastolic, mmHg	120.53 ± 12.62 76.82 ± 8.68
	Heart rate, beats/min	74.45 ± 13.64
	Body mass index, kg/m²	24.02 ± 3.42
Results	Endpoint	Lion's mane (n= 22)	Placebo (n= 21)	p-Value
	Mean subjective stress score on Day 29	4.914	42.53	0.033
	One dose of Hericium erinaceus resulted in quicker performance on the Stroop task at 60 minutes post-dose (p= 0.005). A trend towards reduced subjective stress was observed after 28-day supplementation (p= 0.051). There was also a trend towards a significant reduction in stress scores on Day 29 for the lion’s mane group (mean 33.02) compared to Day 1 (mean 40.64; p= 0.055). A significant treatment × timepoint interaction was observed for delayed word recall accuracy (p= 0.027), with the placebo group recalling significantly more words on Day 29 compared to Day 1 (p< 0.001). There was a trend towards a significant interaction effect for the episodic memory factor, though planned comparisons showed no significant differences between treatments during either assessment.
Adverse Events	N/A
Study Author Conclusions	Lion's mane may improve speed of performance and reduce subjective stress in healthy, young adults.
InpharmD Researcher Critique	Despite the findings, the small sample size may limit the generalizability of the results. It was also suggested that the cognitive assessment utilized in this trial may not have been demanding enough to detect subtle behavioral changes, further limiting the robustness of the conclusions.

References:

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. Published 2023 Nov 20. doi:10.3390/nu15224842

Improvement of cognitive functions by oral intake of Hericium erinaceus
Design	Randomized, double-blind, placebo-controlled parallel-group trial N= 34
Objective	To evaluate the improvement of the cognitive functions by taking the supplement containing Hericium erinaceus (HE) for 12 weeks
Study Groups	HE (n= 16) Placebo (n= 15)
Inclusion Criteria	Healthy Japanese patients >50 years old
Exclusion Criteria	Regularly used other functional foods, drugs, or supplements with similar effects to those being tested; initiated the use of any health foods within the four weeks prior to the study; required medical treatments; had a history of severe disorders; pregnant or lactating
Methods	Patients were randomly assigned to either the HE group (4 HE supplements daily) or the placebo group (4 placebo pills daily). Each HE supplement contained 0.8 g of powdered fruiting body of HE, while the placebo did not contain any HE powder. Cognitive function improvement was assessed using three methods: Mini-Mental State Examination (MMSE), Benton visual retention test, and standard verbal paired-associate learning test. Tests were conducted three times (ex-ante, interim, and ex-post evaluations) at 6-week intervals. Participants recorded daily supplement intake and reported progress every four weeks.
Duration	Intervention: 12 weeks
Outcome Measures	Improvement in cognitive function
Baseline Characteristics		HE (n= 16)*	Placebo (n= 15)*
	Mean age, years	61.8	60.8
	Female	10	10
	*Three out of 34 participants were excluded.
Results	Endpoint	HE (n= 16)*	Placebo (n= 15)*	p-Value
	MMSE mean total score: ex-ante	29.19	28.73	0.462
	MMSE mean total score: interim	29.63	29.13	0.310
	MMSE mean total score: ex-post	30.00	29.53	0.0328
	Benton visual retention test mean score: ex-ante	6.88	6.80	0.922
	Benton visual retention test mean score: interim	6.25	6.40	0.806
	Benton visual retention test mean score: ex-post	7.13	7.00	0.850
	Abbreviations: Mini-Mental State Examination *Results from three out of 34 participants were excluded. Standard verbal paired-associate learning test (S-PA) initially showed slightly higher values in the HE group compared to the placebo group. However, throughout the experiment, there were no statistically significant changes observed in either group or between groups. For all 3 tests, no difference was found in each test between the groups at each time point, except for increased orientation to time (MMSE) in the HE group ex-post (5 vs 4.73, p= 0.0824). Time to change of the two groups (ANCOVA) with age amendment resulted in significant improvement MMSE scores at 12 weeks in HE group vs placebo group (p= 0.029); but these findings were not consistent with Benton visual retention test and S-PA.
Adverse Events	N/A
Study Author Conclusions	MMSE alone showed that oral intake of H. erinaceus significantly improved cognitive functions and prevented from the deterioration.
InpharmD Researcher Critique	While the results showed significant findings for MMSE, limitations such as the small sample size and the inclusion of only healthy Japanese patients may restrict generalizability.

References:

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. doi:10.2220/biomedres.40.125

Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial
Design	Prospective, double-blind, parallel-group, placebo-controlled trial N= 30
Objective	To examine the efficacy of oral administration of Yamabushitake in patients diagnosed with mild cognitive impairment, using a cognitive function scale based on the Revised Hasegawa Dementia Scale (HDS-R) as an indicator
Study Groups	Yamabushitake (n= 15) Placebo (n= 15)
Inclusion Criteria	Japanese patients aged 50-80 years; diagnosed with mild cognitive impairment; scores of 22-25/30 on the HDS-R
Exclusion Criteria	Not described
Methods	Patients were randomized to take four Yamabushitake-containing or placebo tablets TID for 16 weeks; the tablets were 250 mg containing 96% Yamabushitake. Use of donepezil was restricted during the trial, as were other drugs that may improve cognitive impairment via cerebral blood flow increase (e.g., meclofenoxate, ibudilast, etc.) and foods that may affect cognitive impairment (e.g., ginkgo leaf extract) or contain a large amount of docosahexaenoic acid (DHA).
Duration	22 weeks
Outcome Measures	Degree of cognitive impairment, laboratory tests
Baseline Characteristics		Yamabushitake (n= 15)	Placebo (n= 15)
	Weight, kg	54.49 ± 11.40	61.15 ± 13.74
	Body mass index, kg/m²	22.65 ± 3.58	23.60 ± 3.67
	Both groups were similar in scores on the cognitive function evaluation scale determined in the preliminary examination and age (data not provided).
Results	Endpoint	Yamabushitake (n= 14)*	Placebo (n= 15)
	Cognitive scores Notably improved (≥3-point increase) Improved (2-point increase) Unchanged (score shift of -1, 0, or 1) Worsened (≥2-point decrease)	10 (71.4%) 3 (21.4%) 1 (7.1%) 0	1 (6.7%) 1 (6.7%) 13 (86.7%) 0
	* One Yamabushitake subject discontinued the trial due to stomach discomfort at 4 weeks. Scores of cognitive function scale between groups, as well as individual cognitive function scale score of the groups, are depicted in figures. There are significant between-group and between-period differences in scores on the cognitive function scale; the Yamabushitake group showed significant improvement in scores as duration of intake increased, but the scores decreased significantly during the 4 weeks after termination of the 16-week period. Meanwhile, the placebo group showed significantly increased scores at week 16.
	The placebo group showed significant within-group variations in systolic blood pressure, aspartate aminotransferase (GOT), lactate dehydrogenase, high density lipoprotein cholesterol, and serum chloride, while the the Yamabushitake group showed significant within-group variations in creatinine, serum Na, and serum K, albeit within normal limits. Both groups showed significant between-group differences in total cholesterol at trial start, in uric acid at week 16, and in creatinine at start and week 16, but these values were within the normal range.
Adverse Events	Seven subjects and six subjects of the Yamabushitake and placebo groups, respectively, reported mild stomach discomfort and diarrhea that required no treatment.
Study Author Conclusions	Consequently, Yamabushitake can be regarded as a useful food for the prevention of dementia without any adverse effects. This effect may be attributed to promoting NGF by hericenones, but further studies are needed to clarify the mechanism.
InpharmD Researcher Critique	Patients were clinically healthy, with no other comorbidities aside from their cognitive impairment. At the peak of treatment in which significant differences in cognitive scores were found, the figure depicts a four-point difference; the minimum clinically important difference for this scale is uncertain. These findngs may not be applicable to a larger patient population with more severe clinical presentations, other ethnic groups, or younger patients.

References:

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):367-372. doi:10.1002/ptr.2634

Acute Effects of Naturally Occurring Guayusa Tea and Nordic Lion's Mane Extracts on Cognitive Performance
Design	Randomized, double-blind, placebo-controlled, crossover study N= 40
Objective	To assess the effects of guayusa extract and Nordic Lion’s Mane on cognition
Study Groups	Lion's Mane (n= 40) Guayusa (n= 40) Placebo (n= 40)
Inclusion Criteria	Age 18- 50 years; healthy; body mass index (BMI) of 18.5–39.9 kg/m²; consume ≤ 240 mg of caffeine per day
Exclusion Criteria	History of diabetes or pre-diabetes, hepatorenal, musculoskeletal, autoimmune, or neurologic disease; history of malignancy in the previous 5 years; prior gastrointestinal bypass surgery; history or current diagnosis of any mental disorders; used corticosteroids or testosterone replacement therapy; pregnant or nursing
Methods	Participants were randomized to receive a single dose of Nordic Lion's Mane 1 g, guayusa extract 650 mg, or placebo during three separate testing visits with neuropsychological tests and cognitive assessments completed 1 and 2 h post-ingestion. Participants consumed the supplement in the laboratory following their baseline testing, under the supervision of research staff.
Duration	Testing visits: Maximum of 7 days between each visit
Outcome Measures	Neuropsychological assessments, hemodynamics, and adverse events
Baseline Characteristics		Study population (N= 40)
	Age, years	34.0 ± 9.5
	Height, cm	171.8 ± 11.8
	Weight, kg	79.1 ± 16.2
	BMI, kg/m²	26.6 ± 3.6
	Systolic blood pressure, mmHg	118.3 ± 11.7
	Diastolic blood pressure, mmHg	75.6 ± 8.5
	Resting heart rate, beats/min	67.1 ± 12.0
Results	Lion's mane significantly improved reaction time at both time points. Subject rating of "happiness compared to peers" (p< 0.05) and "getting the most out of everything" (p< 0.05) were significant 1 h post ingestion for the lion's mane treatment group. The same group's overall heart rate was significantly reduced at 60 (p< 0.001) and 120 min (p< 0.001) from baseline. These findings were provided within figures.
Adverse Events	No adverse events were reported during the Lion's mane trial
Study Author Conclusions	Lion's mane helped improve working memory, complex attention, and reaction time 2 h post ingestion and perceptions of happiness over a 2 h period. Although this study shows that continuous intake of LM is not necessary to stimulate positive cognitive benefits, a longer duration or higher doses of LM use may be needed to remodel nerve structures in the brain and potentially provide even greater effects acutely and/or chronically
InpharmD Researcher Critique	While improvements were noted specifically during the lion's mane trial, findings may potentially be confounded by guayusa due to the crossover nature of the study. Additionally, the small sample size limits the generalizability of these results.

References:

La Monica MB, Raub B, Ziegenfuss EJ, et al. Acute Effects of Naturally Occurring Guayusa Tea and Nordic Lion's Mane Extracts on Cognitive Performance. Nutrients. 2023;15(24):5018. Published 2023 Dec 6. doi:10.3390/nu15245018

Four Weeks of Hericium erinaceus Supplementation Does Not Impact Markers of Metabolic Flexibility or Cognition
Design	Single-blind, placebo controlled, parallel-longitudinal study N= 24
Objective	To examine the effects of a 4-week Hericium erinaceus (HE) supplementation period on markers of metabolic flexibility (i.e., changes to substrate oxidation rates) with a secondary aim to examine potential changes to markers of cognition, pre-post a fatiguing graded exercise test in a college-age cohort
Study Groups	HE (n= 12) Placebo (n= 12)
Inclusion Criteria	Met the American College of Sports Medicine qualifications for aerobic activity per week (i.e., 150 min of moderate-intensity or 60 min of vigorous-intensity); had not consumed HE in the previous two weeks in any form; were currently weight stable (± 2.5 kg) for at least one month prior to the start of the study
Exclusion Criteria	Not described
Methods	Patients were stratified into the HE or placebo group based on absolute fat oxidation rates (g/min) after visit 2, after which each patient was provided 2 muffins (1 muffin= ~340 kcal) to consume daily in the morning and evening for a total of 4 weeks. Patients in the HE group received an additional 10 g of HE in the muffins (5 g/muffin). All muffins were baked by the lead investigator prior to weekly distribution. HE samples included a 1:1 ratio of dried mushroom:extract supplement (33.69% volume of beta-[1,3][1,6]-glucans). Alcohol and caffeine were to be avoided 24 h prior to each experimental session, in which markers of body composition and metabolic flexibility were tested.
Duration	4 weeks
Outcome Measures	Primary: Metabolic flexibility markers Secondary: Cognition markers
Baseline Characteristics		HE (n= 12)	Placebo (n= 12)
	Age, years	22.3 ± 3.2	21.8 ± 2.7
	Female	8 (67%)	6 (50%)
	Weight, kg	72.6 ± 18.1	74.0 ± 13.0
	Body fat, %	21.4 ± 8.9	19.3 ± 7.3
Results	No significant differences for either group were found in macronutrients or overall caloric load pre-post intervention. Similarly, there were no no significant interactions, main effects, or condition effects for body fat percentage or body mass. Data for fat oxygenation and carbodydrate oxygenation rates are depicted in figures. There were significant decreases to fat oxidation rates across each stage pre- and post-supplementation. There were significantly higher rates of carbohydrate oxidation with placebo bersus HE (p< 0.01).
	No significant group × stage × condition, group × condition, or group × stage interactions were noted in carbohydrate oxidation, fat oxidation, VO2peak, VCO2, RER, HR, RPE, or blood lactate concentration, though variation in effects were noted between groups. No significant group × timepoint × condition, group × condition, or group × timepoint were noted for SCW tests or unanswered questions, nor distance reach for anterior, posterior lateral, and posterior mediolateral directions.
Adverse Events	Not disclosed
Study Author Conclusions	In conclusion, the ingestion of 10 g/day of HE for 4-weeks did not elicit any statistically significant changes to markers of metabolic flexibility or cognition in a college-age cohort. Provided that this is only the fifth study to evaluate the effects of HE in humans, and the first to examine metabolic changes or markers of cognitive performance, the outcomes and duration of HE ingestion are still not well understood. Until a standard HE supplementation duration or dosage is established, evaluating changes among studies will remain difficult; therefore, future studies which aim to establish a minimal effective dose or which attempt to elicit mechanistic changes from HE ingestion in humans are warranted.
InpharmD Researcher Critique	Adverse events with supplementation were not studied; thus, HE's safety profile in humans is still uncertain. The small sample size of healthy college-age volunteers and use of HE supplementation via personally-baked goods limit generalizability to other population subgroups. Dose and duration selected may not be sufficient to reveal metabolic changes, although taste inconsistencies may have unmasked the treatment arms. Use of biomarkers does not preclude clinical significance.

References:

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. Published 2022 Oct 1.

Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake
Design	Prospective, randomized, double-blind, placebo-controlled trial N= 30
Objective	To investigate the clinical effects of H. erinaceus (HE) on menopause, depression, sleep quality and indefinite complaints, using a variety of questionnaires; the Kupperman Menopausal Index (KMI) for menopause, the Center for Epidemiologic Studies Depression scale (CES-D) for depression, the Pittsburgh Sleep Quality Index (PSQI) for sleep quality, and the Indefinite Complaints Index (ICI) for indefinite complaints
Study Groups	HE (n= 12) Placebo (n= 14)
Inclusion Criteria	Female participants with menopause, depression, sleep quality, and indefinite complaints
Exclusion Criteria	<75% intake of test samples; epimenorrhea
Methods	Participants were randomized to either HE cookies, containing 0.5 g of HE, or placebo cookies for four weeks, with a total of four cookies per day. Report forms were filled out by each participant on intake, physical condition, and psychometric measures pre- and post-trial.
Duration	4 weeks
Outcome Measures	Effects of supplementation on menopause, depression, sleep quality and indefinite complaints
Baseline Characteristics		HE (n= 12)	Placebo (n= 14)
	Age, years	41.3 ± 5.6	38.4 ± 4.9
	Body mass index, kg/m²	20.9 ± 2.6	22.0 ± 3.7
	Clinical events Alcohol Cigarette smoking Stress events Menorrhea	25% 17% 25% 17%	50% 7% 21% 21%
	Index scores KMI CES-D PSQI ICI	16.5 ± 10.2 13.9 ± 7.8 6.3 ± 2.3 46.1 ± 23.4	17.1 ± 8.1 15.1 ± 9.6 6.2 ± 2.6 40.4 ± 17.5
	Four participants were excluded: two who took cookies <75% of the total, 1 who reported epimenorrhea (18 days menorrhea/month), and 1 who sent no report.
Results	Endpoint	HE (n= 12)	Placebo (n= 14)	p-value for HE groups*
	Index scores KMI CES-D PSQI ICI	11.2 ± 6.2 10.3 ± 7.3 6.0 ± 2.7 29.6 ± 21.5	11.1 ± 9.9 12.6 ± 9.3 6.4 ± 2.7 31.6 ± 22.3	0.090 0.033 N/A 0.004
	* p-value for pre- and post-intervention; comparison between groups for all indices were non-significant. Data for mean incides scores of HE and placebo groups pre- and post-intervention are depicted in figures. For statistical significance of each subscale on ICI index, "palpitation" and "insensitive" had significantly lower scores with HE versus placebo (p= 0.032 and p= 0.047, respectively). For "irritating," "anxious," and "concentration," HE participants had lower scores than placebo, but differences were non-significant.
Adverse Events	Not disclosed
Study Author Conclusions	As seen above, our results show that H. erinaceus intake has the possibility to reduce depression and anxiety. And it is still relevant to frustration and palpitation because H. erinaceus intake lowers each score of the terms, "frustrating" and "palpitation". These results suggest a different mechanism from NGF-enhancing action of H. erinaceus. To understand the mechanism, additional research in connection with other physiological markers such as autonomic nerve activities and hormones is needed.
InpharmD Researcher Critique	This was a small study that likely lacked power and the ability to detect a difference. Use of questionnaires to determine the effect of HE supplementation does not signify clinically meaningful differences.

References:

Nagano M, Shimizu K, Kondo R, et al. Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res. 2010;31(4):231-237. doi:10.2220/biomedres.31.231