All About: Nootropics

Nootropics are drugs, supplements, or foods and beverages that might improve cognitive functioning, including analytical functions, focus, mood, memory, creativity, and motivation. They are also known colloquially as smart drugs or cognitive enhancers (or cognitive ‘boosters’). There are several drugs that are purported to improve memory and cognition, but increasing attention is being paid to nutritional supplements, herbs, and mushrooms that might improve mental functioning.

Nootropics fall under the umbrella of supplements which, although there may be some benefits to long-term brain health, are primarily designed to improve mental functioning to a better-than-normal state in the short-term, rather than treating a specific pathology or designed to improve function in the future, although commonly the same ingredients can accomplish several of these goals.

Nootropics are supplements designed to improve mental functioning to a better-than-normal state

Purported common nootropics

• Acetylcholine precursors (such as lecithin/phosphatidylcholine and citicoline)
• Acetyl-L-carnitine
• Astaxanthin
• Brahmi (Bacopa monnieri)
• Caffeine and other compounds from coffee, tea, and cocoa
• Ginkgo biloba
• Panax ginseng
• Multivitamins and minerals
• Sage (Salvia officinalis)
• Spearmint
• Lipids (especially DHA from fish oil and medium-chain triglycerides)
• Fungi (especially Hericium erinaceous – Lion’s Mane)

These nootropics are common either as foods, supplements, or traditional medicines with a long history of use, but do they work?

Acetylcholine precursors

Acetylcholine was the first neurotransmitter identified by scientists and is the most abundant neurotransmitter in the peripheral, autonomic, and enteric nervous systems.¹ It is commonly referred to as the ‘mind to muscle link’ because it is the major neurotransmitter involved in signalling the muscles of the body to fire. It is also a major neurotransmitter in the brain, and it has been suggested that it is a key chemical for cognition and mental processes. A reduction in choline has been observed in the brains of people with Alzheimer’s disease. While phosphatidylcholine from lecithin has been shown to reliably increase acetylcholine levels in mice,² reviews of the available research (consisting of two randomised trials) have suggested that lecithin doesn’t improve cognition in Alzheimer’s patients.³ However, citicoline (an intermediate in the creation of phosphatidylcholine from choline) is likely to improve cognition in both dementia patients and healthy people.³

Citicoline is likely to improve cognition in both dementia patients and healthy people

Acetyl-L-carnitine

Acetyl-carnitine is a naturally occurring substance formed in cells when an acetyl group is added to carnitine. Carnitine (created from the amino acid lysine) aids the transport of fatty acids into the mitochondria to be used for energy. Acetyl-carnitine is more easily absorbed and can cross the blood-brain barrier more easily than L-carnitine. Acetyl-L-carnitine has been shown to reduce fatigue, anxiety and depression, and age-related cognitive defects.³

Acetyl-L-carnitine has been shown to reduce fatigue, anxiety and depression, and age-related cognitive defects

Astaxanthin

Astaxanthin is a red-orange carotenoid found mostly in several species of krill, shrimp, algae, and some lichen. Early research suggests that taking an astaxanthin supplement (6mg astaxanthin and 10mg sesamin) daily for 12 weeks could improve psychomotor speed and processing speed in people with mild cognitive impairment.⁴

Bacopa monnieri

Bacopa monnieri (water hyssop, brahmi, Indian pennywort) is a perennial creeping herb native to India, Australia, Europe, Africa, Asia, and the Americas. It is a traditional Ayurvedic medicinal herb with use as a cognition and memory enhancer.⁵ Several studies have demonstrated the potential for brahmi to improve cognition. It is thought to do so by antioxidant neuroprotection, increasing choline, reducing β-amyloid, increased cerebral blood flow, and by modulating neurotransmitters such as acetylcholine, serotonin, and dopamine.⁵ In a 2008 randomised controlled trial, 160 mg brahmi extract (equivalent to 4 g dried herb)  given to volunteers for 90 days, resulting in significant improvements to memory accuracy.⁶ A recent (2014) meta-analysis has summarised the findings from nine existing studies (437 participants), showing improved cognition and reaction times.⁷

Caffeine

Caffeine is a well-known cognitive enhancer. Reviews of the evidence show that caffeine improves attention, vigilance, reaction times, and problem-solving (especially in sleep-deprived people).^{8, 9}

Caffeine improves attention, vigilance, reaction times, and problem-solving

Large scale reviews of the evidence show significant benefits from caffeine for positive mood and lower perceived fatigue. Doses of 12.5 mg up to 400-600 mg (<1 to 4-6 cups per day of coffee) provide a positive effect,^{9, 10} however, greater doses do not always provide greater benefits to cognition and mood, and typically, the first cup provides the majority of benefits.¹⁰ Interestingly, habitual users appear to experience greater cognitive or mood effects compared with low/non‐users.¹⁰

Tea and coffee both produce similar benefits to mood and cognition.¹⁰ In addition to its acute effect on mood and cognition, caffeine-containing beverages may be protective against cognitive decline and dementia. ¹¹

Other constituents from tea

Tea constituents other than caffeine (L-theanine and epigallocatechin gallate) might also improve cognition. A review of the research in this area suggested that caffeine combined with theanine (as found in tea) improved alertness and attention more than caffeine alone. ¹²

Ginkgo biloba

Ginkgo (the maidenhair tree) is one of the most ancient species of tree in existence and has a long history of use in traditional medicine and as a food.

While the use of Ginkgo is extremely common for cognitive improvements, several earlier reviews have found no convincing evidence from randomised trials for a meaningful effect on cognition from ginkgo.^{13, 14} A 2009 Cochrane Database review concluded, “Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo.” But the “evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.” ¹⁵

However, more recent (2014 & 2016) reviews suggest a more positive role for ginkgo extracts for cognition in cognitive decline. In a review of nine trials, it was concluded that ginkgo extract at a dose of 240 mg/day is “able to stabilize or slow decline in cognition, function, and behaviour” in cognitive impairment and dementia, especially for patients with neuropsychiatric symptoms.¹⁶ In a review of 21 trials with 2608 patients, Ginkgo biloba (in combination with conventional medicine) was superior in improving Alzheimer’s and cognitive impairment scores (at 24 weeks) to control.¹⁷

Ginseng

Ginseng is the root of the Korean Ginseng (Panax ginseng) plant. This root has a long history in traditional medicine as an anti-stress and nervous ‘tonic’ purported to improve cognition. Studies have suggested that ginseng might improve cognitive performance,¹⁸ and this effect could be related to one of the known effects of ginseng, which is to help modulate blood sugar levels.^{19, 20} While other studies show a trend towards improved cognition from ginseng, a lack of consistency among studies reduces the ability to draw conclusions from them as a whole.²¹

Ginseng/Ginkgo combination

The use of ginseng and ginkgo in combination has also been studied in healthy adults. A dose-dependent effect on memory was found (320-960 mg of combination vs placebo).²²

Multivitamins

In an 8-week placebo-controlled trial, a standard over-the-counter multivitamin and mineral supplement resulted in significant improvements to contextual recognition and memory performance. Similarly, in a study of school-age children in India, 5 out of 7 memory tests were improved significantly for those taking a multi- versus control.²³ In a study of healthy women over 50, it was found that even a single dose of a multivitamin reduced depression and anxiety, and stress scores several hours after supplementation.²⁴

Sage

Sage or Salvia officinalis is a perennial, evergreen herb common in culinary and medicinal tradition. Sage contains a large array of compounds that may have cognitive effects including caffeic acid, rosmarinic acid, salvianolic acids, sagecoumarin, lithospermic acid, sagerinic acid, yunnaneic acids, luteolin, apigenin, hispidulin, kaempferol, quercetin, a and b-thujone, camphor, 1,8-cineole, ahumulene, b-caryophyllene, viridiflorol, carnosic, acid, ursolic acid, carnosol, and tanshinones. Evidence from in vitro and animal studies suggests that these compounds in sage could improve cognition by reducing amyloid-β (found in higher amounts on Alzheimer’s and other neurodegenerative disorders), increasing choline, reducing anxiety, reducing oxidation and inflammation, and encouraging neuronal repair.²⁵ In studies of healthy people, a single dose of sage has resulted in improved memory scores and mood, alertness and attention, calmness, and overall cognition.^{25, 26}

In studies of healthy people, a single dose of sage has resulted in improved memory scores and mood, alertness and attention, calmness, and overall cognition

Daily use of sage supplements has also been studied. A non-randomised, non-blinded, within-subject study was conducted for 28 days in 14 healthy people (18-40 years). At the completion of the study, significant improvements were seen for reaction time, cognitive accuracy, attention, and short term and working memory.²⁷ Another trial including cognitive function in perimenopausal women found a significant reduction in time for a common cognitive test (Stroop colour test).²⁸

Spearmint

Spearmint (Mentha spicata) is another common herb with purported cognitive effects.

Spearmint extracts (>14.5% rosmarinic acid and 24% total phenolic content) have resulted in improved cognitive scores in several studies. (Interestingly, rosmarinic acid is also common in other herbs such as rosemary, for which it is named, and thyme). In a 90-day randomised, double-blind, placebo-controlled trial, in healthy, active men and women, 900 mg of spearmint extract significantly improved reactive agility.²⁹

Lipids and ‘smart fats’

Omega 3 fats

The omega 3 fats DHA and EPA play an important role in brain development and healthy functioning of the brain and central nervous system. DHA, in particular, makes up the majority of the polyunsaturated fat content of the brain, comprises over 50% of the plasma membrane of neurons, and is essential to the functioning of the brain and optimising cognition and mood.³⁰

Omega-3 fats are linked to reduced mental fatigue,³¹ improved memory and cognition and reduced cognitive decline,^{32, 33} reduced rates of depression and improved structural integrity of the brain.^{34, 35}. Additionally, DHA improves cognition and behaviour in children.³⁶

Medium-chain triglycerides

Medium-chain triglycerides (MCT) are naturally occurring fats found in small amounts in dairy products and greater amounts in coconut oil. They are also commonly used as isolated supplement oils. MCT supplemented diets improve mental performance in those with Alzheimer’s Disease and age-related cognitive decline,^{37, 38} and a single dose of 20 g MCT has been shown to improve cognition.³⁹

Exogenous ketones?

Exogenous ketone supplements provide BOHB directly to the body without requiring ketogenesis and without concurrent elevations in free fatty acids.⁴⁰ They are considered to be a safe and effective way to increase ketone body concentrations,⁴¹ and are being studied for their use as potential treatments for brain injury,⁴² cancer,^{43, 44} Angelman syndrome,⁴⁵ and Alzheimer’s disease,⁴⁶ amongst other conditions.

Exogenous ketone supplements are available as either salts or esters of BOHB. Supplements containing ketone salts are some combination of sodium-, magnesium-, calcium or potassium-BOHB,  and are available commercially from several companies under patent.⁴⁷ Ketone esters have only recently become available for use by the public but are not common at the time of writing and are prohibitively expensive. Both ketone esters and salts elevate BOHB to levels consistent with NK.⁴⁸ Ketone esters increase ketone levels more than equivalent amounts of ketone salts with fewer gastrointestinal symptoms per increment of increase.⁴⁹

Ketone supplements have positive effects on anxiety,⁴⁶ mental performance and memory,⁴⁶ and reduce inflammation by suppressing activation of the NLRP3 inflammasome.⁵⁰ Ketones show promise for helping to treat many of the underlying causes of neurodegeneration cognitive decline.

Elevated ketones reduce the glutamate-GABA imbalance which can commonly result in excessive stress and fatigue.⁵¹ They also have been shown to help reduce the formation and accumulation of brain-damaging misfolded proteins (such as tau proteins and amyloid-β) seen in neurodegenerative disorders like Alzheimer’s disease and dementia.⁴⁶ Animal studies further suggest the utility of ketones to help reduce anxiety,⁴⁶ and improve learning and memory.⁴⁶  

Other ketogenic supplements?

Many supplements are purported to be ketogenic (increasing the internal creation of ketones) including leucine, lysine, short-chain fatty acids, and medium-chain triglycerides (MCTs). Of these, leucine and lysine have limited effects on ketone levels. There is also limited evidence in humans for the effect of short-chain fats (such as acetic acid from vinegar, or butyric acid), however, they are likely to be ketogenic and might be more so than MCT.⁵² The most compelling evidence currently exists for the use of MCTs for ketogenesis, as they reliably and consistently increase ketone concentrations in the blood in a dose-dependent fashion,⁵² and exogenous ketones reliably increase ketones without encouraging ketogenesis per se.  

Fungi

Hericium erinaceus (also called lion’s mane mushroom) is an edible and medicinal mushroom native to North America, Europe and Asia belonging to the tooth fungus group. Lion’s Mane has been shown to increase ‘Nerve Growth Factor’,⁵³ which helps nerves and brain cells to grow and repair.^54-59 Because of this brain-repair effect, Lion’s Mane is being considered as one of the most promising preventative treatments for Alzheimer’s Disease and dementia.^{60, 61} It’s also been demonstrated to significantly reduce depression and anxiety after 4 weeks of treatment,⁵⁵ and to improve cognitive function.⁶² Lion’s Mane might also improve physical performance by reducing perceived fatigue.⁶³

Other mushroom types, especially Turkey Tail (Trametes versicolor), Cordyceps (Ophiocordyceps sinensis), and Reishi (Ganoderma lucidum) are also suggested as benefiting neural health and cognition.

Conclusion

There is no substitute for a good diet, improved sleep, exercise, and living a life of balance, but some supplements can likely provide a boost to your brainpower and offer other, longer-term health and cognitive benefits. The strongest evidence exists for caffeine-containing beverages like coffee and tea, and from nutrient-rich herbs like mint, sage, brahmi, and others such as rosemary and thyme. Additionally, emerging benefits from fungi, most especially Lion’s Mane, but also others like Turkey Tail (Trametes versicolor) and Reishi (Ganoderma spp.) support a powerful effect on cognition. Also, ensuring nutrient density from a quality multivitamin/mineral will help to support cognition, along with providing brain-friendly lipids; MCTs and the omega-3 fats (especially DHA).

References

1.         Brown DA. Acetylcholine. Br J Pharmacol. 2006;147 Suppl 1(Suppl 1):S120-S6.

2.         Domino EF, Mathews BN, Tait SK, Ortiz A. Effects of oral phosphatidylcholine on mouse brain choline and acetylcholine. Archives internationales de pharmacodynamie et de therapie. 1983;265(1):49-54.

3.         Colucci L, Bosco M, Rosario Ziello A, Rea R, Amenta F, Fasanaro AM. Effectiveness of nootropic drugs with cholinergic activity in treatment of cognitive deficit: a review. J Exp Pharmacol. 2012;4:163-72.

4.         Ito N, Saito H, Seki S, Ueda F, Asada T. Effects of Composite Supplement Containing Astaxanthin and Sesamin on Cognitive Functions in People with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Trial. Journal of Alzheimer’s disease : JAD. 2018;62(4):1767-75.

5.         Neuropharmacological Review of the Nootropic Herb Bacopa monnieri. Rejuvenation Research. 2013;16(4):313-26.

6.         Stough C, Downey LA, Lloyd J, Silber B, Redman S, Hutchison C, et al. Examining the nootropic effects of a special extract of Bacopa monniera on human cognitive functioning: 90 day double-blind placebo-controlled randomized trial. Phytotherapy Research. 2008;22(12):1629-34.

7.         Kongkeaw C, Dilokthornsakul P, Thanarangsarit P, Limpeanchob N, Norman Scholfield C. Meta-analysis of randomized controlled trials on cognitive effects of Bacopa monnieri extract. Journal of Ethnopharmacology. 2014;151(1):528-35.

8.         Crawford C, Teo L, Lafferty L, Drake A, Bingham JJ, Gallon MD, et al. Caffeine to optimize cognitive function for military mission-readiness: a systematic review and recommendations for the field. Nutrition reviews. 2017;75(suppl_2):17-35.

9.         Irwin C, Khalesi S, Desbrow B, McCartney D. Effects of acute caffeine consumption following sleep loss on cognitive, physical, occupational and driving performance: A systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews. 2020;108:877-88.

10.       Ruxton CHS. The impact of caffeine on mood, cognitive function, performance and hydration: a review of benefits and risks. Nutrition Bulletin. 2008;33(1):15-25.

11.       Panza F, Solfrizzi V, Barulli MR, Bonfiglio C, Guerra V, Osella A, et al. Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: A systematic review. The journal of nutrition, health & aging. 2015;19(3):313-28.

12.       Camfield DA, Stough C, Farrimond J, Scholey AB. Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis. Nutrition reviews. 2014;72(8):507-22.

13.       Canter P, Ernst E. Ginkgo biloba is not a smart drug: an updated systematic review of randomised clinical trials testing the nootropic effects of G. biloba extracts in healthy people. Human Psychopharmacology: Clinical and Experimental. 2007;22(5):265-78.

14.       Laws KR, Sweetnam H, Kondel TK. Is Ginkgo biloba a cognitive enhancer in healthy individuals? A meta-analysis. Human Psychopharmacology: Clinical and Experimental. 2012;27(6):527-33.

15.       Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database of Systematic Reviews. 2009(1).

16.       Tan M-S, Yu J-T, Tan C-C, Wang H-F, Meng X-F, Wang C, et al. Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis. Journal of Alzheimer’s Disease. 2015;43(2):589-603.

17.       Yang G, Wang Y, Sun J, Zhang K, Liu J. Ginkgo Biloba for Mild Cognitive Impairment and Alzheimer&#8217;s Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Current Topics in Medicinal Chemistry. 2016;16(5):520-8.

18.       Takae R, Goto J, Ohnuki K, Nishide A, Ohnuki K, Sato D, et al. Effects of panax ginseng-containing tea on cognitive performance in adolescence-a randomized, double-blinded, placebo-controlled parallel comparison trial. Japanese Pharmacology and Therapeutics. 2019;47(3):485-91.

19.       Reay JL, Kennedy DO, Scholey AB. Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. Journal of Psychopharmacology. 2005;19(4):357-65.

20.       Reay JL, Kennedy DO, Scholey AB. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained ‘mentally demanding’ tasks. Journal of Psychopharmacology. 2006;20(6):771-81.

21.       Geng J, Dong J, Ni H, Lee MS, Wu T, Jiang K, et al. Ginseng for cognition. Cochrane Database of Systematic Reviews. 2010(12).

22.       Kennedy DO, Scholey AB, Wesnes KA. Differential, Dose Dependent Changes in Cognitive Performance Following Acute Administration of a Ginkgo biloba/Panax ginseng Combination to Healthy Young Volunteers. Nutritional neuroscience. 2001;4(5):399-412.

23.       Vinod Kumar M, Rajagopalan S. Trial using multiple micronutrient food supplement and its effect on cognition. The Indian Journal of Pediatrics. 2008;75(7):671-8.

24.       Macpherson H, Rowsell R, Cox KHM, Scholey A, Pipingas A. Acute mood but not cognitive improvements following administration of a single multivitamin and mineral supplement in healthy women aged 50 and above: a randomised controlled trial. AGE. 2015;37(3):38.

25.       Lopresti AL. Salvia (Sage): A Review of its Potential Cognitive-Enhancing and Protective Effects. Drugs in R&D. 2017;17(1):53-64.

26.       Miroddi M, Navarra M, Quattropani MC, Calapai F, Gangemi S, Calapai G. Systematic Review of Clinical Trials Assessing Pharmacological Properties of Salvia Species on Memory, Cognitive Impairment and Alzheimer’s Disease. CNS Neuroscience & Therapeutics. 2014;20(6):485-95.

27.       Burgum C, Lee D, McGrath K, O’Hare K, Morrin A. The effect of sage (Salvia officinalis) on cognitive and vascular function in healthy young adults.. 2014.

28.       Lally T. The effects of sage (Salvia officinalis) supplementation on vascular health, cognitive function and menopausal symptoms in peri-and post-menopausal women 2018.

29.       Falcone PH, Tribby AC, Vogel RM, Joy JM, Moon JR, Slayton CA, et al. Efficacy of a nootropic spearmint extract on reactive agility: a randomized, double-blind, placebo-controlled, parallel trial. Journal of the International Society of Sports Nutrition. 2018;15(1):58.

30.       Ghasemi Fard S, Wang F, Sinclair AJ, Elliott G, Turchini GM. How does high DHA fish oil affect health? A systematic review of evidence. Critical Reviews in Food Science and Nutrition. 2018:1-44.

31.       Jackson PA, Deary ME, Reay JL, Scholey AB, Kennedy DO. No effect of 12 weeks’ supplementation with 1 g DHA-rich or EPA-rich fish oil on cognitive function or mood in healthy young adults aged 18–35 years. British Journal of Nutrition. 2012;107(8):1232-43.

32.       Lee LK, Shahar S, Chin A-V, Yusoff NAM. Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacology. 2013;225(3):605-12.

33.       Daiello LA, Wellenius G, Ott BR, Buka SL. Role of supplemental docosahexaenoic acid (DHA) for cognition in Alzheimer’s disease and mild cognitive impairment: A&#xa0;systematic review and meta-analysis of randomized controlled trials. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2015;11(7):P611.

34.       O’Connor EM, Power SE, Fitzgerald GF, O’Toole PW. Fish-oil consumption is inversely correlated with depression and cognition decline in healthy Irish elderly adults. Proceedings of the Nutrition Society. 2012;71(OCE2):E151.

35.       Daiello LA, Gongvatana A, Dunsiger S, Cohen RA, Ott BR. Association of fish oil supplement use with preservation of brain volume and cognitive function. Alzheimer’s & Dementia. 2015;11(2):226-35.

36.       Norman S, Edward BN, Erin Cernkovich B, Connye NK. The Relationship of Docosahexaenoic Acid (DHA) with Learning and Behavior in Healthy Children: A Review. Nutrients. 2013;5(7):2777-810.

37.       Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD, Watson GS, et al. Effects of β-hydroxybutyrate on cognition in memory-impaired adults. Neurobiology of Aging. 2004;25(3):311-4.

38.       Cunnane SC, Courchesne-Loyer A, St-Pierre V, Vandenberghe C, Pierotti T, Fortier M, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer’s disease. Annals of the New York Academy of Sciences. 2016;1367(1):12-20.

39.       Matsuo J, Ashida K, Hattori K, Kunugi H, Ota M, Takahashi T, et al. PT599. Effect of single ketogenic diet containing medium chain triglycerides on cognitive functions in elderly adults. International Journal of Neuropsychopharmacology. 2016;19(Suppl 1):20-.

40.       Veech RL. Ketone ester effects on metabolism and transcription. J Lipid Res. 2014;55(10):2004-6.

41.       Hashim SA, VanItallie TB. Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester. J Lipid Res. 2014;55(9):1818-26.

42.       White H, Venkatesh B. Clinical review: ketones and brain injury. Critical Care. 2011;15(2):219-.

43.       Poff AM, Ward N, Seyfried TN, Arnold P, D’Agostino DP. Non-toxic metabolic management of metastatic cancer in VM mice: novel combination of ketogenic diet, ketone supplementation, and hyperbaric oxygen therapy. PloS one. 2015;10(6):e0127407-e.

44.       Poff AM, Ari C, Arnold P, Seyfried TN, D’Agostino DP. Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. International Journal Of Cancer. 2014;135(7):1711-20.

45.       Ciarlone SL, Grieco JC, D’Agostino DP, Weeber EJ. Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model. Neurobiology Of Disease. 2016.

46.       Kashiwaya Y, Bergman C, Lee J-H, Wan R, King MT, Mughal MR, et al. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2013;34(6):1530-9.

47.       D’agostino DP, Arnold P, Kesl S. Compositions and methods for producing elevated and sustained ketosis. Google Patents; 2015.

48.       Holdsworth D, Cox P, Clarke K. Oral ketone body supplementation accelerates and enhances glycogen synthesis in human skeletal muscle following exhaustive exercise. J Clin Lab Invest. 1967;19(3):218-28.

49.       Stubbs B, Evans R, Clarke K, Cox P, editors. Ketone ester drinks increase blood ketone levels more effectively than ketone salt drinks. Proceedings of The Physiological Society; 2016: The Physiological Society.

50.       Youm Y-H, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263-9.

51.       Hertz L, Chen Y, Waagepetersen HS. Effects of ketone bodies in Alzheimer’s disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function. Journal Of Neurochemistry. 2015;134(1):7-20.

52.       Harvey CJdC, Schofield GM, Williden M. The use of nutritional supplements to induce ketosis and reduce symptoms associated with keto-induction: a narrative review. PeerJ. 2018;6:e4488.

53.       Lai P-L, Naidu M, Sabaratnam V, Wong K-H, David RP, Kuppusamy UR, et al. Neurotrophic Properties of the Lion’s Mane Medicinal Mushroom, <i>Hericium erinaceus</i> (Higher Basidiomycetes) from Malaysia. 2013;15(6):539-54.

54.       Park YS, Lee HS, Won MH, Lee JH, Lee SY, Lee HY. Effect of an exo-polysaccharide from the culture broth of Hericium erinaceus on enhancement of growth and differentiation of rat adrenal nerve cells. Cytotechnology. 2002;39(3):155.

55.       Nagano M, Shimizu K, Kondo R, Hayashi C, Sato D, Kitagawa K, et al. Reduction of depression and anxiety by 4 weeks <I>Hericium erinaceus</I> intake. Biomedical Research. 2010;31(4):231-7.

56.       Wong K-H, Vikineswary S, Naidu M, Keynes R. Activity of Aqueous Extracts of Lion’s Mane Mushroom <i>Hericium erinaceus</i> (Bull.: Fr.) Pers. (Aphyllophoromycetideae) on the Neural Cell Line NG108-15. 2007;9(1):57-65.

57.       Wong K-H, Naidu M, David P, Abdulla MA, Abdullah N, Kuppusamy UR, et al. Peripheral Nerve Regeneration Following Crush Injury to Rat Peroneal Nerve by Aqueous Extract of Medicinal Mushroom Hericium erinaceus (Bull.: Fr) Pers. (Aphyllophoromycetideae). Evidence-Based Complementary and Alternative Medicine. 2011;2011:10.

58.       Wong K-H, Naidu M, David RP, Abdulla MA, Kuppusamy UR. Functional Recovery Enhancement Following Injury to Rodent Peroneal Nerve by Lion’s Mane Mushroom, <i>Hericium erinaceus</i> (Bull.: Fr.) Pers. (Aphyllophoromycetideae). 2009;11(3):225-36.

59.       Moldavan M, Grygansky AP, Kolotushkina OV, Kirchhoff B, Skibo GG, Pedarzani P. Neurotropic and Trophic Action of Lion’s Mane Mushroom <i>Hericium erinaceus</i> (Bull.: Fr.) Pers. (Aphyllophoromycetideae) Extracts on Nerve Cells <i>in Vitro</i>. 2007;9(1):15-28.

60.       Mizuno T. Bioactive Substances in <i>Hericium erinaceus</i> (Bull.: Fr.) Pers. (Yamabushitake), and Its Medicinal Utilization. 1999;1(2):105-19.

61.       Mori K, Obara Y, Moriya T, Inatomi S, Nakahata N. Effects of <I>Hericium erinaceus</I> on amyloid &beta;(25-35) peptide-induced learning and memory deficits in mice. Biomedical Research. 2011;32(1):67-72.

62.       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.

63.       Liu J, Du C, Wang Y, Yu Z. Anti-fatigue activities of polysaccharides extracted from Hericium erinaceus. Experimental and therapeutic medicine. 2015;9(2):483-7.