Cutting edge science for cognitive enhancement
There has been an astonishing increase in average life expectancy over the last 100 years. Each generation is living longer, and our intelligence is steadily rising. That means there is a high premium on maintaining a cognitive edge—one that lasts for our entire lifespan. Science is now discovering nutraceuticals that can boost our brainpower, sharpen our memory, lift our mood, heighten our awareness, and protect our neural circuitry from the slow deterioration that aging might otherwise bring. In Part 1 of this series we discussed two nutraceuticals: citicoline (CDP-choline) and rosmarinic acid-enriched spearmint extract. Today we’ll review the effects of coffee cherry, Lion’s mane mushroom (Hericium erinaceus), and American ginseng.
Clear as a bell with coffee cherry
Coffee’s praises have been sung across many cultures. The inky drink has even been compared to a nectar of the gods, offering vivid clarity and energy as well as protection from heart disease, chronic respiratory diseases, diabetes, pneumonia, and influenza. Moderate coffee consumption has even been shown to lower total mortality, including that resulting from neurologic diseases.
A coffee bean is a seed of the coffee plant and the source for coffee. It is the pit inside the red or purple fruit often referred to as a cherry. Until recently, we’ve only known coffee through its bean: green when raw, polished and dark when roasted. Coffee cherry, however, has its own complement of nutrients, including antioxidants such as proanthocyanidins, chlorogenic acid, quinic acid, ferulic acid, and caffeic acid.,,, Importantly, the neuroprotective benefits of coffee are not due to caffeine alone, but rather to the other bioactive compounds in coffee., Chlorogenic acid in particular has neuroprotective effects, and it has been shown to improve spatial learning and memory in animals.
Coffee cherry has been reported to enhance brain-derived neurotrophic factor (BDNF), a protein essential for cognitive function, sleep, and stable mood.
Coffee cherry has been reported to enhance brain-derived neurotrophic factor (BDNF), a protein essential for cognitive function, sleep, and stable mood.  Along with nerve growth factor (NGF), BDNF is a member of the neurotrophin family of growth factors, which are proteins that induce the survival, development, and function of neurons. BDNF serves as a neurotransmitter modulator that is crucial for learning and memory.,, During learning, there is a rapid increase of BDNF expression in the hippocampus, a brain region that is required for many forms of long-term memory. Studies also have shown an increase in BDNF in the cortex of primates who are learning to use a new tool. Conversely, losses of BDNF are associated with Alzheimer’s disease and Parkinson’s disease.,, Thus compounds that increase BDNF are being avidly pursued as potential new therapies for these conditions.,
Enter coffee cherry, stage left. This subtly aromatic red fruit can induce high levels of BDNF. In a 2012 study, whole coffee fruit concentrate (WCFC) was shown to significantly boost plasma levels of BDNF in healthy subjects. Because caffeine is also known to increase BDNF, three different formulations containing caffeine were tested: green coffee caffeine (72.8% caffeine), green coffee bean extract (2% caffeine), and WCFC (0.7% caffeine). A substance high in polyphenols but lacking caffeine, grape seed extract, was also tested, along with a placebo. Twenty-five healthy adults were randomly divided into groups of five, each receiving one of the five supplements after fasting for 12 hours, and blood levels of BDNF were measured an hour later. WCFC increased blood levels of BDNF by an average of 137%, while green coffee caffeine and grape seed extract modestly increased BDNF, but not by a statistically significant amount.
A follow-up study confirmed these remarkable results. Twenty healthy individuals aged 25 to 35 fasted for twelve hours and then were given WCFC, freshly brewed coffee, or a placebo on three successive days. Supplementation with a single dose of WCFC nearly doubled the quantity of BDNF in the blood after 60 minutes, and the effects were sustained for at least two hours after ingestion. Moreover, WCFC increased BDNF levels significantly more than fresh coffee consumption at 60 min and 120 min, suggesting that the unique ingredients in coffee cherry were responsible for the effect.
Memorize that mushroom!
Mushrooms contain a multitude of potent medicinal and immune-boosting compounds. Mushrooms have attracted interest due to their neuroprotective, antioxidant, and anti-inflammatory properties, as demonstrated in various experimental models of disease. Among other effects, emerging data suggests that mushrooms can reduce beta amyloid-induced toxicity (one of the major causes of Alzheimer’s disease).24
One mushroom in particular is known for its ability to regenerate neurons and improve learning and memory. It is called lion’s mane (Hericium erinaceus), and is very popular in China and Japan. It contains novel compounds known as hericenones (found in the fruiting bodies) and erinacines (found in the mycelia) that stimulate the growth and re-myelination of neurons.,, Myelin is the protective sheath that surrounds each neuron, which can degenerate with age or neurodegenerative disease.
Detailed investigations of lion’s mane began in 1991 at Shizuoka University in Japan. Scientists studying bioactive ingredients derived from medicinal mushrooms found that they stimulated the production of NGF by astroglial cells, which are cells that form myelin and provide support and protection for neurons. Considering that NGF is important for cognitive functions, and decreases with aging, a loss of this neurotrophic factor might contribute to an age-dependent decline in cognitive function. Based on their studies, the Japanese group predicted that the enhancement of NGF production would help prevent disorders of the central and peripheral nervous system.
Erinacines in particular significantly induced the synthesis of NGF in vitro., Further studies confirmed this work and showed that both H. erinaceus and another mushroom, Lignosus rhinocerotis (Tiger milk mushroom), stimulate neurite outgrowth in brain, spinal cord, and retina cells, resulting in neuronal differentiation and elongation. In animal studies of nerve injury, H. erinaceus enhanced functional recovery by stimulating neuron regrowth, and also improved myelination in the brain., The prominent beneficial effect of erinacine A in the central nervous system was confirmed in a study showing that animals given this compound had increased levels of NGF in both in the hippocampus and locus coeruleus (LC), a region that plays a major role in alertness. Erinacine A also stimulated NGF biosynthesis and was neuroprotective in a stroke model in mice.
A 2011 study of H. erinaceus in an Alzheimer’s model in mice produced remarkable results. Mice were first injected with amyloid-beta peptides, which led to amyloid plaque formation similar to that seen in Alzheimer’s patients’ brains. The mice were challenged by a maze designed for testing memory. Mice that developed plaque could no longer memorize the maze. But when they were fed a diet containing five percent dried lion’s mane mushrooms for three weeks, the mice performed significantly better and spent more time exploring new objects in their environment. A further study confirmed the beneficial effects of supplemental H. erinaceus in an Alzheimer’s mouse model, and showed that four weeks’ supplementation significantly enhanced the acetylcholine concentrations in the hypothalamus. In an animal model of physiological aging, two months of daily supplementation with H. erinaceus reversed the age-related decline of recognition memory (the ability to recognize previously encountered objects.)
A double-blind, placebo controlled study of 30 clinically healthy Japanese men and women, aged 50 to 80 years old, found that H. erinaceus significantly boosted memory.
Research in humans is equally tantalizing. In 2009, a double-blind, placebo controlled study of 30 clinically healthy Japanese men and women, aged 50 to 80 years old, found that H. erinaceus significantly boosted memory. The men and women took four tablets three times a day, containing either placebo or 250 mg each of lion’s mane dry powder. At weeks 8, 12 and 16 of the trial, the group that received H. erinaceus showed significantly increased scores on a cognitive function scale compared with the placebo group. The effect diminished within four weeks of the conclusion of the intake period.
In addition to memory, H. erinaceus may even boost mood in healthy individuals. A 2010 double-blind, placebo-controlled study of 30 post-menopausal women found that after taking 2000 mg of lion’s mane daily for four weeks, not only did concentration improve, depression and anxiety were also decreased.
Altogether, lion’s mane is a remarkable functional food with a long history of culinary and medical use. As summarized in a 2015 study by researchers at Henan Agricultural University in China: “Hericium erinaceus and its components could be useful as potent protective agents for neurodegenerative disorders.”
American ginseng (Panax quinquefolius)
Ginseng is any of eleven species of plants with fleshy roots, all belonging to the botanical genus Panax. American ginseng (Panax quinquefolius) is a perennial herb commonly used in traditional medicine. The name Panax is derived from the Greek “panacea,” and ginseng has long been revered as a health elixir that can promote vigor and longevity and enhance physical and mental performance. It is an adaptogen—able to increase the body’s ability to adapt to stress, boost energy and endurance, and stabilize physiological processes in the body.
New evidence suggests that ginseng also assists the brain, enhancing working memory and the ability to pay attention. Ginseng contains ginsenoside saponins, plant chemicals that increase uptake of choline by synapses, and stimulate release of the neurotransmitter acetylcholine. Ginsenosides also influence the brain’s concentration of the feel-good neurotransmitter serotonin. It was observed that an extract from American ginseng containing a high concentration of a particular ginsenoside was able to protect human neural stem cells from toxicity induced by amyloid-beta peptide.
The P. quinquefolius extract significantly improved working memory speed and capacity in healthy middle-aged adults.
A standardized extract of P. quinquefolius containing a minimum of 10% ginsenosides significantly improved several parameters of memory in healthy young adults. The placebo-controlled, randomized crossover study tested 16 men and 16 women aged 18 to 40. Participants were given capsules containing 100, 200, or 400 mg of the ginseng extract or a placebo at each assessment session, spaced by a seven-day washout period. Tests of verbal, numeric, and working memory were given at one, three, and six hours after administration. At various timepoints, for each of the dosages a significant increase in immediate word recall, reaction time, and working memory was seen compared to placebo. A second double-blind, placebo-controlled crossover study assessed similar parameters in healthy middle-aged adults aged 40 to 60, considering only a 200 mg dose of the P. quinquefolius standardized extract, and found the extract significantly improved working memory speed and capacity, as well as reaction time accuracy (response accuracy and speed) at three hours.
Today, as we live longer smarter lives, we can turn to these potent brain foods to preserve our cognitive edge. “We now know that particular nutrients influence cognition by acting on molecular systems or cellular processes that are vital for maintaining cognitive function,” concludes Dr. Fernando Gomez-Pinilla, a UCLA professor who has analyzed the effects of foods on neuronal health. Foods that stimulate neuronal plasticity and survival, including coffee cherry, lion’s mane, and American ginseng, may help stave off the age-related loss of memory and help protect against neurodegenerative disease. So, make sure to feed your brain!Click here to see References
 Loftfield E, et al. Association of coffee consumption with overall and cause-specific mortality in a large US prospective cohort study. Am J Epidemiol. 2015 Dec 15;182(12):1010-22.
 Ding M, et al. Association of coffee consumption with total and cause-specific mortality in three large prospective cohorts. Circulation. 2015 Dec 15;132(24):2305-15.
 Liang N, Kitts DD. Role of chlorogenic acids in controlling oxidative and inflammatory stress conditions. Nutrients. 2015 Dec 25;8(1)
 Kobayashi T, et al. Effects of coffee cherry on the immune system in SHN mice. Anticancer Res. 199616:1827–30.
 Kobayashi T, et al. Effects of coffee cherry on the activation of splenic lymphocytes in mice. Anticancer Res. 1997;7913–16.
 Mattila P, et al. Phenolic acids in berries, fruits, and beverages. J Agric Food Chem. 2006;54(19):7193-9.
 Shukitt-Hale B, et al. Coffee, but not caffeine, has positive effects on cognition and psychomotor behavior in aging. Age (Dordr). 2013 Dec;35(6):2183-92.
 Sc Y, Muralidhara S. Beneficial role of coffee and caffeine in neurodegenerative diseases: a minireview. AIMS Public Health. 2016 Jun 20;3(2):407-22.
 Han J, et al. Neuroprotective effect of 3,5-di-O-caffeoylquinic acid on SH-SY5Y cells and senescence-accelerated-prone mice 8 through the up-regulation of phosphoglycerate kinase-1. Neuroscience. 2010;169(3):1039–45.
 Barde YA, et al. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982;1(5):549-53.
 Finder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors. 2004 September; 22(3):123–31.
 Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015 Dec 10;11(6):1164-78.
 Zigova T, et al. Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol Cell Neurosci. 1998 Jul;11(4):234-45.
 Hall J, et al. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci. 2000 Jun;3(6):533-5.
 Ishibashi H, et al. Tool-use learning selectively induces expression of brain-derived neurotrophic factor, its receptor TRKb, and neurotrophin 3 in the intraparietal multisensory cortex of monkeys. Brain Res Cogn Brain Res. 2002 Jun;14(1):3-9.
 Murer MG, et al. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol. 2001 Jan;63(1):71-124.
 Fusco FR, et al. Co-localization of brain-derived neurotrophic factor (BDNF) and wild-type huntingtin in normal and quinolinic acid-lesioned rat brain. Eur J Neurosci. 2003 Sep;18(5):1093-102.
 Rahmani F, et al. Plasma levels of brain-derived neurotrophic factor in patients with Parkinson disease: A systematic review and meta-analysis. Brain Res. 2019 Feb 1;1704:127-36.
 Eremenko E, et al. BDNF-producing, amyloid β-specific CD4 T cells as targeted drug-delivery vehicles in Alzheimer’s disease. EBioMedicine. 2019 May;43:424-34.
 Lu B, et al. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 2013 Jun;14(6):401-16.
 Reyes-Izquierdo T, et al. Modulatory effect of coffee fruit extract on plasma levels of brain-derived neurotrophic factor in healthy subjects. Br J Nutr. 2013 Aug 28;110(3):420-5.
 Reyes-Izquierdo T, et al. Stimulatory effect of whole coffee fruit concentrate powder on plasma levels of total and exosomal brain-derived neurotrophic factor in healthy subjects: an acute within-subject clinical study. Food Nutr Sci. 2013;4:984-90.
 Stamets P. Notes on nutritional properties of culinary-medicinal mushrooms. Int J Med Mushrooms. 2005;7:109-16.
 Phan CW, et al. Therapeutic potential of culinary-medicinal mushrooms for the management of neurodegenerative diseases: diversity, metabolite, and mechanism. Crit Rev Biotechnol. 2015;35(3):355-68.
 Ma BJ, et al. Hericenones and erinacines: stimulators of nerve growth factor (NGF) biosynthesis in Hericium erinaceus. Mycology: An International Journal on Fungal Biology. 2010;1(2):92-8.
 Li IC, et al. Neurohealth properties of Hericium erinaceus mycelia enriched with erinacines. Behav Neurol. 2018 May 21;2018:5802634.
 Kolotushkina EV, et al. The influence of Hericium erinaceus extract on myelination process in vitro. Fiziol Zh. 2003;49(1):38-45.
 Kawagishi H, et al. Compounds for dementia from Hericium erinaceum. Drugs of the Future. 2008 Feb 1;33(2):149.
 Ma Bing-Ji , et al. Hericenones and erinacines: stimulators of nerve growth factor (NGF) biosynthesis in Hericium erinaceus. Mycology: An International Journal on Fungal Biology. 2010;1(2):92-8.
 Belanger M, Magistretti P. The role of astroglia in neuroprotection. Dialogues Clin Neurosci. 2009 Sep;11(3):281–5.
 Kawagishi H, et al. The anti-dementia effect of Lion’s Mane mushroom (Hericium erinaceum) and its clinical application. Townsend Letter for Doctors and Patients. 2004 Apr 1(249):54-7.
 Kawagishi H, et al. Erinacines A, B and C, strong stimulators of nerve growth factor (NGF)-synthesis, from the mycelia of Hericium erinaceum. Tetrahedron Lett. 1994;35:1569–72.
 Ma BJ , et al. Hericenones and erinacines: stimulators of nerve growth factor (NGF) biosynthesis in Hericium erinaceus. Mycology. 2010 Jun 23;1(2):92-8.
 Samberkar S, et al. Lion’s Mane, Hericium erinaceus and Tiger Milk, Lignosus rhinocerotis (Higher Basidiomycetes) medicinal mushrooms stimu- late neurite outgrowth in dissociated cells of brain, spinal cord, and retina: an in vitro study. Int J Med Mushrooms. 2015;17(11):1047-54.
 Wong KH, et al. Functional recovery enhancement following injury to rodent peroneal nerve by lions mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (Aphylloph- oromycetideae). Int J Med Mushrooms. 2009;11:225–36.
 Moldavan M, et al. Neurotropic and trophic action of Lion’s Mane Mushroom Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) extracts on nerve cells in vitro. Int J Med Mushrooms. 2007;9:15–28.
 Shimbo M. et al. Erinacine A increases catecholamine and nerve growth factor content in the central nervous system of rats. Nutrition Research. 2005;25(6):617-23.
 Samuels ER, Szabadi E. Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr Neuropharmacol. 2008 Sep;6(3):235-53.
 Hazekawa M, et al. Neuroprotective effect of repeated treatment with Hericium erinaceumin mice subjected to middle cerebral artery occlusion, J. Health Sci. 2010;56:296-303.
 Mori K, et al. Effects of Hericium erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in mice. Biomed Res. 2011;32(1):67-72.
 Zhang J, et al. The neuroprotective properties of Hericium erinaceus in glutamate-damaged differentiated PC12 cells and an Alzheimer’s disease mouse model. Int J Mol Sci. 2016 Nov 1;17(11):1810.
 Ratto D, et al. Hericium erinaceus improves recognition memory and induces hippocampal and cerebellar neurogenesis in frail mice during aging. Nutrients. 2019 Mar 27;11(4):715.
 Mori K, et al. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double‐blind placebo‐controlled clinical trial. Phytother Res. 2009 Mar;23(3):367-72.
 Nagano M, et al. Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res. 2010 Aug; 31(4):231-7.
 Phan CW, 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. Food Funct. 2014 Dec;5(12):3160-9.
 Benishin C. Actions of ginsenoside Rb1 on choline uptake in central cholinergic nerve endings. Neurochem Int. 1992;21:1–5.
 Zhang J, et al. Preliminary study on antiamnesic mechanism of ginsenosides Rg1 and Rb1. China Med J. 1990;103:932–8.
 Shin K, et al. Cereboost™ an American ginseng extract improves cognitive function via up-regulation of choline acetyltransferase expression and neuroprotection. Regul. Toxicol. Pharmacol. 2016;78:53–58.
 Scholey A, et al. Effects of American ginseng (Panax quinquefolius) on neurocognitive function: an acute, randomised, double-blind, placebo-controlled, crossover study. Psychopharmacology (Berl). 2010 Oct;212(3):345-56.
 Ossoukhova A, et al. Improved working memory performance following administration of a single dose of American ginseng (Panax quinquefolius L.) to healthy middle-age adults. Hum Psychopharmacol. 2015 Mar;30(2):108-22.
 Gomez-Pinilla F. Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci. 2008 Jul;9(7):568-78.