The Effects of Twenty-One Nutrients and Phytonutrients On Cognitive Function - A Narrative Review

Journal of Clinical and Translational Research 2021; 7(4): 575-620
Journal of Clinical and Translational Research

Journal homepage: http://www.jctres.com/en/home
REVIEW ARTICLE
The effects of twenty-one nutrients and phytonutrients on cognitive

function: A narrative review
John E. Lewis1*, Jillian Poles2, Delaney P. Shaw3, Elisa Karhu4, Sher Ali Khan5, Annabel E. Lyons6, Susana Barreiro Sacco7,
H. Reginald McDaniel8
1
Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA, 2Department of Exercise and
Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 3Institute of Human Nutrition, Vagelos College of Physicians and
Surgeons, Columbia University, New York, NY, USA, 4Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA,
5
Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA, 6School of Nursing and Health Studies,
University of Miami, Coral Gables, FL, USA, 7Department of Internal Medicine, Mount Sinai Medical Center Miami Beach, FL, USA, 8Wellness Quest,
LLC, Grand Prairie, TX, USA
ARTICLE INFO ABSTRACT
Article history Background and Aim: Brain health is becoming more important to the average person as the number
Received: January 24, 2021 of people with cognitive impairments, such as Alzheimer’s disease (AD), is rising significantly. The
Revised: June 17, 2021 current Food and Drug Administration-approved pharmacotherapeutics for dementia neither cure nor
Accepted: July 09, 2021 halt cognitive decline; they just delay the worsening cognitive impairment. This narrative review
Published online: August 4, 2021 summarizes the effects of nutrients and phytonutrients on cognitive function.
Methods: A comprehensive literature search of PubMed was performed to find clinical trials in
Key words: humans that assessed the effects of nutrients and phytonutrients on cognitive function published in
Alzheimer’s disease English between 2000 and 2021. Six independent reviewers evaluated the articles for inclusion in this
cognitive function review.
cognitive impairment Results: Ninety-six articles were summarized in this narrative review. In total 21 categories of
memory nutrients and phytonutrients were included, i.e., α-lipoic acid, Bacopa monnieri, B vitamins,
nutrients cholinergic precursors, vitamin D, vitamin E, Ginkgo biloba, ginseng, lion’s mane mushroom,
phytonutrients N-acetyl cysteine, omega-3 fatty acids, aloe polysaccharides, Rhodiola rosea, rosemary, saffron, tart
cherries, turmeric, wild yam, Withania somnifera, xanthines, and zinc. Particular noteworthy effects
*Corresponding author: on cognition included memory, recollection, attention, intelligence, vocabulary, recognition, response
John E. Lewis, PhD inhibition, arousal, performance enhancement, planning, creative thinking, reaction time, vigilance,
Department of Psychiatry and Behavioral task switching, orientation to time, place, and person, reading, writing, comprehension, accuracy,
Sciences, University of Miami Miller School of learning, information processing speed, executive function, mental flexibility, daily functioning,
Medicine, 1120 NW, 14th Street, Suite #1482A decrease in mental fatigue, and freedom from distractibility. Some nutrients and phytonutrients also
(D28), Miami, FL 33136, USA. improved mood and contentedness and reduced anxiety and the need for caregiving. These effects
Phone: +1 305-243-6227, Fax: +1 305-243-1619
are not completely consistent or ubiquitous across all patient populations or health statuses. Adverse
E-mail: [email protected]
effects were minimal or nonexistent.
Conclusion: Due to the growing population of people with cognitive impairment and the lack of
© 2021 Lewis, et al. This is an Open
Access article distributed under the terms effective pharmacotherapeutics, it is prudent for those afflicted or their caregivers to find alternative
of the Creative Commons Attribution- treatments. Our narrative review shows that many of these nutrients and phytonutrients may be
NonCommercial 4.0 International License promising for treating some aspects of cognitive impairment, especially for people afflicted with AD.
(http://creativecommons.org/licenses/ Relevance for Patients: As demonstrated in a number of clinical trials, healthy adults and patients with
bync/4.0/), permitting all non-commercial use, various health challenges (e.g., AD, mild cognitive impairment, multiple sclerosis, and Parkinson’s
distribution, and reproduction in any medium, disease) exhibiting a wide range of severity in cognitive defects would be best served to consider
provided the original work is properly cited. multiple nutrients and phytonutrients to improve aspects of their cognitive function.
DOI: http://dx.doi.org/10.18053/jctres.07.202104.014
576 Lewis et al. | Journal of Clinical and Translational Research 2021; 7(4): 575-620
1. Introduction 3. Results
While cardiovascular disease and cancer continue to be 3.1. Nutrients
the leading causes of death worldwide [1], shifting trends in
3.1.1. Antioxidant nutrients
morbidity and mortality have resulted in an increasing interest
in brain health, particularly driven by the rising incidence 3.1.1.1. α-lipoic acid
of Alzheimer’s disease (AD). Moreover, AD is now the sixth
Lipoic acid is a metabolic co-factor that comes in several
leading cause of death of Americans, and one-third of the
different forms and has been suggested as an anti-inflammatory
elderly will die from AD or another form of dementia [2]. It
is currently the only major cause of death and disability that and neuroprotective treatment for AD. Its diverse mechanisms of
has no efficacious conventional treatment, and it also has no action for counteracting the pathology of dementia and AD are: (1)
widely accepted preventative strategy. The issue with AD today activating choline acetyltransferase, which elevates acetylcholine
is reminiscent of that with HIV/AIDS in the early 1990s, before production; (2) increasing glucose uptake, which increases acetyl
the advent of antiretroviral medication. coenzyme A production and thus elevates acetylcholine; (3)
Given that the 5 Food and Drug Administration (FDA)- chelating transition metals that inhibit the formation of hydrogen
approved drugs for dementia can only delay the decline of peroxide and hydroxyl radicals, which may counteract aggregation
AD for a short period of time before continued decline in of amyloid-beta (Aβ) peptide, due to an age-dependent reaction
functioning until death [2], those affected by this disease (e.g., with excess brain metal ions; (4) scavenging reactive oxygen
patients and their primary caregivers) have sought alternatives. species and lipid peroxidation products; and (5) inducing enzymes
Aside from strategies such as hyperbaric oxygen treatment, of glutathione synthesis and other antioxidant enzymes [99].
cognitive training, and acupuncture, among others, nutritional In addition, lipoic acid’s low molecular weight allows it to be
science is an evolving field in its application to brain health, readily absorbed from the diet to cross the blood-brain barrier.
in both preventative and restorative study models. In particular, Furthermore, lipoic acid and its reduced form, dihydrolipoic acid,
dietary supplements offer an approach to adding key nutrients or are both potent antioxidants that improve intracellular glutathione
phytonutrients to a person’s daily consumption of food and drink. levels [100]. Thus, lipoic acid may offer potential for managing
Historically, supplements such as Ginkgo biloba and vitamins neurodegenerative conditions that have known inflammatory and
B12 and E have been studied for their effects on brain health and oxidant etiologies or relationships.
cognitive functioning among healthy older adults and in those In perhaps the first controlled trial of α-lipoic acid in
with varying degrees of cognitive impairment. Recently, other probable AD and related dementias, 9 study subjects were
nutrients and phytonutrients, such as polysaccharides, saffron, given 600 mg/day in addition to the standard treatment of
choline, and vitamin D, have also been evaluated for their acetylcholinesterase (AChE) inhibitors (AChEI) over an
efficacy on cognitive functioning. This review will summarize average of 337 days [3]. AChE degrades acetylcholine, a
the recent findings for these nutrients and phytonutrients and neurotransmitter, particularly in nerves [101], and cognitive
assess whether they offer potential for helping those affected dysfunction in AD is related to a pathophysiological decrease of
by AD and other neurodegenerative disorders and for those cholinergic neurons [102]. At the end of the treatment period,
interested in preventing cognitive dysfunction and maintaining cognitive function was stabilized according to the Mini-Mental
brain health. Given the recent rapid increase in the incidence State Examination (MMSE) [103] and AD Assessment Scale-
of AD and related diseases, this summary should be of interest cognitive score (ADAS-cog) [104]. Before study enrollment,
to lay people (patients and their caregivers), clinicians, and the subjects were declining in their cognitive abilities according
researchers alike. to these neuropsychological tests, but α-lipoic acid was able to
delay further deterioration.
2. Methods In a follow-up study by the same group of investigators,
A comprehensive search for articles was performed using 43 patients with mild to moderate dementia being treated with
PubMed. Articles published in English between 2000 and AChEIs were given 600 mg/day of α-lipoic acid for up to
2021 with full text available were searched using the name of 48 months [4]. In those subjects with mild dementia (ADAS-
the nutrient or phytonutrient and the term “cognitive function/ cog<15), the disease progressed extremely slowly (ADAS-cog:
ing.” Inclusion criteria were: (1) a study published within the +1.2 points/year and MMSE: −0.6 points/year), and in those with
past 21 years and (2) a clinical trial conducted in humans. Six moderate severity the disease progression was about twice as fast
independent reviewers evaluated the articles for inclusion in as the mild group. Nonetheless, the rate of progression for the
the review. The search returned 2,234 total articles, of which moderate severity group was far lower than for those who were
96 were included in this review. See Table 1 for a summary of untreated or only taking an AChEI.
the nutrient or phytonutrient according to the treatment amount, Lipoic acid was utilized in a randomized placebo-controlled
population under study, and the most significant effects on trial as an addition to intervention with omega-3 (Ω-3) fatty
cognitive function. acids in patients with a diagnosis of probable AD [5]. Thirty-
Lewis et al. | Journal of Clinical and Translational Research 2021; 7(4): 575-620 577
Table 1. Summary of effects of nutrients and phytonutrients on cognitive function in clinical trials
Nutrient or Study Study Sample size (n) Daily dose Main cognitive results
phytonutrient authors population
Antioxidant nutrients
α-lipoic acid Hager et al., Probable AD Treatment: 9 600 mg/day of α-lipoic acid Cognitive function stabilized according to the
2001 [3] and related over an average of 337 days MMSE and ADAS-cog
dementias
Hager et al., Mild-to- Treatment: 43 600 mg/day of α-lipoic Loss of cognitive function was progressively slower
2007 [4] moderate acid for up to 48 months in those with mild dementia compared to those with
dementia moderate-early and moderate-advanced dementia
according to the MMSE and the ADAS-cog
Shinto et al., Probable AD Ω-3: 13 α-lipoic acid/Ω-3 Less cognitive decline compared to placebo
2014 [5] Ω-3 + LA: 13 combination 600 mg 3 measured with the IADL and when compared to
Placebo: 13 times/day for 12 months placebo and Ω-3 only measured with the MMSE
Vitamin E (α- and Dysken et al., Mild-to- α-tocopherol: 140 2,000 IU/day of vitamin E Delay of 19%/year in clinical progression (ADL)
γ-tocopherols) 2014 [6] moderate AD Memantine: 142 for average of 2.27 years of AD and attenuated an increase in caregiver time
Combination: 139 compared to placebo
Placebo: 140
Lloret et al., Mild-to-severe Treatment: 19 800 IU/day of vitamin E Vitamin E respondents had lower blood-oxidized
2009 [7] AD Placebo: 14 for 6 months glutathione and scores on cognitive tests (the
MMSE, Blessed-Dementia Scale, and Clock
Drawing Test) were maintained, whereas when
vitamin E was not effective in preventing oxidative
stress (non-respondents) cognition decreased to
levels lower than those subjects on placebo
N-acetyl cysteine Breier et al., Early Treatment: 30 Escalating doses of NAC Significant decrease in negative symptoms (Positive and
2018 [8] schizophrenia Placebo: 30 (600 mg to 3,600 mg/day) Negative Syndrome Scale score), negative symptom
for 52 weeks factor, and disorganized thought factor compared to
placebo, but no improvement in positive symptoms
(Positive and Negative Syndrome Scale score)
Rapado-Castro Psychosis Treatment: 27 2,000 mg/day of NAC for Significant improvement in working memory
et al., 2017 [9] Placebo: 31 24 weeks performance as compared to placebo
Hoffer et al., Mild TBI Treatment before 24 h 4 g loading dose, then Significant symptom improvement including
2013 [10] (blast induced) NAC: 29 4 g/day for first 4 days, resolution of balance dysfunction, headache,
Placebo before 24 h: 31 and 3 g/day for the next confusion, and restoration of TMT performance
Treatment after (26 – 4 days of NAC scores to the age-based norms compared to placebo,
72 h) NAC: 12 and significantly more improvement noted in those
who were treated earlier than later with NAC
Placebo after (26 – 72
h): 9
Not primarily antioxidant nutrients
B vitamins Aisen et al., Mild-to- Treatment: 240 5 mg folic acid, 1 mg B12 No significant change was noted in cognition
2008 [11] moderate AD Placebo: 169 (cyanocobalamin), and according to the ADAS-cog
25 mg B6 (pyridoxine
hydrochloride) per day for
18 months
Durga et al., Middle-aged Treatment: 406 800 µg/day of folic acid Memory, information processing speed, and
2007 [12] subjects with Placebo: 413 for 3 years sensorimotor speed all significantly improved in the
elevated folic acid group compared to placebo
plasma
homocysteine
McMahon Elderly Treatment: 138 1,000 μg folic acid, 500 No assessments of cognitive functioning improved
et al., 2006 subjects Placebo: 138 μg B12, and 10 mg B6 per
[13] with plasma day for 2 years
homocysteine
concentrations
≥13 μmol/liter
(Contd...)
Table 1. (Continued)
De Jager et al., Elderly Treatment: 133 0.8 mg folic acid, 0.5 mg Executive function was maintained in the B vitamin
2012 [14] subjects with Placebo: 133 B12, and 20 mg B6 per group compared to placebo and in those with baseline
MCI day for 2 years homocysteine above the median value (11.3 mmol/L),
global cognition (MMSE), episodic memory (Hopkins
Verbal Learning Test–delayed recall), and semantic
memory (Category Fluency) improved in the B
vitamin group compared to placebo
Cholinergic Cotroneo Elderly Treatment: 265 1,000 mg/day of citicoline Cognitive function (MMSE) maintained
precursors - choline et al., 2003 subjects with Control: 84 for 9 months significantly more in citicoline group than control
(citicoline), lecithin [15] mild vascular group
(phosphatidylcholine), cognitive
and phosphatidylserine impairment
Alvarez-Sabin Subjects with Treatment: 172 1 g/day of citicoline for Attention, executive function, and temporal
et al., 2013 first-ever Control: 175 12 months orientation improved in the citicoline group
[16] ischemic compared to the control group
stroke
Knott et al., Healthy 24 (crossover) Subjects received 4 Executive function as measured by Groton Maze
2014 [17] subjects capsules of either 500 mg Learning Task was higher on the 500 mg dose,
with EEG or 1,000 mg citicoline in 3 while auditory gating executive function as indexed
similarities to separate testing sessions by suppression of the P50 event-related potential in
Schizophrenia a paired-stimulus paradigm was higher on the 1,000
mg dose
De Jesus Mild-to- Treatment: 132 400 mg of choline Cognitive function significantly improved as
Moreno et al., moderate AD Placebo: 129 alfoscerate 3 times/day for measured by the ADAS-cog
2003 [18] 180 days
Kato-Kataoka Subjects with PS100: 26 100 mg/day or 300 mg/ Significant improvement in delayed verbal recall
et al., 2010 mild memory PS300: 26 day of phosphatidylserine noted in both phosphatidylserine groups as
[19] impairment Placebo: 26 for 6 months compared to placebo
Richter et al., Older subjects Treatment: 30 300 mg/day of Significant improvements noted in memory
2013 [20] with age- phosphatidylserine for 12 recognition, memory recall, executive functioning,
associated weeks and mental flexibility on the computerized test and
memory total learning and immediate recall on the AVLT
impairment
More et al., Elderly Treatment: 40 300 mg/day of Significant improvements noted in memory
2014 [21] subjects with Placebo: 32 phosphatidylserine and according to the WMS and mood according to
memory 240 mg/day phosphatidic the List of Depressive Symptoms as compared to
problems acid for 3 months placebo
AD Treatment: 55 300 mg/day of Daily functioning (i.e., 7 ADLs) maintained in the
Placebo: 39 phosphatidylserine and treatment group significantly more than placebo
240 mg/day phosphatidic
acid for 2 months
Vitamin D Darwish et al., Relapse- Deficient/treatment: 41 Subjects who were Vitamin D3 significantly improved cognitive
2017 [22] remitting MS Sufficient/usual care: 47 25(OH)D deficient performance in the 25(OH)D deficient group as
consumed 10,000 IU/ compared to 25(OH)D sufficient group, according to
day of vitamin D3 for 3 the MoCA and the Brief Visuospatial Memory Test
months
Hu et al., 2018 Elderly Treatment: 93 400 IU/day of vitamin D3 Significant improvement noted in several domains
[23] subjects with Placebo: 88 for 12 months of the WAIS-R, e.g., information, digit span,
MCI vocabulary, block design, and picture arrangement
test, as compared to placebo, and significant
improvement noted in full IQ, verbal IQ, and
performance IQ in the vitamin D group
Jia et al., 2019 AD Treatment: 105 800 IU/day of vitamin D Significant improvements noted in several domains
[24] Placebo: 105 for 12 months of cognitive function, that is, full scale IQ,
information, digit span, vocabulary, block design,
and picture arrangement, as compared to placebo
(Contd...)
Dean et al., Healthy adults Treatment: 63 5,000 IU/day of No significant improvements noted in working
2011 [25] Placebo: 65 cholecalciferol for 6 memory (N-Back task), response inhibition (Stop-
months signal task), and cognitive flexibility (Set shifting
task)
Pettersen et al., Healthy adults Low dose: 40 Either high dose (4,000 Significant improvement noted in nonverbal
2017 [26] with baseline High dose: 42 IU/day) or low dose (visuospatial) memory in high dose group
25(OH)D≤100 (400 ID/day) vitamin D3
nmol/L (cholecalciferol) for 18
weeks
Omega-3 fatty acids Chiu et al., AD and Treatment: 24 1.8 g/day consisting of Significant improvement in cognition in patients
2008 [27] patients with Placebo: 22 720 mg DHA and 1,080 with minimum cognitive impairment, but not in
minimum mg EPA for 24 weeks AD patients, and a higher proportion of EPA in red
cognitive blood cell membranes was associated with better
impairment cognitive outcomes
Shinto et al., Probable AD Ω-3: 13 3 g/day consisting of 675 Significantly lesser decline noted in cognitive
2014 [5] Ω-3 + LA: 13 mg DHA and 975 mg EPA ability (MMSE) and functional ability (IADL) in the
Placebo: 13 and/or 600 mg/day of combination group (Ω-3 and LA) versus placebo or
racemic LA for 12 months Ω-3 alone, and Ω-3 only group also showed lesser
decline in functional ability (IADL) as compared to
placebo
Zinc Maylor et al., Healthy Younger 0 mg/day: 63 15 or 30 mg/day of zinc Significant improvements in both zinc groups
2006 [28] younger and Younger 15 mg/day: 60 for 6 months compared to placebo in cognitive function as
older adults Younger 30 mg/day: 65 measured with spatial working memory errors and
matching to sample visual search latency
Older 0 mg/day: 67
Older 15 mg/day: 66
Older 30 mg/day: 66
Phytonutrients
Aloe polysaccharides Wang et al., Healthy Treatment: 10 1-time polysaccharide Significant enhancements noted in the power of
2004 [29] male college Placebo: 10 mixture of 1 tablespoon EEG brain frequencies (theta, alpha, and beta) that
students containing 3.9 g of were related to attention and arousal in 30 min after
carbohydrates, 0.28 g of consumption as compared to placebo
protein, and 14 calories
Stancil et al., College 62 (crossover) 1-time polysaccharide Performance enhancement noted on the visual
2009 [30] students mixture of 1 tablespoon of discrimination task and on the first part of the
Ambrotose Complex in 4 simple working memory test after consumption
ounces of noncaloric fruit-
flavored water
Best et al., Middle-age Polysaccharides: 15 1-time consumption of No significant difference in cognitive function was
2008 [31] healthy Glucose: 15 either polysaccharides noted, but the scores were higher on immediate
subjects Placebo: 15 combination (7 g of and delayed recall and recognition 15 min after
powdered Ambrotose consumption compared to glucose
Complex) or glucose (25
g of powder)
Best et al., Middle-age Polysaccharides: 23 1-time consumption of Significantly higher scores on recognition and
2015 [32] healthy adults Sucrose: 24 either 4 g (1 tablespoon) working memory 30 min after consumption as
Placebo: 26 of a polysaccharide compared to the placebo and sucrose groups
mixture (Ambrotose
complex) or 4 g of
sucrose (icing sugar)
Lewis et al., Moderate-to- Treatment: 34 Aloe polymannose Clinically and statistically significant improvements
2013 [33] severe AD multinutrient complex noted in cognitive function (ADAS-cog) at 9 and 12
formula (20 g/day) for 12 months follow-up compared to baseline
months
McDaniel Relapse- Treatment: 15 Multinutrient, Significant improvements noted in all cognitive
et al., 2019 remitting MS polysaccharide dietary functioning and mood symptoms as measured by
[34] supplement regimen (~18 the Functional Assessment of MS and the Self-
g/day) for 12 months Assessment of Severity of MS Symptoms Scale
(Contd...)
Bacopa monnieri (L.) Sadhu et al., AD and Healthy: 109 Polyherbal formula Cognition improved in AD patients (per digit
Wettst. 2014 [35] healthy elderly AD: 123 including Bacopa symbol substitution, word recall immediate, and
individuals monnieri, sea buckthorn, attention span) and in healthy participants (per
and dioscorea (500 mg/ MMSE, digit symbol substitution, and word recall
day) for 12 months delayed) as compared to placebo
Goswami Newly Treatment: 50 300 mg Bacopa monnieri Significant improvements in cognition were noted
et al., 2011 diagnosed AD standardized extract as compared to baseline for orientation of time/
[36] twice/day for 6 months place/person, attention, reading, writing, and
comprehension measured with the MMSE
Kumar et al., Healthy Treatment: 28 150 mg standardized Significant improvements noted in attention,
2016 [37] medical Placebo: 18 extract Bacopa monnieri freedom from distractibility, and working memory
students twice/day for 6 weeks (digit span backwards test), immediate recall of
logical material and language comprehension
(logical memory test) as compared to placebo
Calabrese Elderly Treatment: 27 300 mg/day of Improvements noted in AVLT (delayed recall)
et al., 2008 subjects Placebo: 27 standardized Bacopa and Stroop Test scores as compared to baseline
[38] without signs monnieri extract for 12 and decreased anxiety (State-Trait Anxiety
of dementia weeks Inventory) and improved mood on the Center for
Epidemiologic Studies Depression scale
Stough et al., Healthy adults Treatment: 23 300 mg/day of Bacopa Significantly improved speed of visual information
2001 [39] Placebo: 23 monnieri extract for 2 processing (AVLT) and decreased anxiety (State-
weeks Trait Anxiety Inventory)
Stough et al., Healthy adults Treatment: 33 300 mg/day of Bacopa Significant improvements noted in spatial working
2008 [40] Placebo: 29 monnieri extract for 90 memory accuracy and RVIP (Cognitive Drug
days Research computerized assessment battery)
compared to placebo
Morgan et al., Elderly Treatment: 49 300 mg/day of Bacopa Significant improvements noted in verbal learning,
2010 [41] subjects Placebo: 49 monnieri extract for 12 memory acquisition, and delayed recall according to
weeks AVLT compared to placebo
Ginkgo biloba leaf and Attia et al., Brain tumor Treatment: 34 120 mg/day of Ginkgo Significant improvements noted in executive
Ginkgo biloba extract 2012 [42] survivors biloba leaf for 24 weeks function (TMT B), attention/concentration (TMT A)
(EGb 761) and intermediate, delayed recall non-verbal memory
(ROCFT), quality of life (Functional Assessment of
Cancer Therapy brain and physical subscales), and
distressed mood (Profile of Mood States)
Lewis et al., Healthy older Ginkgo Synergy + Ginkgo Synergy (120 mg/ Significant improvements in time on the TMT B
2014 [43] subjects with choline: 33 day Ginkgo biloba leaf, and COWA Trial-S as compared to baseline for the
no cognitive OPC Synergy + 80 mg/day Ginkgo biloba Ginkgo Synergy plus choline group
deficits Catalyn: 31 whole extract, and other
Placebo: 33 compounds) plus 700 mg/
day of choline or OPC
Synergy plus Catalyn for
6 months
Solomon et al., Community- Treatment: 115 40 mg/day of Ginkgo No improvements in learning, memory, attention, or
2002 [44] dwelling Placebo: 115 biloba for 6 weeks concentration
healthy older
subjects
Mix et al., Adults without Treatment: 24 180 mg/day EGb 761 for Significant improvement noted in speed of processing
2000 [45] cognitive Placebo: 24 6 weeks abilities (Stroop Test) as compared to placebo
dysfunction
Mix et al., Community- Treatment: 131 60 mg EGb 761 3 times/ Significant improvements noted in delayed free
2002 [46] dwelling older Placebo: 131 day for 6 weeks recall and recognition (SRT and WMS-III Faces II)
subjects as compared to placebo
Kaschel et al., Healthy Treatment: 94 240 mg/day of EGb 761 Significant improvements noted in the number of
2011 [47] middle-aged Placebo: 94 for 6 weeks correctly recalled appointments (immediate and delayed
subjects recall) and the quality of immediate and delayed recall
(ratio of false-to-correct) as compared to placebo
(Contd...)
Snitz et al., Older subjects Treatment: 1,545 120 mg EGb 761 2 times/ No significant improvement was noted in cognitive
2009 [48] with normal Placebo: 1,524 day for a median of 6.1 function as compared to placebo
cognitive years
function or
minimal
cognitive
impairment
Kanowski Pre-senile and Treatment: 106 240 mg/day of EGb 761 Statistically significant, but not clinically significant,
et al., 2003 senile AD and Placebo: 99 for 24 weeks improvements in cognitive function (SKT and
[49] multi-infarct ADAS-cog) compared to placebo
dementia
McCarney Mild-to- Treatment: 88 120 mg/day of EGb 761 No significant improvement was noted in cognitive
et al., 2008 moderate Placebo: 88 for 6 months function
[50] dementia
Mazza et al., Mild-to- Ginkgo: 25 160 mg/day of EGb 761 Significant improvements noted in cognitive
2006 [51] moderate AD Donepezil: 25 for 24 weeks function (SKT) and in overall patient condition
Placebo: 26 and therapeutic efficacy (CGI) in EGb 761 and
donepezil groups compared to placebo
Napryeyenko Probable/ Treatment AD: 106 240 mg/day of EGb 761 Significant improvements noted as compared to
et al., 2010 possible AD Treatment vascular: 94 for 22 weeks placebo in all cognitive function testes used, that is,
[52] or vascular Placebo AD: 112 Short Syndrome Test total scores, Neuropsychiatric
dementia Inventory, the Verbal Fluency Test, the Clock-
Placebo vascular: 88
Drawing Test, the Hamilton Rating Scale for
Depression, and the Gottfries-Bråne-Steen Scale,
and no differences between AD and vascular
dementia
Herrschaft Mild-to- Treatment: 205 240 mg/day of EGb 761 Significant improvements compared to placebo
et al., 2012 moderate AD Placebo: 205 for 24 weeks in cognitive function measured with the SKT,
[53] or vascular Neuropsychiatric Inventory, ADCS CGI of Change,
dementia the Verbal Fluency Test, the ADL International
Scale overall mean score, the Dementia Quality of
Life Instrument-Proxy total score, and the 11-point
box scale for dizziness
Lovera et al., MS Treatment: 61 240 mg/day of EGb 761 No improvement noted in cognitive function as
2012 [54] Placebo: 60 for 12 weeks compared to baseline or placebo
Gavrilova MCI Treatment: 80 240 mg/day of EGb 761 Improvements noted in cognition and global ratings
et al., 2014 Placebo: 80 for 24 weeks (TMT A and B) and anxiety (State-Trait Anxiety
[55] Inventory), while a trend was noted for the Geriatric
Depression scale score
Beck et al., Elderly Treatment: 31 240 mg/day of EGb 761 Significant improvement in cognitive flexibility
2016 [56] subjects with Placebo: 30 for 60 days (task-set switch costs) compared to placebo and a
subjective trend of improvement in response inhibition (Go-
memory NoGo-task reaction times) compared to placebo
impairment
Li et al., 2019 Vascular MCI Treatment (Pushen): 30 Either 19.2 mg/day of Significant improvements noted for both groups
[57] patients Control (Ginkgo): 32 EGb 761 or 1.8 mg 3 (Ginkgo and Pushen) in cognitive function as
times/day of Pushen for measured by the MoCA, but only the Pushen group
12 weeks showed significant improvement in the MMSE,
while the Ginkgo group showed only modest
improvement, both groups had higher scores for
Subjective Memory Loss, and the Pushen group
showed improvement in forgetting acquaintance’s
name, while the Ginkgo group performed
significantly worse for this component as compared
to Pushen
(Contd...)
Ginseng - Panax Wesnes et al., Middle age Total: 279 Either of 2 doses of a Quality of memory index significantly improved
ginseng C.A. Mey and 2000 [58] healthy Ginkgo biloba/Panax with the Ginkgo biloba/Panax ginseng combination
Panax (American) subjects ginseng combination; 160 for both doses, when compared to baseline, as well
quinquefolius mg twice daily and 320 as with the placebo, but other aspects of cognition
mg in the morning daily such as speed of memory index, continuity of
for 14 weeks attention, and power of attention did not improve
significantly
Park et al., MCI Treatment: 45 3 g/day of Panax ginseng Immediate recall and delayed recall (measured with
2019 [59] Placebo: 45 powder in capsules for 6 the ROCFT) significantly improved in the ginseng
months group compared to placebo, but no significant
improvements were noted in the K-MMSE,
K-IADL, and the Seoul Neuropsychological
Screening Battery
Heo et al., AD Low dose: 15 Either low dose (4.5 g/ Cognitive and functional performance (measured by
2008 [60] High dose: 15 day) or high dose (9 g/ ADAS and CDR) significantly improved in the high
Control: 31 day) Korean red ginseng dose ginseng group versus control
for 12 weeks
Heo et al., Moderately- Low dose: 10 Low dose (1.5 g/day), Cognitive function (measured with ADAS-
2012 [61] severe AD Intermediate dose: 10 intermediate dose (3 g/ cog and MMSE) significantly improved in the
High dose: 10 day), or high dose (4.5 g/ high-dose ginseng group compared to baseline,
day) of ginseng (SG-135) but no improvements were noted in the low- or
Control: 10
for 24 weeks intermediate-dose ginseng groups or placebo
Mariage et al., Healthy HRG80 (red ginseng): Either 2 capsules/day Error rate (d2 test) significantly reduced and
2020 [62] subjects with 17 (418 mg each) of red attention (d2 test) significantly improved in the
significant PGS (white ginseng): Panax ginseng Meyer root red ginseng group vs placebo, but not in the white
mental 16 preparation or 2 capsules/ ginseng group versus placebo, and memory (the
workload Placebo: 17 day (384 mg each) of computerized memory test) showed significant
during white Panax ginseng improvement in both red and white ginseng groups
workdays standard preparation for compared to placebo
2 weeks
Lee et al., AD Treatment: 58 Korean white ginseng Cognitive function (measured by the ADAS-cog
2008 [63] Control: 39 (Panax ginseng powder) and MMSE) significantly improved in the ginseng
4.5 g/day daily for 12 group vs control group, but improvement became
weeks insignificant after discontinuation of ginseng
Scholey et al., Healthy 32 (crossover) Received a 1-time dose of Cognition significantly improved (within 6 h of
2010 [64] subjects either 100, 200, or 400 mg treatment) from baseline, and each dose of ginseng
of Panax quinquefolius showed significant improvements for specific
extract in a capsule in aspects of cognition compared to placebo
separate treatments with
crossovers occurring after
7 days of wash-out
Chen et al., Stable Treatment: 32 1 capsule (100 mg) of Compared to baseline, visual working memory
2012 [65] schizophrenia Placebo: 32 ginseng (HT1001) twice/ significantly improved in the ginseng group but
day for 4 weeks not placebo, and verbal working memory did not
improve in the ginseng group, but significantly
worsened in the placebo group
Lion’s mane mushroom Mori et al., MCI Treatment: 15 4 tablets (250 mg each) Significant improvement in cognitive function
(Hericium erinaceus) 2009 [66] Placebo: 15 containing 96% lion’s according to the HDS-R in the lion’s mane group
mane powder 3 times/day compared to placebo
for 16 weeks
Saitsu et al., Over 50 years Treatment: 16 4 capsules (0.8 g each) Significant improvement in cognitive function
2019 [67] old with intact Placebo: 15 of lion’s mane/day for 12 according to the MMSE in the lion’s mane group
cognition weeks compared to placebo
(Contd...)
Rhodiola rosea Darbinyan Healthy young Group A (SHR-5 then Daily dose of SHR-5 Significant improvement in the total fatigue index
(Rhodiola rosea L.) et al., 2000 physicians placebo): 26 (170 mg of Rhodiola (based on results of 5 tests that measured visual
[68] with Group B (placebo then rosea and 4.5 mg of and audial perception speed, attention capacity, and
nonspecific SHR-5): 30 salidroside) for 2 weeks short-term memory as indicators of fatigue) after 2
fatigue followed by 2 weeks of weeks of taking the SHR-5 dose when compared to
wash-out then 2 weeks of placebo
placebo (order reversed
for the other group)
Cropley et al., Healthy, Treatment: 40 Daily dose of 200 mg of Significant improvements in self-reported anxiety
2015 [69] mildly anxious Control: 41 Vitano (main ingredient is and stress, significantly lower levels of anger,
university Rosalin (WS 1375), a dry depression, and confusion, and significantly
students extract from the roots of improved overall mood in the treatment group at 14
Rhodiola rosea) 2 times days compared to control; no significant differences
daily (30 min before in sleep, sleepiness, or cognitive performance
breakfast and 30 min between the control and treatment groups
before lunch) for 14 days
Fintelmann Adults with Group 1: 60 Vigodana (a vitamin Significantly improved physical performance noted
et al., 2007 physical and Group 2: 60 and mineral supplement at 12 weeks compared to baseline (assessed by
[70] cognitive containing a combination 4-point rating scale) and significant improvement
disabilities of vitamins E, B6, and in cognitive performance and decrease in cognitive
B12, folate, magnesium, impairment symptoms (assessed by digit connection
and Rhodiola rosea root test and 4-point rating scale) noted in both treatment
extract) taken 2 times/ groups compared to baseline; group 1 showed
day for 12 weeks. Group consistently higher improvements in both physical
1 took 2 capsules/day and cognitive performance by week 12 compared to
after breakfast and group group 2, though both groups showed significantly
2 took 1 capsule after improved performance compared to baseline
breakfast and 1 after
lunch daily
Aslanyan Healthy Treatment: 20 A single dose of 270 mg of Significantly improved performance on d2 Test
et al., 2010 females with Placebo: 20 ADAPT-232 (containing a of Attention and the Stroop Test that measured
[71] chronic stress standardized combination attention, speed, and accuracy of mental
extract ratio of 2.8:1 for performance in treatment group compared to
Rhodiola rosea, 1.4:1 placebo group
for Schisandra chinensis
(Turcz.) Baill., and 10.5:1
for Eleutherococcus
senticosus Maxim)
Rosemary (Rosmarinus Pengelly 2012 Healthy 28 (crossover) Received in random order Significant improvements noted for the lowest dose
officinalis L.) [72] elderly one of 4 doses of dried in speed of memory measurements, continuity of
subjects rosemary (750, 1,500, attention, quality of working memory as compared to
3,000, or 6,000 mg) or placebo and/or baseline within 6 h of consumption,
placebo on 5 separate but the higher dose negatively affected performance
1-day treatment sessions and subjective feelings of alertness
every week for 5 weeks
Lindheimer Young adults Rosemary: 26 1-time consumption of 1.7 Transient and statistically insignificant decrements
et al., 2013 with low Black pepper: 26 g of rosemary were noted in mental fatigue on a visual analog
[73] energy Placebo: 24 scale and false alarms during the primary cognitive
task in 60 and 90 min after consumption
Moss et al., Healthy adults Rosemary water: 40 1-time consumption of Small to moderate beneficial effects for performance
2018 [74] Plain water: 40 250 mL water infused on several tasks: the Corsi blocks mean span length,
with rosemary serial threes and serial sevens correct responses,
RVIP correct responses and errors, and immediate
and delayed word recall, and a slight negative effect
was noted on fatigue on a visual analog scale
(Contd...)
Moss et al., Healthy Rosemary: 48 1-time ambient Significantly higher scores on a secondary memory
2003 [75] subjects Lavender: 48 aromatherapy with subfactor (indicating better accuracy during
Control: 48 4 drops of rosemary memory-related tasks) and subjective feelings of
essential oil alertness and contentedness compared to control,
but the control group had significantly quicker
responses (speed of memory factor and speed of
attention factor)
Saffron (Crocus sativus Akhondzadeh Mild-to- Treatment: 23 30 mg/day of saffron for Significant improvements in cognitive function
L.) et al., 2010 moderate AD Placebo: 23 16 weeks (ADAS-cog and CDR-SB) compared to the placebo
[76] group
Akhondzadeh Mild-to- Saffron: 27 30 mg/day of saffron or Improvements in cognitive function (ADAS-cog
et al., 2010 moderate AD Donepezil: 27 10 mg/day of donepezil and CDR-SB) were similar in both groups
[77] for 22 weeks
Farokhnia Mild-to- Saffron: 34 30 mg/day of saffron or Improvements noted in cognitive function (Severe
et al., 2014 moderate AD Memantine: 34 20 mg/day of memantine Cognitive Impairment Rating Scale and Functional
[78] for 12 months Assessment Staging) were similar in both groups
Tsolaki et al., Amnestic MCI Treatment: 17 Saffron extract for 12 Significant improvement noted in saffron group
2016 [79] Control: 18 months (MMSE) while control group deteriorated
Tart cherries (Prunus Kent et al., Older adults Treatment: 24 200 mL/day of cherry Significant improvements noted in cognitive
cerasus L.) 2017 [80] with mild- Control: 25 juice for 12 weeks performance as measured by the category verbal
to-moderate fluency task, AVLT total, AVLT delayed recall, and
dementia AVLT 20-min delayed recall tasks
Caldwell et al., Older adults Young, healthy: 6 1-time crossover No improvements in acute cognition as measured
2016 [81] with dementia, Older adults: 5 consumption of with AVLT, pattern and letter comparison, or task-
older adults, Older adults with anthocyanin-rich cherry switching tests
and young dementia: 5 juice in one of 2 dose
healthy adults schemes: (1) a single 300
mL dose at 0 h or (2) 100
mL doses at 0, 1, and 2 h
Keane et al., Middle-aged 27 (crossover) 1-time crossover No improvement in cognitive function
2016 [82] subjects consumption of either
60 mL of tart cherry
concentrate or placebo
Turmeric Cox et al., Healthy adults Treatment: 30 400 mg (~80 mg Significant improvements in sustained attention
(Curcuma longa L.) 2015 [83] Placebo: 30 curcumin) of Longvida (digit vigilance task), working memory (serial threes
(a solid lipid curcumin subtraction task), alertness, contentedness, mood,
formulation) for 4 weeks and fatigue in comparison to placebo
Cox et al., Healthy older Treatment: 46 400 mg (~80 mg Significant improvements in working memory
2020 [84] adults Placebo: 43 curcumin) of Longvida performance on the virtual Morris Water Maze and
(a solid lipid curcumin on serial threes and serial sevens as compared to
formulation) for 12 weeks placebo
Rainey-Smith Community- Treatment: 80 500 mg 3 times/day Although no significant effects were noted,
et al., 2016 dwelling, Placebo: 80 Biocurcumax, a curcumin Biocurcumax did delay cognitive decline as
[85] cognitively- formulation for 12 months compared to placebo
healthy older
adults
Small et al., Middle Treatment: 21 Theracurmin (90 mg twice Significant improvements in SRT Consistent
2018 [86] age and Placebo: 19 a day highly bioavailable Long-Term Retrieval, SRT Total, Brief Visual
older adults nanoencapsulated Memory Test-Revised, and attention as compared
with intact curcumin) for 18 months to placebo, and significant decrements of brain Aβ
cognition and tau accumulation in amygdala in brain positron
emission tomography scans as compared to placebo
Wild yam (Dioscorea Tohda et al., Healthy adults Treatment: 18 50 mg/day of diosgenin- Significant age-dependent improvement noted
villosa L.) 2017 [87] Placebo: 13 rich yam extract for 12 in cognitive function (Repeatable Battery for the
weeks Assessment of Neuropsychological Status) as
compared to placebo
(Contd...)
Withania somnifera (L.) Choudhary Adults with Treatment: 25 300 mg of KSM-66 Significantly improved performance on immediate
Dunal - Ashwagandha et al., 2017 MCI Placebo: 25 Ashwagandha taken 2 and general memory, executive function, attention,
[88] times/day for 8 weeks and information-processing speed after 8 weeks of
ashwagandha compared to placebo; working memory
and visuospatial processing were insignificant
Chengappa Bipolar Treatment: 30 500 mg/day of Withania Significant improvements in performance on
et al., 2013 disorder Placebo: 30 somnifera extract Flanker Test (neutral mean response time), Auditory
[89] (Sensoril) for 8 weeks Digit Span (mean digit span backward), and Penn
Emotional Acuity Test (mean social cognition
response rating) of Withania somnifera compared to
placebo at 8 weeks
Xanthines (caffeine) Soar et al., Regular 43 (crossover) Caffeinated coffee Significantly faster mean reaction time on the
2016 [90] caffeine users (~50 mg caffeine) or Stroop Test and performed significantly better on the
decaffeinated coffee Jansari Assessment of Executive Functions (average
administered at 2 points 1 performance, planning, creative thinking, event
week apart based prospective memory, time based prospective
memory, and action based prospective memory)
Smith et al., Healthy adults Caffeinated: 64 1-time consumption of Significantly faster simple reaction times, indicating
2013 [91] Decaffeinated: 64 either caffeinated coffee increases in speed of encoding and response to a
(65 mg caffeine) or novel stimulus, extroverts performed better in the
decaffeinated coffee running memory task, and introverts performed
worse, and caffeine improved performance in the
mental rotation task for those with high anxiety and
hindered performance in those with low anxiety
Haskell- Regular coffee 72 (crossover) 1-time crossover Significantly better digit vigilance accuracy and
Ramsay et al., drinking consumption of either reaction time, compared to the decaffeinated coffee
2018 [92] young adults caffeinated coffee (100 mg and placebo groups, respectively, significantly faster
caffeine), decaffeinated RVIP reaction time compared to the placebo group,
coffee, or coffee-flavored and significantly better mood and mental fatigue
placebo water ratings noted as compared to placebo
Higashi et al., Healthy adults Treatment: 14 1-time consumption of On average, the number of answers per session
2004 [93] either caffeinated coffee increased in the caffeine group and decreased in the
(180 mg caffeine) or decaffeinated group, likely due to mental fatigue
decaffeinated coffee and
then crossed over to the
other beverage after at
least 1 week
Hindmarch Habitual 30 (crossover) Caffeinated black leaf tea Caffeinated beverages significantly maintained
et al., 2000 caffeine (either 37.5 mg/1 cup or performance throughout the day (critical flicker
[94] drinkers 75 mg/2 cups), caffeinated fusion task), at the same dose of caffeine, tea
black coffee (75 mg/1 produced a rapid increase in the critical flicker
cup or 150 mg/2 cups) or fusion threshold between 30 and 90 min post-
bottled water at 4 different consumption significantly more than coffee, at the
times of the day same caffeine dose, compared to tea, coffee was
associated with significantly faster reaction times
between 10 and 90 min post-consumption
De Bruin et al., Healthy adults 26 (crossover) 1-time consumption of 2 Significantly more correct responses on intersensory
2011 [95] servings of black tea (50 attention subtasks (auditory and visual) and
mg caffeine and 23 mg responded faster (visual) compared to placebo,
theanine/serving) over and significantly more correct responses for task
60 min switching and felt significantly more alert, but less
calm compared to placebo
Healthy adults 32 (crossover) 1-time consumption of 3 A trend for more correct responses noted for
servings of black tea (30 visual unisensory subtask (although statistically
mg caffeine and 12 mg insignificant), and correct responses for the task
theanine/serving) over switching and feeling of alertness and contentedness
90 min were significantly higher than in placebo
(Contd...)
Dietz et al., Moderate/ 23 (crossover) Matcha tea or a matcha Significant improvement noted in tasks measuring
2017 [96] habitual snack bar (each basic attention abilities, and psychomotor speed
consumers of containing 4 g matcha in response to stimuli as compared to placebo, no
caffeine (100- powder with 67 mg significant changes in mood noted, and in most
400 mg/day) theanine and 136 mg cognitive tasks the drink outperformed the snack
caffeine) or placebo tea bar, particularly in tasks measuring the speed
or placebo bar; treatment of spatial working memory and delayed picture
repeated for 4 days recognition
and each day cognitive
function was assessed
Smit et al., Chocolate 20 (crossover) 1-time consumption of Significantly faster simple reaction time response
2004 [97] consumers chocolate with cocoa speeds and significantly higher self-reported
powder or chocolate energetic arousal occurred after administration of
containing 250 mg the cocoa powder and caffeine, while significantly
theobromine and 19 mg better performance on the RVIP task and
caffeine significantly improved hedonic tone occurred after
administration of the caffeine compared to placebo
Chocolate 22 (crossover) 1-time consumption High methylxanthine significantly increased
consumers of 60 g portions (12 reaction speed compared to zero methylxanthine
squares) of chocolate for the simple reaction time task, and both low and
with no methylxanthines high methylxanthine significantly improved RVIP
(placebo), low performance compared to zero methylxanthine,
methylxanthines (8 mg and mood scores for energetic arousal and hedonic
caffeine + 100 mg tone were not significantly different between the
theobromine), or high treatment groups
methylxanthines (20
mg caffeine + 250 mg
theobromine)
Sumiyoshi Japanese Dark chocolate: 10 Dark chocolate (26.8 mg Dark chocolate significantly increased the number
et al., 2019 undergraduate White chocolate: 8 caffeine and 197.5 mg of correct answers on the modified Stroop Test after
[98] students theobromine/day) or white consumption and maintained a marginally higher
chocolate (non-detectable number of correct responses at 30 days follow-up,
methylxanthine) for 30 as compared to baseline, dark chocolate significantly
days increased the total performance (digital cancellation
test) after consumption and at 30 days follow-up
compared to baseline, and white chocolate did not
improve any of the above at any stage
nine subjects aged 55 years or older were enrolled in a 12-month 3.1.1.2. Vitamin E (α- and γ-tocopherols)
intervention and randomized into one of 3 groups: (1) Ω-3 fatty
Vitamin E (α- and γ-tocopherols) is an essential fat-soluble
acids of 3 g/day including 675 mg of docosahexaenoic acid
vitamin and antioxidant. Dietary sources of vitamin E include nuts,
(DHA) and 975 mg eicosapentaenoic acid (EPA; n=13); (2) the
seeds, and vegetable oils. As a potent natural antioxidant, vitamin
same Ω-3 fatty acids plus racemic lipoic acid 600 mg/day (n=13);
E scavenges free radicals in the cell membrane and protects
or (3) placebo of various excipients and oils (n=13). Oxidative polyunsaturated fatty acids from lipid peroxidation [105,106].
stress was the primary outcome, and cognitive and functional The central nervous system (CNS) is especially vulnerable to lipid
performance were secondary outcomes. The combined treatment peroxidation due to its high lipid content, so it is possible that the
group showed less decline according to the Instrumental Activities fat solubility of vitamin E may prove advantageous for protecting
of Daily Living (IADL) scale compared to placebo. The combined these lipids [107]. Systemic oxidative stress is a hallmark of AD
treatment also showed less of a decline according to the MMSE and is correlated with cognitive function [7]. In relation to AD
compared to placebo and Ω-3 fatty acids alone, but not according pathogenesis, it is proposed that Aβ imparts its neurotoxicity
to the ADAS-cog. Oxidative stress was not improved by either through a cascade of free radicals within the neurons that disrupt
treatment regimen. Thus, while the combination treatment slowed functioning [106,108]. Vitamin E can block hydrogen peroxide
the cognitive and functional decline in probable AD patients over formation and its resultant free radical cytotoxicity [108].
12 months, despite no changes in the biomarkers, it is uncertain It has been demonstrated that depletion of vitamin E in an AD
if the effects were due to the synergy between the compounds or mouse model reduced Aβ clearance from the brain and the blood
lipoic acid alone, since a lipoic acid-only group was not studied. and resulted in Aβ accumulation [105]. Therefore, vitamin E
may play an important role in Aβ clearance. Lipid peroxidation NAC has been investigated in cases of psychotic disorders, such
was also significantly increased and localized where Aβ had as schizophrenia and psychosis. Schizophrenia is characterized
accumulated. Subsequent vitamin E supplementation following by negative symptoms and cognitive impairment [112], often
depletion partially reduced these effects. These results suggest that leading to poor quality of life and functional deficits [113]. Early
in individuals who are genotypically predisposed to AD, vitamin schizophrenia is often marked by progressive loss of brain mass,
E deficiency may pose a risk factor for acceleration of the disease. with reductions in cortical thickness [114], which is hypothesized
In a retrospective study from the Consortium to Establish to be caused by oxidative stress [115], inflammation [116], and
a Registry for AD database, patients diagnosed with probable glutamatergic excitotoxicity [117]. Therefore, the antioxidant
AD who had taken at least 5 mg/day of donepezil and 1,000 IU/ effects of NAC, such as increases in glutathione and mitigation
day of vitamin E had a significantly lesser decline than patients of pro-inflammatory cytokine levels [118], as well as its ability to
who received no treatment [109]. Although this finding does not regulate glutamatergic function [119], make it a good candidate
establish efficacy for vitamin E in treating or attenuating AD for treating chronic schizophrenia.
progression, it demonstrates that vitamin E probably does not Thus, 60 subjects with early schizophrenia were randomized
interfere with the action of donepezil, an FDA-approved AD for 52 weeks to receive either escalating doses of NAC (600 mg –
treatment. In a study, patients with mild-to-moderate AD taking 3,600 mg/day; n=30) or placebo (n=30), in addition to stable doses
AChEIs who were given vitamin E treatment of 2,000 IU/day for of antipsychotic medications [8]. Those who received NAC had
an average of 2.27 years experienced a 19%/year delay in clinical significant decreases in the Positive and Negative Syndrome Scale
progression measured by the Activities of Daily Living (ADL) total score, negative symptom factor, and disorganized thought
scale and an attenuation of increased caregiver time, compared factor compared to placebo. Although brain morphology did not
to placebo [6]. change, the change in total Positive and Negative Syndrome Scale
In another study, where 33 AD patients were given either score was significantly associated with baseline right, left, and total
800 IU/day of vitamin E (n=19) or placebo (n=14) for 6 months, mean cortical thickness, baseline right, left, and middle temporal
the concept of respondents and non-respondents to vitamin E thickness, baseline right, left, and superior parietal thickness,
supplementation was proposed [7]. Those who experienced a and baseline left caudal middle frontal thickness at 24 weeks
reduction in blood glutathione oxidative stress (respondents) with and baseline left superior parietal thickness at 52 weeks in the
NAC group, with greater thickness being associated with more
vitamin E supplementation also saw maintenance of cognitive
improvement. Thus, NAC seems to improve multiple cognitive
function, according to the MMSE, Blessed-Dementia Scale,
symptoms of schizophrenia but does not appear to improve
and Clock Drawing Test, while those who did not experience a
Positive and Negative Syndrome Scale positive symptoms. In
reduction in oxidative stress (non-respondents) actually had a
addition, while NAC treatment does not confer changes in brain
decrease in cognitive function to a level less than that of those
morphology, it appears that baseline thickness of multiple regions
taking placebo. Approximately half of the AD patients were non-
is positively associated with the degree of symptom improvement.
respondents and did not see a decrease in markers of oxidative
Therefore, adjunctive NAC could potentially improve function
stress [7]. The negative outcomes observed in non-respondents
in patients with schizophrenia, especially those with less severe
possibly occurred through vitamin E acting as a pro-oxidant and
progressive brain mass loss.
imparting deleterious effects. Because vitamin E is lipophilic, it
In another study, 58 patients with psychosis were randomized
acts on membrane lipids to scavenge radicals. Oxidized vitamin
for 24 weeks to receive either 2,000 mg/day of NAC (n=27)
E can be restored to its antioxidant form by passing the radical or placebo (n=31) [9]. NAC significantly improved working
to a hydrophilic electron acceptor that is free to move within memory performance, with significantly higher performance
the aqueous cytoplasm [110]. If the oxidized vitamin E is not at 24 weeks compared to placebo. Therefore, NAC had a
subsequently reduced, it can act as a pro-oxidant on surrounding significant impact on cognitive functioning in patients with
membrane lipids [110]. Based on these findings, it may be psychosis through improvements in working memory, a crucial
beneficial to combine the fat-soluble vitamin E treatment with prognostic variable that currently has not been improved with
supplementation of a water-soluble antioxidant, such as vitamin C pharmaceutical approaches [120]. Overall, NAC appears to
(i.e., ascorbic acid) for superior antioxidant activity. be effective in treating symptoms of cognitive impairment in
3.1.1.3. N-acetyl cysteine (NAC) psychotic disorders.
NAC has also been investigated in treating symptoms of acute
NAC is a precursor to glutathione and is the rate-limiting conditions, such as mild traumatic brain injury (mTBI). Diagnosis
substrate for glutathione synthesis. Thus, supplementation of mTBI requires the occurrence of a traumatic event, with a loss or
with NAC has been found to increase intracellular glutathione alteration of consciousness, accompanied by at least 1 neurologic
in erythrocytes [111], possibly giving it the potential to exert or cognitive symptom (most commonly dizziness) [121]. However,
the same effect in the brain. Since multiple neurodegenerative not all TBIs can be treated equally; e.g., treatment for blunt head
disorders are characterized by glutathione deficits in the CNS and trauma is not necessarily the same as that for blast injury [122].
impaired response to oxidative stress, NAC supplementation may Therefore, subjects with mTBI from significant blast exposure
be beneficial in these patients and in those with brain injury. during military deployment were randomized to receive either
NAC or placebo for 7 days (4 g loading dose, followed by persons with dementia and AD [124]. Studies have shown that
4 g/day for the first 4 days, and 3 g/day for the remaining 4 days) combinations of B vitamins are generally more effective than a
to investigate if the neuroprotective effects of NAC extended to single vitamin treatment, but inconsistencies in the findings on
symptoms of mTBI [10]. In addition, the differential outcome cognitive function may be due to polymorphisms in B vitamin-
effects of early (within 24 h; treatment n=29, placebo n=31) and associated biochemical pathways and methodological differences
delayed (26-72 h; treatment n=12, placebo n=9) diagnosis and across studies, e.g., different doses, treatment periods, assessments,
treatment were examined. The NAC group was significantly more and baseline vitamin levels [123,125]. In addition, a recent meta-
likely to achieve symptom resolution after 7 days of treatment. analysis revealed that although plasma homocysteine, a known
The number of symptoms on day 7 was attributed independently risk factor for cognitive impairment and dementia, is lowered with
to both the treatment itself and early treatment initiation, with B vitamin intake, cognitive functioning is generally not improved
significantly less symptoms in the early treatment NAC group by the same treatment in both adults with and without existing
compared to the delayed treatment placebo group. However, cognitive dysfunction [126]. The lack of benefit on cognitive
the number of symptoms in the delayed treatment NAC group functioning through B vitamin supplementation could be due to
did not differ significantly from either of the placebo groups. variation in the type of treatment, duration of the intervention,
The early treatment NAC group had the best odds of complete and other study design differences. Nonetheless, some of these
symptom resolution at day 7. Regression analysis revealed that findings are discussed below.
NAC treatment was significantly better than placebo, and early In a large multi-center trial executed by the Alzheimer Disease
intervention was significantly better than delayed intervention. Cooperative Study consortium, 409 subjects with mild-moderate
More specifically, early NAC treatment had a significant effect AD (MMSE between 14 and 26) and normal levels of folic acid,
on the resolution of balance dysfunction and absence of headache B12, and homocysteine were randomized to either (1) 5 mg/day
on day 7. Confusion resolution at day 7 was also significantly folic acid, 1 mg/day B12 (cyanocobalamin), and 25 mg/day B6
associated with early treatment time compared to delay. Treatment (pyridoxine hydrochloride; n=240) or (2) an identical placebo
with NAC also restored normal Trail Making Tests (TMT) A and tablet (n=169) for 18 months [11]. The ADAS-cog score was
B performance within 7 days, reaching equivalent scores to age- the primary outcome, along with other measures of cognition
based norms, while those in the placebo group remained impaired. and quality of life, and homocysteine and other biomarkers were
TMT time was also impacted by the presence of symptoms. Those secondary outcomes of interest. The change in the ADAS-cog
with symptoms had prolonged times, while those without had score over the 18-month period was 0.40 points/month for the B
shorter times, indicating that these symptoms impacted cognitive vitamin treatment group compared to 0.37 points/month for the
function. Day 3 symptoms were significantly predicted by both placebo group, which was non-significantly different. In addition,
NAC treatment status and tympanic membrane perforation, which changes in all secondary cognition and quality of life measures
is a common injury in those with blast exposure. However, for the were also similar, despite a significant reduction in plasma
early treatment group, reduction in day 7 symptoms with NAC homocysteine in the B vitamin treatment group. Thus, vitamin B
supplementation was not able to delay cognitive decline in mild to
treatment occurred independently of tympanic membrane status.
moderate AD patients.
Therefore, NAC appears to be an effective way to treat symptoms
In another large multi-center study as part of the Folic Acid
of mTBI from blast exposure and should ideally be administered
and Carotid Intima-media Thickness trial, the effect of 3 years of
within 24 h of injury.
folic acid supplementation was examined on cognitive function in
3.1.2. Not primarily antioxidant nutrients adults 50 – 70 years of age with intact cognitive function, elevated
plasma homocysteine, and normal serum vitamin B12 levels [12].
3.1.2.1. B vitamins Participants (n=819) were randomly assigned to receive 800 µg/
day of folic acid (n=406) or identical placebo (n=413) and were
The B vitamins, B6 (pyridoxine), B9 (folic acid or folate), assessed at baseline and 3 years on various measures of cognitive
and B12 (cobalamin), have known relationships with neuronal functioning. Serum folate increased and plasma homocysteine
development, maintenance, and function, and their deficiencies decreased in those on folic acid compared to placebo. Changes in
are linked to dementia (cognitive dysfunction) and psychiatric memory, information processing speed, and sensorimotor speed
disorders, such as depression, schizophrenia, and bipolar [123]. all significantly improved in the folic acid group compared to
B vitamins are crucial for methyl group donation reactions during placebo. Thus, folic acid demonstrated improvements in certain
the synthesis of proteins, lipids, nucleic acids, neurotransmitters, domains of cognitive functioning and a decrease in homocysteine,
and hormones, e.g., methylenetetrahydrofolate reductase, and which may prove important for maintaining intact cognition in
B9 and B12 are a part of the methionine synthase complex that older normal adults.
reduces homocysteine to methionine [123]. Folate is required Another large clinical trial was conducted in 276 healthy adults
for cellular synthesis, repair, and methylation, and it is necessary aged ≥65 years of age with plasma homocysteine concentrations
to keep homocysteine at a normal value and for its methylation of ≥13 μmol/liter [13]. Subjects were randomized for 2 years to
to methionine [124]. It has previously been found that serum receive either a daily dose of folate of 1,000 μg, B12 of 500 μg,
homocysteine is higher and folate and B12 are lower in and B6 of 10 mg (n=138) or an identical placebo (n=138) and
were assessed using a neuropsychological battery of multiple under 80 years with mild vascular cognitive impairment [15].
assessments of cognitive functioning at baseline and after 1 and The citicoline group (n=265) consumed 1,000 mg/day versus no
2 years of intervention. Although plasma homocysteine was treatment in the comparison group (n=84) for 9 months. Change
significantly lower at 12 and 24 months in the active treatment in cognitive function was analyzed from baseline to 3 months
group compared to placebo, none of the assessments of cognitive and 9 months using the MMSE, and functionality was assessed
functioning differed between groups. Thus, this treatment regimen using the ADL and IADL scales. Overall, significant differences
of B vitamins did not improve cognitive function, despite a on the MMSE were noted between the citicoline and comparison
reduction in homocysteine. groups at 3 and 9 months. The ADL and IADL scores were not
In a clinical trial of adults aged ≥70 years of age with mild different between the 2 groups at any time point. Thus, citicoline
cognitive impairment (MCI), 166 subjects were randomized was effective for improving cognitive function compared to no
for 2 years to receive a daily treatment of 0.8 mg of folic acid, treatment for patients with mild vascular cognitive impairment,
0.5 mg of B12, and 20 mg of B6 (n=133) or an identical placebo and the compound was well-tolerated without adverse effects.
(n=133) [14]. MCI leads to dementia in about 50% of cases, Cognitive dysfunction is most likely to arise after an initial stroke
so a remedy to slow or reverse this condition is a public health (compared to subsequent strokes), and stroke also increases the risk
priority [127]. While the rate of brain atrophy was the primary of vascular dementia [131]. Thus, treatments are needed to lessen
outcome of interest in the original study, a large battery of the complications after the first stroke, particularly in maintaining
cognitive functioning and plasma homocysteine was collected as cognitive function. Because citicoline has shown greater efficacy
secondary outcomes. Plasma homocysteine decreased by 30% in in the early phase of stroke recovery compared to placebo [132],
the B vitamin group compared to placebo. In addition, executive studying its effects on cognitive function after stroke is warranted,
function, a measure of cognitive function, was maintained in the particularly in light of the lack of viable treatment options. Thus, in
B vitamin group compared to placebo. In those subjects with a study of patients with first-ever ischemic stroke, 347 subjects were
baseline homocysteine above the median value (11.3 mmol/L), randomized for 12 months to citicoline (1 g/day) plus usual treatment
global cognition (according to the MMSE), episodic memory (n=172) compared to usual treatment (n=175), 6 weeks after suffering
(according to the Hopkins Verbal Learning Test-delayed recall), a qualifying stroke [16]. Subjects were assessed on 6 domains of
and semantic memory (Category Fluency) improved in the B cognitive functioning at 1, 6, and 12 months after stroke. Compared
vitamin group compared to placebo. Thus, B vitamin treatment with usual treatment only, patients on citicoline scored higher on
may diminish the rate of cognitive decline in persons with MCI, assessments of attention-executive function and temporal orientation
particularly those with a high level of plasma homocysteine. at 6 and 12 months. Thus, citicoline shows promise in improving
some domains of cognitive functioning in the first 12 months of post-
3.1.2.2. Cholinergic precursors - choline (citicoline), lecithin
stroke recovery and did not cause significant adverse events.
(phosphatidylcholine), and phosphatidylserine
Persons with schizophrenia have lower auditory sensory gating
Choline is an essential nutrient that must be attained from the and related cognitive dysfunction [133], likely due in part to altered
diet and is the precursor to acetylcholine, a key metabolic mediator expression and function of the alpha-7 nicotinic acetylcholine
of memory within the brain [128,129]. Phosphatidylserine is the receptor [134,135]. Given that choline is a selective alpha-7 nicotinic
primary phospholipid in the brain and is mainly found in the acetylcholine receptor agonist, citicoline holds promise as a treatment
plasma neuronal membrane. It acts as an antioxidant in the brain approach [136]. Thus, healthy adults with electroencephalogram
and increases brain glucose metabolism [20,21]. Thus, decreasing (EEG) similarities to those with schizophrenia (n=24) treated with
levels of phosphatidylserine are related to memory impairment [21]. either citicoline or placebo were assessed on executive function
Among other pathological features, AD is characterized by a loss using the Groton Maze Learning Task of the CogState Schizophrenia
of cholinergic function in the neocortex and hippocampus, which Battery and on auditory gating, as indexed by suppression of the P50
was the basis for the use of AChEI and precursors of acetylcholine, event-related potential in a paired-stimulus paradigm [17]. Subjects
such as choline, lecithin, and phosphatidylserine [128]. However, were randomized to receive 4 identical-looking capsules of either
the results of treatment on cognitive functioning with these 500 mg citicoline, 1,000 mg citicoline, or placebo in 3 separate
cholinergic precursors have been inconsistent at best. testing sessions, with testing occurring 3 h after administration of
the treatment. Subgroup analysis revealed that performance on the
3.1.2.2.1. Citicoline Groton Maze Learning Task was better after the 500 mg dose, and
Citicoline has been hypothesized as a superior form of choline, gating was better after the 1,000 mg dose. Thus, citicoline showed
due to its choline content and its lower susceptibility to being preliminary benefits for executive function in this sample of subjects
transformed into trimethylamine, a compound that may later with EEG similarities to those with schizophrenia, implying it may
undergo hepatic oxidization to trimethylamine N-oxide, a suspected be effective in those with the disorder.
factor in various chronic diseases [130]. Thus, the effects of
3.1.2.2.2. Choline alfoscerate
citicoline on cognitive function have been investigated in various
populations. In a study, the efficacy of citicoline was investigated Mild to moderate AD patients (n=261) were randomized to
in a large sample (n=349) of older people with a mean age of just receive choline alfoscerate (400 mg; n=132) or placebo (n=129)
3 times/day for 180 days to determine its effects on cognitive were randomly assigned for 2 months to either 300 mg/day of
functioning according to the ADAS-cog, MMSE, and other phosphatidylserine and 240 mg/day of phosphatidic acid (n=55)
measures from baseline to after 90 and 180 days of treatment [18]. or placebo (n=39) and were assessed on daily functioning, mental
The ADAS-cog score significantly improved by 2.4 and 3.2 health, emotional state, and self-reported general condition. Daily
points at 90 and 180 days, respectively, in the choline alfoscerate functioning (i.e., performance on 7 ADLs) stayed the same in the
group, whereas it significantly deteriorated by 0.4 and 2.9 points treatment group, but declined in the placebo group, and the group
in the placebo group. Other cognitive measures also generally difference was significant. Overall deterioration and stability were
improved in the choline group compared to placebo. Thus, choline significantly better in the treatment group compared to placebo.
alfoscerate demonstrated significant improvement in cognitive Approximately half of the treatment group reported an overall
functioning in AD patients without adverse effects. increase in general condition compared to just over one-quarter of
the placebo group. Overall, the combination of phosphatidylserine
3.1.2.2.3. Phosphatidylserine
and phosphatidic acid showed significant improvements in elderly
Older Japanese people (50 – 69 years old) with mild memory subjects with memory complaints and in AD patients for multiple
impairment participated in a randomized trial evaluating the effects outcomes, including cognition, mood, daily functioning, and
of 2 different amounts of soybean-derived phosphatidylserine general condition.
compared to placebo on various measures of cognition
3.1.2.3. Vitamin D
functioning [19]. Eligible subjects (n=78) were randomized to
take either (1) 100 mg/day of phosphatidylserine (n=26), (2) Vitamin D is now universally recognized for its importance
300 mg/day of phosphatidylserine (n=26), or (3) placebo (n=26) in preventing a host of chronic diseases, and its deficiency
for 6 months. Hasegawa’s Dementia Scale, Rivermead Behavioral (25-hydroxyvitamin D (25(OH)D) level <20 ng/mL) or insufficiency
Memory Test, and MMSE, equally improved in all 3 groups at the (25(OH)D level 21 – 29 ng/mL) is a serious global public health
end of the study, possibly due to practice effects. Nonetheless, challenge, with insufficiency affecting as many as 1 billion people
those subjects in both phosphatidylserine groups who scored worldwide [137]. Even with the recognized importance of vitamin
lower at baseline on the cognitive assessments showed significant D for cellular function, the exact insufficiency level is still debated,
increases in delayed verbal recall compared to placebo, which did the desired clinical values are related more to skeletal health, not
not change. Thus, phosphatidylserine may help some aspects of cognitive outcomes, and the optimal level is also unclear [26,138].
cognitive functioning among older people who have subjective Nonetheless, related to mechanistic aspects of brain function, it has
memory complaints, without adverse effects. been shown that vitamin D increases acetylcholine levels [139]
In a smaller study of older adults (aged 50-90; n=30) and hippocampal neuron densities [140] and augments Aβ
with age-associated memory impairment, soybean-derived clearance [141]. In addition, the vitamin D receptor localized in the
phosphatidylserine was evaluated on various measures of brain is involved in complex planning, processing, and forming new
cognitive functioning before and after 12 weeks of treatment [20]. memories [142], which would portend importance for cognitive
Subjects consumed 300 mg/day of phosphatidylserine, and function and better overall neurological health [143]. Likewise, it
cognitive functioning was assessed with a computerized test has been shown that both older mildly demented and non-demented
battery and the Rey Auditory Verbal Learning Test (AVLT). adults who were vitamin D deficient were more likely to have mood
At the conclusion of the intervention, memory recognition, disorders and performed worse on some assessments of cognitive
memory recall, executive functioning, mental flexibility on the function [144]. However, reviews of observational, cross-sectional,
computerized test, and total learning and immediate recall on the and case–control studies show that the relationship between vitamin
AVLT all significantly improved. In addition, no adverse effects D and cognitive function is inconclusive, owing to methodological
were noted. Thus, phosphatidylserine may be beneficial for older issues, disparities between global versus specific assessments of
adults with memory complaints. cognitive function, heterogeneity of the populations sampled, and
A proprietary blend of phosphatidylserine and phosphatidic lack of control for confounders [145,146].
acid, both made from soy lecithin, was evaluated in 2 groups: Nonetheless, despite the inconsistent associations between
(1) non-depressed elderly people with memory problems and vitamin D and cognitive function in observational research,
(2) patients with AD [21]. In the first group of elderly with the relationship between vitamin D and cognitive function is
memory problems (n=72), subjects were randomized for significant in patients with multiple sclerosis (MS), who have
3 months to 300 mg/day of phosphatidylserine and 240 mg/day been shown to be deficient in serum vitamin D [147] and have
phosphatidic acid (n=40) or placebo (n=32) and were evaluated cognitive dysfunction [148]. Thus, supplementing with vitamin
on memory with the Wechsler Memory Scale (WMS) and mood D may hold promise in improving cognitive function among
with the List of Depressive Symptoms. Subjects receiving the this population. In a study, relapse-remitting MS patients (n=88)
phosphatidylserine and phosphatidic acid combination showed being treated with IFN beta who had a deficient 25(OH)D level
significant improvements in memory and feelings of depressed (<25 ng/ml; n=41) were compared to MS patients with a sufficient
mood compared to the placebo group at the end of treatment. 25(OH)D level (>35 ng/ml; n=47) on cognitive performance
In the second group of patients with AD (n=94), participants from baseline to 3 months follow-up [22]. The subjects who
were 25(OH)D deficient consumed vitamin D3 10,000 IU/day at 12 months and compared to placebo in several domains of
and those who were 25(OH)D sufficient continued with usual cognitive function, e.g., full-scale IQ, information, digit span,
treatment, with the possibility of taking vitamin D3 at varying vocabulary, block design, and picture arrangement. While both
levels. The cognitive function battery included the Montreal groups’ scores significantly declined for arithmetic, the change
Cognitive Assessment (MoCA), the Stroop Test, the Symbol Digit was lesser in the vitamin D group. Finally, the vitamin D group
Modalities, and the Brief Visuospatial Memory Test. At 3 months, significantly improved at 12 months and compared to placebo in
vitamin D3 significantly improved cognitive performance in the several blood Aβ-related biomarkers (i.e., AB42, APP, BACE1,
25(OH)D deficient group, according to the MoCA and the Brief APPmRNA, and BACE1mRNA), providing mechanistic support
Visuospatial Memory Test. for the clinical enhancements. Thus, 800 IU/day of vitamin D3 for
As previously mentioned, older adults who are vitamin D 12 months improved various domains of cognitive function and
deficient may be more prone to cognitive dysfunction. In addition, several Aβ-related biomarkers in AD patients, showing promise
given the problem of an increasing elderly population with a rising in a disease with few existing treatment options.
prevalence of MCI [127], the use of vitamin D as a treatment may Given that 25(OH)D insufficiency or deficiency is common
help to avoid advancing from MCI into dementia. Thus, in a study among the general population and in the elderly in particular [145],
of elderly 65 years of age or older with MCI (n=181), subjects it is important to study vitamin D treatment among healthy
were randomized for 12 months to receive either 400 IU/day of individuals to determine if it may be of benefit for cognitive
vitamin D3 (n=93) or placebo (n=88), to determine the effect on function. In a study of younger healthy adults, 128 subjects
cognition and lipid concentrations [23]. Subjects were not able were randomized for 6 weeks to receive either 5,000 IU/day of
to use dietary supplements known to interfere with nutrition cholecalciferol (n=63) or placebo (n=65) to investigate the effects
status, vitamin D metabolism, or cognitive function within the on cognitive functioning and secondary emotional measures [25].
3 months before the trial. Subjects were assessed at baseline and Subjects were assessed on working memory (N-Back task),
6 and 12 months follow-up on the MMSE and the Wechsler Adult response inhibition (Stop-signal task), and cognitive flexibility
Intelligence Scale (WAIS)-Revised (WAIS-R), which includes (Set shifting task) at baseline and at 6 weeks. While the group
11 domains of cognitive function. Serum 25-D (the less active receiving vitamin D significantly increased serum 25(OH)D and
precursor) and 1,25-D concentrations were significantly higher the placebo group did not, no measure of cognitive functioning
in the vitamin D group compared to placebo. Concentrations of improved at 6 weeks follow-up.
lipids (i.e., triglycerides, total cholesterol, high-density lipoprotein
On the other hand, in another clinical trial of healthy adults, 82
cholesterol, and low-density lipoprotein cholesterol) significantly
subjects with baseline 25(OH)D≤100 nmol/L were randomized
decreased in the vitamin D group and increased in the placebo
for 18 weeks to either high dose (4,000 IU/day; n=42) or low
group. Several domains of the WAIS-R, e.g., information, digit
dose (400 ID/day; n=40) vitamin D3 (cholecalciferol) to evaluate
span, vocabulary, block design, and picture arrangement test,
the resultant effect on cognitive function according to the Symbol
significantly increased at the 12-month follow-up in the vitamin D
Digit Modalities Test, verbal (phonemic) fluency, digit span,
group versus placebo. Full intelligence quotient (IQ), verbal IQ,
and the Cambridge Automated Neuropsychological Test Battery
and performance IQ also significantly increased at the 6- and/or
(CANTAB) computerized battery [26]. Serum 25(OH)D level
12-month follow-up assessments in the vitamin D group. Thus,
increased significantly more in the high dose group. Performance in
daily vitamin D3 supplementation of 400 IU in a group of elderly
nonverbal (visuospatial) memory improved in the high dose group
with MCI showed promising effects on cognitive functioning,
(approaching statistical significance after adjusting for demographics
which were hypothesized to at least be partially related to
decreases in blood lipids. and baseline performance), and those with lower baseline 25(OH)D
AD is a serious public health crisis with no known efficacious (<75 nmol/L) level in the high dose group improved significantly.
conventional therapy for treating the condition, and its effects The results suggest that an increased 25(OH)D level is crucial for
are costly and widespread from the individual with the disease higher executive functioning, such as nonverbal memory. Overall,
to society. In addition, vitamin D deficiency is highly related to a vitamin D shows preliminary support for its use in improving
greater risk of developing dementia [149]. Thus, it is imperative to cognitive functioning in a variety of populations, with a particular
evaluate treatments such as vitamin D with known neurocognitive emphasis on bettering the lives of those afflicted with AD. Vitamin D
effects in AD that may provide some benefit to these patients, who supplementation should continue to be evaluated for its efficacy.
otherwise are left with an ominous prognosis. In a study, 210 AD 3.1.2.4. Ω-3 fatty acids
patients 65 years of age or older were randomized for 12 months
to receive either 800 IU/day of vitamin D (n=105) or placebo Ω-3 fatty acids are polyunsaturated fatty acids with anti-
(n=105) to determine the effects on cognitive function and Aβ- inflammatory properties. They inhibit the conversion of highly
related biomarkers [24]. Subjects were assessed at baseline and reactive Ω-6 arachidonic acid into pro-inflammatory factors [150],
6 and 12 months with the WAIS-R, ADL scale, the MMSE, and decreasing T-cell proliferation [150], and inhibiting leukocyte
blood draws. The vitamin D group showed significant increases migration [151]. The three Ω-3 essential fatty acids are DHA,
in serum 25-D and 1,25-D at follow-up compared to baseline and EPA, and α-linolenic acid. DHA and EPA are plentiful in fish oil,
placebo. The vitamin D group also scored significantly higher while α-linolenic acid can be found in plant oils and is especially
plentiful in flaxseed [152]. DHA is highly concentrated in the prone to zinc deficiency [163]. A study found that only 44% of
neuronal and synaptic membranes [153], facilitating its anti- adults over 70 years of age had sufficient zinc status [164]. An
inflammatory activity in the brain. insufficient zinc level is considered a significant clinical problem
Long-chain Ω-3 has a direct impact on AD pathology by in this population [165]. For example, reduced hippocampal zinc
reducing Aβ production, minimizing its aggregation into plaques, has been linked to an age-related decline in spatial memory [161].
and increasing Aβ clearance [154]. Depletion of DHA can result in However, studies in older adults have found that greater dietary
an increased Ω-6:Ω-3 fatty acid ratio, which creates a physiological intake of zinc was associated with better cognitive function [166],
environment of inflammation and excessive oxidative stress [155,156]. the cause has not yet been established.
Both inflammation and oxidative stress are conditions known to In a study, healthy younger (55 – 70 years; n=188) and older
enhance the production of Aβ plaques. Brain DHA levels tend to (70 – 87 years; n=199) adults were randomized for 6 months to
decrease with age, even more so in AD patients [157]. Serum and receive either 15 or 30 mg/day of zinc or placebo [28]. Cognitive
brain levels of DHA are reported to be lower in AD patients compared function was assessed at baseline and after 3 and 6 months of
to normal adults [158], either due to the low dietary intake of Ω-3 supplementation using parallel versions of the CANTAB at each
fatty acids or increased oxidative stress. session. At baseline, zinc intake was similar between both groups,
Several clinical trials have investigated the efficacy of Ω-3 but the erythrocyte zinc level was significantly higher in the
supplementation in adults at risk for AD and cognitive decline. younger group compared to the older group. Urinary zinc level
Ω-3 fatty acid consumption yielded a modest attenuation of was significantly lower in the younger group, but serum zinc was
cognitive decline in the elderly without dementia, but was not not significantly different between groups. Urinary and serum
associated with prevention or treatment of AD [159]. Mechanisms zinc showed dose-dependent increases with supplementation,
behind the potential benefits of Ω-3 fatty acids warrant further independent of age. At baseline, serum zinc and pattern recognition
study into their efficacy for the prevention and treatment of AD. memory latency, erythrocyte zinc and pattern recognition
Ω-3 supplementation produced no adverse effects and improved memory latency for males and between 5-choice reaction time
the clinical condition in AD and MCI patients aged 55 – 90 years and erythrocyte zinc for females were significantly correlated. At
(n=46) [27]. Participants who supplemented Ω-3 (1.8 g/day baseline, younger adults excelled comparatively at cognitive task
consisting of 720 mg DHA and 1080 mg EPA for 24 weeks; n=24) performance, as they were significantly more accurate (pattern
improved in general health compared to placebo (n=22), likely recognition memory, spatial working memory, and spatial span),
due to cardiovascular and immunological health improvements faster (pattern recognition memory, matching to sample visual
resulting from Ω-3 supplementation. Patients with MCI on search, 5-choice reaction time, and 5-choice movement time),
the Ω-3 diet saw a significant improvement in cognition, but and more efficient (spatial working memory strategy) compared
this effect was not seen in patients with mild-moderate AD. In to older adults. Significant interactions between treatment and
addition, a higher proportion of EPA in red blood cell membranes time were noted for spatial working memory errors (with greater
was associated with better cognitive outcomes. improvements from baseline to 3 months for the 2 treatment
In another study, 39 individuals 55 years and older with a groups compared to placebo and with greater improvements from
diagnosis of probable AD were given either an Ω-3 supplement (3 g months 3 to 6 for the 15 mg group compared to the 30 mg group)
Ω-3/day with 675 mg DHA and 975 mg EPA; n=13), a combination and matching to sample visual search latency (due to greater
Ω-3 and lipoic acid supplement (3 g Ω-3/day plus 600 mg racemic improvements over 6 months for placebo and 30 mg compared to
lipoic acid; n=13), or placebo (n=13) [5]. Oxidative stress did not 15 mg). However, the analysis did not provide any clear evidence
differ significantly between the treatment and placebo groups. The that either of the 2 treatment doses provided a substantial or lasting
treatment group that received a combination of Ω-3 and lipoic acid benefit for spatial working memory error compared to placebo.
had less of a decline in cognitive function (according to MMSE) These findings were also independent of sex, education, baseline
and functional ability (measured by IADL) over 12 months. The zinc intake, and serum zinc. Therefore, age-related deficits for
group that received Ω-3 only also showed less of a decline in performance on the CANTAB were discovered, and the effects
IADL compared to the placebo. In both treatment groups, EPA and of zinc supplementation on cognitive function were limited. The
DHA in the red blood cell membranes significantly increased from beneficial effect of both doses on spatial working memory errors
baseline. Because these positive effects of treatment were observed was only found at 3 months, and the effect of the 15 mg dose on
without a concurrent decrease in markers of oxidative stress, it is matching to sample visual search latency was detrimental. Thus,
possible that Ω-3 and Ω-3 + lipoic acid may impart their benefits further investigation is warranted, perhaps in a more vulnerable
against AD pathogenesis in ways unrelated to oxidative stress. and/or zinc deficient population.
3.1.2.5. Zinc 3.2. Phytonutrients
Zinc is a key antioxidant for the CNS, influencing brain
3.2.1. Aloe polysaccharides
structure and function [160], especially in the hippocampus and
amygdala [161]. Therefore, zinc deficiency can delay physical Complex polysaccharides, e.g., arabinose, mannose, xylose,
and cognitive development [162]. Older adults are especially rhamnose, and fucose, are important compounds utilized in the
bio-assembly line process by every cell in the body [167]. Most In an evaluation of the effect of consuming a polysaccharide
importantly, during the second major step of biosynthesis in all cells, formula 1 time on cognitive function and memory, 62 college
9 molecules of mannose, a key polysaccharide, are required in the students participated in a study of 2 separate neuropsychological
endoplasmic reticulum to initiate the assembly of glycoproteins tests [30]. Subjects were randomized to receive a polysaccharide
and glycolipids. This process demonstrates that polysaccharides product (1 tablespoon of Ambrotose Complex in 4 ounces of
are not only metabolized to provide energy, but that they are noncaloric fruit-flavored water) or placebo (1 tablespoon of
also used for glycosylation (i.e., the addition of saccharides to rice starch in noncaloric fruit-flavored water) before testing,
amino acid chains or free fatty acid chains) in the endoplasmic and the other drink after testing, or vice versa. In the first test,
reticulum and the Golgi. The significance of the coding capacity subjects (n=30) completed the Standard Progressive Matrices, the
of polysaccharides in glycoproteins and glycolipids is provided in Stroop Test, and the Same-Different visual discrimination task.
a series of review articles in a glycomics-dedicated issue of Acta In the second test, subjects (n=32) completed the Reading Span
Anatomica [168]. The addition of 9 molecules of mannose in 3 and Operation Span tasks as measures of simple and complex
chains in the endoplasmic reticulum constitutes the establishment working memory, respectively. Those subjects who consumed
of a domain on which instructions for life processes are transmitted the polysaccharide formula before assessment performed more
between cells. In the Golgi, other polysaccharides are added, and correctly on the visual discrimination task and on the first part of
the number of mannose units is modified to provide a code of the simple working memory test. Thus, acute consumption of a
information for conducting host defense, repair, growth, healing, mixture of polysaccharides may offer an advantage for short-term
and homeostasis. This domain is the principal site for coordinating cognitive performance in certain domains.
activities for the trillions of cells that make up the human body. In the first of 2 studies conducted by the same research group,
This fundamental supporting biochemistry is why supplying middle-aged healthy men and women (n=45) were randomized to
polysaccharides from food sources results in a broad spectrum determine the effect on memory performance of an acute 1-time
of health-supporting benefits. In addition, concentrated levels of administration of a combination of either polysaccharides (7 g of
polysaccharides in dietary supplements, compared to their levels powdered Ambrotose Complex; n=15), glucose (25 g of powder;
in foods, are advantageous in that a higher amount of nutrients n=15), or a placebo (2 drops of concentrated liquid stevia; n=15),
allows a greater number of bioactive compounds to be created. all mixed in a 300 mL low-calorie, and raspberry-flavored
Thus, innate mechanisms of defense and repair coded in the genes drink [31]. Subjects were assessed with a battery of memory
can be enhanced to be more effective against infectious agents and tests 15 min after drinking their assigned treatment. The tests
compromises in health. consisted of immediate and delayed recall, recognition, short-
These polysaccharides come from many plants, e.g., rice bran, term memory, working memory, and general cognitive function.
aloe vera, dioscorea, and others, and they have been characterized While performance on the tests did not differ significantly among
by several different investigators [169-171]. Polysaccharides the treatments, higher scores on immediate and delayed recall and
have diverse structure, composition, and molecular heterogeneity recognition were noted for the polysaccharide treatment compared
that lend them to a wide variety of mechanisms of action, e.g., to the glucose treatment. Thus, the polysaccharide combination
the effects on colonic microflora and gastrointestinal physiology, may affect measures of memory performance rather than the
immunomodulation, anti-neoplastic, and wound healing, performance of working memory.
among others [172]. The capacity for polysaccharides to affect In the second study, another group of healthy middle-aged
neurobiology and resultant cognitive function is not entirely clear adults (n=73) participated in an experiment to determine if a
and has not been well identified, despite the fact that glucose, a polysaccharide mixture was more effective than a rice flour
monosaccharide, is the major source of fuel for the brain [29]. placebo or a sucrose control on measures of mood and cognitive
Nonetheless, it has been shown that glucose affects memory function that was administered to create mental fatigue [32].
function directly in the hippocampus [173] and through indirect Subjects were randomized to a 1-time consumption of either 4 g
hormone signaling [174]. Polysaccharides have been shown to (1 tablespoon) of a polysaccharide mixture (n=23; Ambrotose
combine with proteins and lipids for structural development (i.e., complex), 4 g of a rice flour placebo (n=24), or 4 g of a sucrose
creation of glycoconjugates) of the brain, perform synaptogenesis, (icing sugar) control (n=26) in 100 mL of water. Subjects were
and enable the formation of neurotransmitters, all of which assessed at baseline, consumed their treatment, waited for 30 min,
ultimately help to determine cognitive function [29,31,175]. and then were assessed with different forms of the same tests.
In addition, in 20 healthy male college students, compared to The group that took the polysaccharide mixture had significantly
placebo (n=10), a 1-time polysaccharide mixture (a proprietary higher scores on recognition and working memory compared to
blend of 1 tablespoon of all-natural ingredients containing 3.9 g the placebo and control treatments, and these differences were
carbohydrates, 0.28 g protein, and 14 calories; n=10) 30 min after unrelated to changes in blood glucose. Thus, the results suggest
consumption showed significantly enhanced power according to that certain aspects of cognitive function can be improved with a
EEG activity in 3 brain wave frequencies (theta, alpha, and beta) mixture of polysaccharides that affect metabolic pathways other
that are related to attention and arousal [29]. Thus, the basis for than increased blood glucose.
clinical evaluation of the effects of polysaccharides on cognitive While acute cognitive performance studies may help to create a
function is justified and warranted. framework to understand how polysaccharides affect neurobiology,
the impact of polysaccharides on neurodegenerative disorders like MS patients showed promising effects of polysaccharide formulae
AD is a crucial question to answer, given the current inability of on various components of cognitive function in these patient
conventional medicine to offer solutions for these patients. As populations that otherwise have few efficacious conventional
AD has continued to elude an efficacious conventional treatment treatment options.
and the intake of key polysaccharides has been shown to increase
the production of adult stem cells [176], a pilot study of 48 AD 3.2.2. Bacopa monnieri (L.) Wettst.
patients showed that a polysaccharide multinutrient formula had Bacopa monnieri is an ancient plant from the Scrophulariaceae
a beneficial effect on overall quality of life [177]. That promising family that thrives in damp locations. Both its leaves and stem
result led to a more formal open-label controlled trial to investigate have medicinal uses. In Ayurveda, the ancient Indian system of
the effect of an aloe polymannose multinutrient complex formula medicine, Bacopa monnieri has been used for the treatment of
on cognitive and immune functioning over 12 months among neurological disorders associated with intellectual decline and
adults diagnosed with moderate to severe AD [33]. Subjects memory loss, such as AD [185].
(n=34) consumed 4 teaspoons/day (~20 g/day) of the formula The main bioactive components of Bacopa monnieri are
and were assessed at baseline and 3, 6, 9, and 12 months follow- non-polar molecules, bacosides, that can easily cross the blood–
up with the ADAS-cog, MMSE, AD Cooperative Study-ADL, brain barrier, leading to anti-inflammatory and antioxidant
and the Severe Impairment Battery. Cytokines and lymphocyte effects directly within the brain. This is essential in Bacopa
and monocyte subsets were assessed at baseline and 12 months. monnieri’s role against AD, as multiple studies have shown
While the other assessments did not detect changes, the ADAS-
that inflammatory compounds and reactive oxygen species,
cog cognition scores clinically (≥4-point change) and statistically
such as hydroxyl radical and nitric oxide, cause stress-mediated
significantly improved at 9 and 12 months from baseline. In
neurodegeneration in this disease [186]. In addition to various
addition to the significant finding on the ADAS-cog, multiple
measures of cognitive functioning, these anti-inflammatory and
immune and inflammatory markers improved at 12 months
antioxidant effects were studied in a clinical trial of 12 months
follow-up. Participants tolerated the dietary supplement with few
in healthy elderly individuals (n=109) and AD patients (n=123)
adverse reactions.
[35]. The healthy subjects were randomized to either a polyherbal
A subsequent analysis on the same sample of AD patients was
formula including Bacopa monnieri, sea buckthorn, and dioscorea
conducted to determine if the aloe polymannose multinutrient
(500 mg/day) or a placebo, and the AD subjects were randomized
formula resulted in any significant relationships between
to either the polyherbal formula or donepezil (20 mg/day). The
mature brain-derived neurotrophic factor (BDNF) and its
results indicated that cognitive functioning improved in subjects
precursor proBDNF and the battery of cognitive functioning
measures [178]. As BDNF is key in neurosynaptic function, with AD (according to digit symbol substitution, word recall
apoptosis, plasticity, long-term potentiation, learning memory immediate, and attention span) and healthy subjects (according
processes, and higher-order thinking [179-184], it could be a to the MMSE, digit symbol substitution, and delayed word
useful target for the treatment of AD. While proBDNF and BDNF recall) who were taking the polyherbal formula compared to
did not significantly change from baseline to 12 months follow-up, their respective placebo subjects. The memory-enhancing effects
the correlations between the ADAS-cog total score and BDNF and were hypothesized to be due to the polyherbal formula’s ability
BDNF/proBDNF ratio were statistically significant at 12 months. to decrease markers of both inflammation (i.e., homocysteine,
Other correlations were noted for various cognitive functioning C-reactive protein, and TNFα) and oxidative stress (i.e.,
assessments and BDNF and/or BDNF/proBDNF at 12 months, glutathione peroxidase, glutathione, and thiobarbituric acid).
suggesting that the aloe polysaccharide multinutrient formula was In another trial of newly diagnosed AD patients, subjects
consequential on these relationships. (n=50) between the ages of 60 and 65 years were given 300 mg
A similar study was executed by the same group on relapse- of Bacopa monnieri standardized extract twice/day for 6 months
remitting MS patients (n=15) who consumed a multinutrient [36]. Subjects were compared on the MMSE from baseline to
and polysaccharide dietary supplement regimen (~18 g/day) 6 months, and statistically significant improvements were noted
for 12 months to determine its impact on multiple biomarkers for orientation of time/place/person, attention, reading, writing,
(infections, cytokines, growth factors, and T- and B-cell subsets) and comprehension at the end of the trial. Additionally, self-
and self-report and clinician-administered measures [34]. reported quality of life improved at the conclusion of the study,
Cognitive functioning and mood symptoms were components of primarily due to decreased irritability and insomnia.
2 separate measures, the Functional Assessment of MS and the It is known that the brains of AD patients have a higher level of
Self-Assessment of Severity of MS Symptoms Scale, utilized in lipid peroxidation created by oxidative processes [187], which can
the battery that was given at baseline and quarterly for 12 months. be decreased by Bacopa monnieri, especially in the hippocampus,
All of the cognitive functioning and mood symptoms showed prefrontal cortex, and striatum [188]. Extracellular Aβ deposits
statistically significant improvements over the course of the in senile plaques, intracellular neurofibrillary tangles, reactive
intervention. In addition, at 12 months, total infections decreased microgliosis, and astrogliosis are hallmarks of AD, and numerous
significantly, and inflammatory markers and immune functioning studies indicate that bacosides protect the brain against oxidative
significantly improved. Thus, the results of the research on AD and damage and age-related cognitive deterioration by preventing Aβ
aggregation and formation of fibrils and by protecting neurons the Bacopa monnieri group compared to placebo at the end of
against Aβ-induced toxicity [186]. treatment.
Even though the findings in AD patients have been positive, In another study, healthy elderly subjects (n=98) over 55 years
Bacopa monnieri has primarily been evaluated for its effectiveness of age were randomized for 12 weeks to receive 300 mg/day of
on cognitive function in healthy adults. In a clinical trial with Bacopa monnieri extract (n=49) or an identical placebo (n=49)
healthy medical students, subjects (n=46) were randomized to [41]. The neuropsychological and memory assessment included
either 150 mg of a standardized extract of Bacopa monnieri (n=28) the AVLT, the Rey-Osterrieth Complex Figure Test (ROCFT), the
or placebo (n=18) twice daily for 6 weeks and were assessed on TMT, and the Memory Complaint Questionnaire. Verbal learning,
a comprehensive assessment of cognitive functioning [37]. At memory acquisition, and delayed recall according to the AVLT
the 6-week assessment, the digit span backwards test (measuring significantly improved in the Bacopa monnieri group compared to
attention, freedom from distractibility, and working memory) and placebo at 12 weeks, while the other assessments showed minor
the logical memory test (evaluating immediate recall of logical improvements that did not differ significantly between the 2
material and language comprehension) significantly improved in groups. The Bacopa monnieri group also reported some incidents
the Bacopa monnieri group compared to placebo, but no other of gastrointestinal side effects. Thus, several clinical trials show
tests changed. No adverse effects were reported, showing that significant and consistent improvements in various domains of
treatment with Bacopa monnieri was safe. cognitive functioning from 3 to 12 months across samples of
In a clinical trial of adults age 65 or older without signs of dementia, healthy adults and those with AD with minimal adverse effects,
subjects (n=54) were randomized for 12 weeks to receive either primarily related to gastrointestinal upset.
300 mg/day of standardized Bacopa monnieri extract (n=27) or
placebo (n=27) to determine its effect on cognition and mood [38]. The 3.2.3. Ginkgo biloba leaf and extract (EGb 761) - Ginkgo biloba L.
primary outcome measure was the delayed recall score from the AVLT, Ginkgo biloba is thought to be beneficial to human health as
and additional cognitive tests included the Stroop Test, the Divided
a neuroprotective agent, antioxidant, free-radical scavenger,
Attention Task, and the WAIS letter-digit test. Mood was assessed with
membrane stabilizer, and inhibitor of platelet-activating factor
the State-Trait Anxiety Inventory, Center for Epidemiologic Studies
(through terpene ginkgolide B). It has also been shown to
Depression scale, and the Profile of Mood States. The participants who
stimulate choline uptake in the hippocampus and to inhibit Aβ
took the Bacopa monnieri extract had improved AVLT and Stroop
deposition [189]. EGb 761 is the standard preparation of Ginkgo
Test scores, whereas the placebo group’s scores were unchanged. No
biloba extract that contains 24% ginkgo flavonoid glycosides, 6%
significant differences were found for the Divided Attention Task or the
terpene lactones, and no more than 5 ppm ginkgolic acids [189],
WAIS. The Bacopa monnieri group also showed improved State-Trait
and its neuroprotective benefits may be due to its capacity to
Anxiety Inventory and Center for Epidemiologic Studies Depression
reduce oxidative damage and stimulate apoptosis [190]. Several
scale scores, and few adverse effects were reported.
studies assessing herbal therapies for the treatment of cognitive
In the first of 2 trials of healthy adults from the same research
deficits have focused on Ginkgo biloba and its EGb 761 extract,
group, subjects (n=46) aged 18 to 60 years were randomly
based on its multifaceted therapeutic potential [45,191-193].
assigned for 12 weeks to either 300 mg/day of Bacopa monnieri
extract (n=23) or placebo (n=23) [39]. Cognitive function was In fact, compared to other nutrients, phytonutrients, and natural
assessed with a comprehensive battery including the Cognometer compounds, Ginkgo biloba and EGb 761 may be the most widely
tests of working memory, the Digit Symbol Substitution Test, studied material for cognitive functioning in both healthy adults
Speed of Comprehension Test, Digit Span, TMT, AVLT, and and those with early to late cognitive impairment or dementia. For
Inspection Time, and state anxiety was assessed with the example, a meta-analysis was conducted among studies of AD
State-Trait Anxiety Inventory. The results at 12 weeks showed patients in 3 – 6 month treatment periods with 120 – 240 mg/day of
significantly increased speed of visual information processing Ginkgo biloba and revealed a small though significant effect size of
according to the Inspection Time task, improved learning rate 0.40 (comparable to the effect of donepezil, which is 0.42-0.48) on
and memory consolidation on the AVLT, and decreased anxiety objective measures of cognitive function (i.e., ADAS-cog) [194].
in the Bacopa monnieri group. In their second trial, healthy According to a summary review of studies at that time, Ernst
participants (n=62) aged 18 – 60 years old were randomized found that Ginkgo biloba was effective at improving memory,
for 90 days to either 300 mg/day of Bacopa monnieri extract concentration, fatigue, anxiety, and depressed mood [195].
(n=33) or a matching placebo (n=29) to determine its effects 3.2.3.1 Ginkgo biloba leaf
on cognition [40]. Cognitive functioning was assessed with
the Cognitive Drug Research computerized assessment battery In a phase II open-label study, symptomatic irradiated brain
that included 5 domains (secondary memory, working memory, tumor survivors (n=34) were given 120 mg/day of Ginkgo
speed of memory, speed of attention, and accuracy of attention) biloba for 24 weeks followed by a 6-week washout period to
and a rapid visual information-processing task. Spatial determine its effect on cognitive function, quality of life, and
working memory accuracy of the working memory domain mood [42]. Assessments were performed at baseline and 12, 24
and the number of false-positives recorded in the Rapid Visual (end of treatment), and 30 (end of washout) weeks. Of the 34
Information Processing (RVIP) task significantly improved in subjects enrolled, 23 (68%) completed 12 weeks of treatment and
19 (56%) completed the full 24 weeks of treatment. Five subjects Outcome measures included the MMSE, the Stroop Test, TMT
discontinued treatment due to toxicity (4 with GI symptoms and A and B, and the WMS - Logic Memory I and II and Visual
1 with intracranial bleed), 5 subjects discontinued treatment Reproduction I and II. The EGb761 group showed significantly
because of no perceived benefit, and 5 subjects discontinued more improvement at 6 weeks compared to placebo on the Stroop
treatment due to intercurrent illness. Global cognitive function Test, which is a measure of the speed of processing abilities. No
was measured by the MMSE. Executive function was measured other assessments changed at the end of the intervention for either
by the TMT B. Attention and concentration were measured by group. More participants receiving EGb 761 rated their ability
the TMT A and Digit Span Test. Visual-constructional skills and to remember at the end of treatment as “improved” compared to
figural memory were measured by the ROCFT. Verbal fluency was placebo.
measured by the F-A-S Test. Verbal learning and memory were In a study by the same investigators in the previous study,
assessed by the California Verbal Learning Test Part II (CVLT-II). community-dwelling volunteers aged 60 years and older (n=262)
At baseline, cognitive impairment was clinically significant, as were randomly assigned to EGb 761 (60 mg 3 times/day; n=131)
mean scores on attention, concentration, memory, and executive or placebo (n=131) for 6 weeks, to investigate the impact of
function were >1.5 SDs worse than in an age-matched normative Ginkgo biloba treatment on neuropsychological functioning of
sample. At 24 weeks, executive function on the TMT B, attention/ cognitively intact older adults [46]. Outcome measures included
concentration on the TMT A, and intermediate and delayed recall the Buschke Selective Reminding Test (SRT), the WAIS-III Block
non-verbal memory on the ROCFT all significantly improved. All Design and Digit Symbol Coding tests, and the WMS-III Faces
other cognitive function tasks did not change at 24 weeks. Quality I and II. Subjects receiving EGb 761 treatment had significantly
of life, according to the Functional Assessment of Cancer Therapy greater improvement on the SRT tasks of delayed free recall and
brain and physical subscales and distressed mood on the Profile of recognition compared to placebo at the end of the intervention. On
Mood States, both significantly improved at 24 weeks compared the WMS-III Faces II, the placebo group performed significantly
to baseline. better at baseline, but delayed recognition on this assessment was
In our laboratory, we investigated the effect of commercial performed better by the EGb 761 group at 6 weeks. More subjects
formulations Ginkgo Synergy (120 mg/day Ginkgo biloba leaf, in the treatment group rated their overall ability to remember as
80 mg/day Ginkgo biloba whole extract, and other compounds) “improved” on the subjective follow-up questionnaire. No other
plus 700 mg/day of choline (n=33) and OPC Synergy plus significant differences were detected between groups at the end of
the intervention.
Catalyn (n=31) versus placebo (n=33) in a 6-month, randomized,
In a study of middle-aged healthy volunteers aged 45 – 56 years
double-blind trial on cognitive and immune functioning among
(n=188), subjects were randomized for 6 weeks to receive
English-speaking, non-smoking, healthy older adults with no
240 mg/day of EGb 761 (n=94) or placebo (n=94), to determine
cognitive deficits [43]. A neuropsychological battery, including
the effects on memory performance in a demanding standardized
the Stroop Test, TMT A and B, Controlled Oral Word Association
free recall paradigm (list of appointments) and a less demanding
(COWA), Hopkins Verbal Learning, MMSE, and Digit Symbol,
standardized recognition test (driving route) [47]. At 6 weeks in
was administered at baseline and 3 and 6 months follow-up to
the EGb 761 group, the number of correctly recalled appointments
assess cognitive functioning. According to time on the TMT B,
(immediate and delayed recall) significantly increased from
the Ginkgo Synergy plus choline arm showed improvement from
baseline, as compared to placebo. The EGb 761 treatment group
baseline to 3 months follow-up. On the COWA Trial-S, the scores
also had improved quality of immediate and delayed recall (ratio
significantly increased for the Ginkgo Synergy plus choline arm
of false-to-correct) after 6 weeks, as compared to placebo. The
from baseline to 6 months follow-up, and for the OPC Synergy change from baseline to 6 weeks between the treatment and
plus Catalyn arm from baseline to 3 months follow-up. No serious placebo groups on the less demanding recognition test was not
adverse events were recorded. Thus, this study showed modest significantly different.
positive effects of the combination of Ginkgo biloba plus choline In a long-term, multi-site study, and community-dwelling adults
on isolated cognitive functioning scales. aged 72 – 96 years who had normal cognitive function or MCI
Solomon et al. investigated the effect of 40 mg/day of Ginkgo (n=3,069) were randomized to receive 120 mg 2 times/day of EGb
biloba (n=115) compared to placebo (n=115) on cognitive 761 (n=1,545) or placebo (n=1,524) for a median of 6.1 years,
functioning for 6 weeks among 230 community-dwelling healthy to determine if Ginkgo biloba slows global or domain-specific
participants 60 years of age and older [44]. The results of the study cognitive function decline in older adults [48]. Outcomes were the
did not show any improvements in learning, memory, attention, or rates of change for the Modified MMSE (3MSE), the ADAS-cog,
concentration between the 2 groups at the follow-up assessment. and neuropsychological domains of memory, attention, visual-
3.2.3.2 Ginkgo biloba extract (EGb 761) spatial construction, language, and executive function. Memory
was assessed by the CVLT and recall from the modified ROCFT.
In a study of adults aged 55 – 86 years without a history of Visual-spatial construction was assessed by the copy condition of
cognitive dysfunction (n=48), subjects were randomized for the ROCFT and the modified WAIS-R Block Design. Language
6 weeks to 180 mg/day EGb 761 (n=24) or placebo (n=24) to was assessed by a 30-item Boston Naming Test and semantic
investigate its short-term efficacy for enhancing cognition [45]. verbal fluency. Attention and psychomotor speed were measured
by WAIS-R Digit Span and the TMT A. Executive function was clinical efficacy to donepezil in the treatment of AD on cognitive
measured by the TMT B and the Stroop Test. Outcomes (3MSE functioning and global improvement.
and ADAS-cog) were administered every 6 months through Napryeyenko et al. randomized 400 subjects (≥50 years of
the first 4 years of follow-up, and then the ADAS-cog was age) with dementia (218 with probable AD or possible AD with
administered annually after that. Rates of annual decline in the cerebrovascular disease and 182 with probable vascular dementia)
neuropsychological domains did not significantly differ between to assess the effect of 22 weeks of EGb 761 of 240 mg/day versus
groups. Rates of change in the 3MSE and ADAS-cog varied based placebo on the Short Syndrome Test, a cross-culturally validated
on initial cognitive status, but no differences were found between cognitive test battery, the Neuropsychiatric Inventory, the Verbal
groups. Thus, long-term treatment with the Ginkgo biloba extract Fluency Test, the Clock-Drawing Test, the Hamilton Rating Scale
did not attenuate cognitive decline in older adults with normal for Depression, and the Gottfries-Bråne-Steen Scale [52]. Those
cognitive function or MCI. with AD and vascular dementia taking the Ginkgo biloba extract
In a study of outpatients with pre-senile and senile AD type had higher Short Syndrome Test total scores compared to the
dementia and multi-infarct dementia (n=205), subjects were participants on placebo, whose scores decreased. Significant drug-
randomized for 24 weeks to receive either 240 mg/day of EGb 761 placebo differences were noted for all other outcome variables,
(n=106) or placebo (n=99) [49]. Cognitive function was initially with no differences between AD and vascular dementia subgroups.
measured using the Syndrom-Kurztest Cognitive Battery (SKT) Adverse events were higher for the placebo group.
and was converted to an estimated ADAS-cog. The Ginkgo biloba In a study of patients with mild to moderate dementia (AD or
treatment group improved by 2.1 and 2.7 points on the SKT and vascular dementia) associated with neuropsychiatric symptoms
estimated ADAS-cog, respectively, at 24 weeks, whereas the (n=410), subjects were randomized for 24 weeks to receive
placebo group improved by 1.0 and 1.3 points on the SKT and 240 mg/day of EGb 761 (n=205) or placebo (n=205) to determine
estimated ADAS-cog, respectively. These 2 differences were its effect on the SKT and the Neuropsychiatric Inventory score [53].
significant between groups. A change in the estimated ADAS-cog On the SKT total score, subjects in the treatment group improved
score of at least 4 points is defined as a clinically significant treatment by 2.2+3.5 points, while those receiving placebo improved only
response. The response rate in the Ginkgo biloba group was 35%, by 0.3+3.7 points, and this difference was statistically significant.
and it was 19% in the placebo group, which was significantly On the Neuropsychiatric Inventory composite score, subjects in
different. When a 2-point improvement in the estimated ADAS- the treatment group improved by 4.6+7.1 points compared to the
cog score was used to define treatment response (an improvement placebo group that improved by 2.1+6.5 points, and this difference
that is less clinically significant, but still important to patients), was also statistically significant. Several secondary outcomes,
61% of the Ginkgo biloba group were responders, and 37% of including the ADCS CGI of change, the Verbal Fluency Test,
the placebo group were responders, which was also statistically the ADL International Scale overall mean score, the Dementia
significant. The Ginkgo biloba group had a significantly different Quality of Life Instrument-Proxy total score, and the 11-point box
improvement in the Clinical Global Impression (CGI) of change scale for dizziness, were significantly better in the treatment group
(item 2). On the other hand, Ginkgo biloba extract treatment had compared to placebo at the end of the intervention.
no significant effect on cognitive functioning as measured by the In a study of patients with MS, subjects (n=121) were
ADAS-cog and participant and caregiver-related quality of life, randomized for 12 weeks to receive 240 mg/day of EGb 761
in another study where subjects with mild to moderate dementia (n=61) or placebo (n=60), to investigate its effects on cognitive
(n=176) were randomized for 6 months to receive 120 mg/day of functioning [54]. The Stroop Test, CVLT-II, COWA, and the
EGb 761(n=88) or placebo (n=88) [50]. Paced Auditory Serial Addition Task were used as screening and
In a study of patients with mild to moderate AD aged 50 – outcome assessments. Treatment with EGb 761 did not improve
80 years (n=76), participants were randomized for 24 weeks cognitive performance at 12 weeks compared to baseline or
to receive either 160 mg/day of EGb 761 (n=25), 5 mg/day of compared to placebo.
donepezil (n=25), or placebo (n=26) as compared to donepezil In a study of patients with MCI, subjects (n=160) were
and placebo, to investigate its efficacy on cognitive function randomized for 24 weeks to receive EGb761 240 mg/day (n=80)
according to the SKT and the MMSE [51]. Changes in overall or placebo (n=80) to determine its effects on cognition and
patient condition and therapeutic efficacy were assessed using the neuropsychiatric symptoms [55]. Cognition and global ratings of
CGI. The MMSE improved non-significantly after 12 weeks in change were measured by the TMT A and B. The treatment group
the EGb 761 and donepezil groups. The placebo group worsened had higher scores on the TMT A and B and had better outcomes
after 12 weeks, but function was not significantly different from according to the caregiver’s global impression of change at
baseline. SKT scores significantly improved in the EGb 761 and 24 weeks. The treatment group also had a significant improvement
donepezil groups, as compared to placebo. The placebo group on the State-Trait Anxiety Inventory and a trend toward a better
had a significantly worse SKT score after 12 weeks compared to Geriatric Depression Scale score at 24 weeks.
baseline. The SKT scores were not different between the EGb 761 In a study of healthy male and female elderly volunteers
and donepezil groups at 24 weeks. The CGI scores significantly with subjective memory impairment (n=61), subjects were
improved for the EGb 761 and donepezil groups at 24 weeks randomized for 60 days to receive either 240 mg/day of Ginkgo
compared to baseline. Thus, Ginkgo biloba treatment had similar biloba extract EGb 761 (n=31) or placebo (n=30) [56]. The
primary outcomes were task-set switching, response inhibition, in promoting longevity, acting as an adaptogen, and serving as
delayed response, prospective memory, task-related fMRI blood- an adjunct treatment in numerous conditions including diabetes,
oxygen-level-dependent signals, and the Trier Social Stress cardiovascular disease, and inflammatory disorders [196]. The
Test. The Ginkgo biloba treatment group showed significantly proposed beneficial effect in cognitive disorders may be mediated
improved cognitive flexibility compared to placebo according to through disease-modifying pathways such as reduction in
decreased task-set switch costs, which was not due to differences amyloidogenesis, inflammation, or neurotoxicity. Mechanistically,
in depression symptoms, an unequal ratio of genders between the the ginsenosides Rg3, Rh1, Rh2, Rb1, Rd, Rg2, and Rb3 and the
groups, or because of changes in brain activation, indicating a low aglycones PPD and PPT have shown encouraging results in
cost of neural systems/resources. Thus, this result was likely due to animal and cell-based studies [197]. Likewise, the metabolite
increased cognitive processing efficiency. A trend was also noted Compound K has shown neuroprotective effects in non-human
for improved response inhibition in the Ginkgo biloba treatment trials. However, pharmacological and human clinical trial data
group, as demonstrated by Go-NoGo-task reaction times corrected in the use of ginseng have been largely equivocal and limited by
for error rates. These 2 findings (better cognitive flexibility without poor methodological quality of studies [197].
changes in brain activation and improved response inhibition) are In a double-blind, placebo-controlled, parallel-group, multi-
compatible with mild enhancement of prefrontal dopamine, but center trial of 279 healthy middle-aged volunteers, 2 dosing
the effects of Ginkgo biloba on prefrontal dopaminergic functions regimens (160 mg 2 times/day or 320 mg/day) of a capsule of
require further research. No other outcomes significantly changed a standardized extract of 60 mg Ginkgo biloba (GK501), and a
at the end of the intervention. standardized extract of 100 mg Panax ginseng were administered
In a study of outpatient vascular MCI patients (n=62), Ginkgo for 14 weeks to assess various aspects of cognitive function
biloba was used as a control compared to Pushen (a capsule that [58]. At baseline and weeks 4, 8, 12, and 14, the volunteers
contains many Traditional Chinese Medicine ingredients) on performed attention and memory tests from the Cognitive Drug
measures of cognitive function [57]. Subjects were randomized Research computerized cognitive assessment system prior to
but not blinded for 12 weeks to treatment with Pushen (1.8 mg, morning dosing and again at 1, 3, and 6 h later. A quality index for
3 times/day; n=30) or Ginkgo biloba (19.2 mg/day of EGb 761; working and long-term memory significantly improved by 7.5%
n=32). Cognitive outcomes were the MMSE, the MoCA, and in response to the Ginkgo biloba/Panax ginseng combination. The
the Subjective Memory Loss Rating Scale scores. At 12 weeks, memory improvement occurred throughout the 12-week dosing
period and remained after a 2-week washout.
the MMSE score of the Pushen group was significantly higher
In a double-blind, placebo-controlled clinical trial, and 90
than baseline, but not significantly different from the Ginkgo
Korean volunteers with MCI were randomized for 6 months to
biloba group. The MMSE score modestly improved at 12 weeks
either 3 g/day of Panax ginseng powder (n=45) or starch placebo
in the Ginkgo biloba group. The MoCA score and the delayed
(n=45) to determine its cognition-enhancing effects [59]. Cognition
recall item score were significantly higher at week 12 compared
was assessed using the Korean Mini-Mental Status Examination
to baseline for both groups. The Subjective Memory Loss score
(K-MMSE), the ROCFT for immediate and 20-min delayed recall,
and the cognitive function “forgetting acquaintance’s name” were
the Korean IADL, and the Seoul Neuropsychological Screening
higher at 12 weeks compared to baseline in the Pushen group. The
Battery. The Panax ginseng group improved significantly on both
Ginkgo biloba group improved in the overall Subjective Memory
immediate and 20-min delayed recall tests on the ROCFT compared
Loss score but performed significantly worse than the Pushen
to placebo. No serious adverse events were noted. These results
group for “forgetting acquaintance’s name” at 12 weeks. Thus,
suggest that Panax ginseng may be beneficial in improving visual
the results suggest that cognitive function improved comparably memory function but does not appear to influence verbal memory.
between Pushen and Ginkgo biloba. Another 12-week open-label randomized trial sought to
Overall, Ginkgo biloba and its extract EGb 761 show promise examine the efficacy of Korean red ginseng as an adjuvant
as a clinically significant compound for improving cognitive therapy to conventional anti-dementia medications in patients
function in cognitively normal adults and in those with MCI or with AD [60]. Sixty-one patients were randomized to low-dose
varying degrees of dementia. In general, these improvements are Korean red ginseng (4.5 g/day; n=15), high-dose Korean red
without adverse effects. Nonetheless, some inconsistencies in ginseng (9 g/day; n=15), or control (n=31), and cognitive function
the findings of the studies can be due to dose, plant form, extract was assessed using the ADAS, the K-MMSE, and the Clinical
strength, and other associated production and quality factors in Dementia Rating (CDR) scale. Patients in the high-dose ginseng
addition to differences in study design and population. group showed significant improvements on the ADAS and CDR
3.2.4. Ginseng - Panax ginseng C.A. Mey and Panax (American) after 12 weeks of treatment compared to controls. However, the
quinquefolius ADAS-non-cog and MMSE scores were not significantly different
between the 2 ginseng groups and the controls.
Ginseng is one of the most widely consumed herbal products The same group investigated different doses of ginseng in
in the world and has long been used for its apparent medicinal another open-label study of AD patients [61]. Forty patients were
and performance-enhancing properties. The root extract is randomized into one of 3 different dose groups (1.5 g/day, 3 g/day,
highly regarded in Asian herbal medicine due to its reputation or 4.5 g/day; n=10 each) or the control group (n=10), and the ADAS
and MMSE were used to assess cognitive function for 24 weeks. the 100 mg dose. Thus, ginseng appears capable of improving
Patients in the highest dose group (4.5 g/day) showed statistically working memory in healthy adults.
significant improvements in the ADAS-cog, ADAS-non-cog, and HT1001, a proprietary North American ginseng extract, was
MMSE scores at 12 weeks and at the 24-week follow-up, while investigated for its effects on working memory over 4 weeks in
the lower dosing and control groups did not exhibit significant a double-blind, placebo-controlled study of 64 individuals with
improvement over the course of the study. stable schizophrenia [65]. Verbal working memory and visual
A hydroponically cultivated red Panax ginseng Meyer root working memory were assessed at baseline and at the end of the
preparation (HRG80) and a traditionally harvested white Panax treatment period using the Letter-Number Span Test and Visual
ginseng standard preparation (PGS) were evaluated for their Pattern Test. Symptoms and medication side effects were also
effects in a number of tests including the attention d2 test for assessed. HT1001 treatment (n=32) led to improvement in visual
cognitive function, a computerized memory test, and the perceived working memory compared to placebo (n=32). Interestingly, the
stress score [62]. The effects of HRG80 and PGS were studied in HT1001 treatment group after 4 weeks also showed a decrease
this 3-arm, randomized, double-blinded, and placebo-controlled in extrapyramidal symptoms, while no change in extrapyramidal
crossover trial of 50 healthy subjects for 2 weeks. Subjects either symptoms was noted in the placebo group. The improvement
took 2 capsules/day (418 mg each) of HRG80 (n=17), 2 capsules/ in working memory and reduction in extrapyramidal effects
day (384 mg each) of PGS (n=16), or placebo (n=17). A statistically warrant further investigation of HT1001 as an adjunct therapy
significant interaction effect between time and treatment was in schizophrenia. A reduction in medication-related side effects
observed in the attention d2 and memory tests, indicating that could greatly improve the quality of life and functional status of
HRG80 treatment was more beneficial than the placebo. The individuals with schizophrenia.
effect of PGS was not statistically significant in the attention test, Overall, although many individual studies suggest that ginseng
although it was better than placebo. A significant difference was has potentially beneficial effects on cognition, further larger scale,
seen between the effects of HRG80 and PGS in attention, both randomized, and placebo-controlled trials are needed to determine
after a single dose (day 1) and after repeated administrations on its role in enhancing cognitive function. Importantly, ginseng may
days 5 and 12 of treatment. Overall, HRG80 treatment with a improve cognitive function in AD patients, but more subjects over
higher content of ginsenosides was superior to PGS and placebo, a longer period of study are needed to corroborate the current
according to attention and perceived-stress scores after single and findings. In addition, the positive results are difficult to generalize
repeated administrations for 5 and 12 days, while memory scores because of differences in dose and type of ginseng, which further
during both HRG80 and PGS supplementation were superior to
study could elucidate.
placebo at the same time points.
In an open-label study of patients with AD, 97 participants 3.2.5. Lion’s mane mushroom (Hericium erinaceus)
were randomized to a 4.5 g/day Panax ginseng powder (n=58) or
a control group (n=39) for 12 weeks [63]. Cognitive performance Many mushrooms have been historically used to treat
was measured using the MMSE and ADAS during 12 weeks of ailments [198], and lion’s mane mushroom is used for both
ginseng treatment and at 12 weeks after ginseng discontinuation. culinary and medicinal purposes, showing the ability to enhance
Ginseng treatment showed improvements in the ADAS-cog and the brain through neurological growth [199]. In animal models,
MMSE scores that continued up to 12 weeks, with declines to its active compounds have demonstrated the ability to delay
control levels after discontinuation of ginseng. These results neuronal death in neurodegenerative diseases such as ischemic
suggest that ginseng may improve cognitive performance in AD stroke, Parkinson’s disease, AD, and depression, and it has been
patients, although ginseng was not studied against placebo. shown to promote nerve regeneration and functional recovery in
In a double-blind, crossover study, healthy young adults (n=32) neuropathic pain or presbycusis [199]. In addition, lion’s mane
were assessed on acute neurocognitive effects after receiving, in has been shown to prevent the loss of spatial short-term and
random order, either 100, 200, or 400 mg of American ginseng visual recognition memory induced by Aβ25-35 in mice [200].
(Cereboost composed of Panax quinquefolius standardized to Similarly, it has been shown in vitro that lion’s mane fruiting
10.65% ginsenosides) or a placebo [64]. Treatment occurred body extract induces neurite outgrowth of neuron cells NG108-
over 4 separate days, with a 7-day washout period in between 15 and PCI2 cells, promotes nerve growth factor (NGF) mRNA
each administration. Cognitive function was measured at 1, 3, expression, and modulates the secretion of NGF from 1321N1
and 6 h following ginseng administration with the Computerized human astrocyte cells [201]. Although the preclinical data are
Mental Performance Assessment System battery, which was promising, the results from clinical trials are currently limited.
developed to include tests sensitive to nutritional manipulations. Lion’s mane was assessed for its efficacy on cognitive function
A significant improvement in working memory was found. with the Revised Hasegawa Dementia Scale (HDS-R) in a double-
Corsi block performance, a measure of spatial span and speed blind, placebo-controlled trial of Japanese men and women 50 –
of response, also improved for all doses at all testing times. 80 years old with MCI (n=30) [66]. Subjects were randomized for
Differential effects of all doses on other working memory 16 weeks to either four 250 mg tablets containing 96% of lion’s
tasks were noted across the testing day, while choice reaction mane dry powder 3 times/day (n=15) or placebo (n=15). At weeks
time accuracy and calmness were significantly improved after 8, 12, and 16, the lion’s mane group showed significantly higher
scores on the HDS-R compared to placebo. The improvement term memory as indicators of fatigue. The result was calculated
was greater with increasing duration of the lion’s mane intake. as a fatigue index, which was the ratio of the test score before
However, after 4 weeks of termination of treatment, the HDS-R night duty to the test score after night duty multiplied by 100.
significantly declined. No side effects of the treatment were The results revealed that the total fatigue index was significantly
observed throughout the study. Hence, the results indicated that improved after 2 weeks of taking the SHR-5 dose when compared
treatment with lion’s mane could lead to improved cognitive to placebo, with no reported adverse effects.
function in older people with MCI with no side effects. The effect of Rhodiola rosea on the stress, anxiety, mood, sleep,
In a more recent double-blind, placebo-controlled study sleepiness, and cognitive function of healthy, mildly anxious
assessing the effect of lion’s mane on cognitive function, healthy university students (ages 18 to 35; n=81) was assessed in a
older adults over 50 years of age (n=31) were randomized for randomized open-label trial [69]. A group (n=40) received 200 mg/
12 weeks to either 4 times/day dose of 0.8 g of lion’s mane day of Vitano (Rosalin (WS 1375) dry extract from Rhodiola
(3.2 g/day total; n=16) or placebo (n=15) [67]. Cognitive rosea root) 2 times/day (30 min before breakfast and 30 min
function was assessed at baseline and 6 and 12 weeks using the before lunch) for 14 days. The control group (n=41) received no
MMSE, the Benton visual retention test, and the Standard verbal treatment. Stress, anxiety, mood, sleep, and sleepiness levels were
paired-associate learning test. The results showed significant all self-reported through a questionnaire. Simple reaction time,
improvement in cognitive function in the lion’s mane group choice reaction time, sustained assessment to response test, and
compared to placebo on the MMSE at 12 weeks, but no other symbol digit processing were assessed through cognitive tests.
assessments were significantly different. Thus, in these 2 clinical The study had 4 phases: (1) a baseline questionnaire and cognitive
trials, lion’s mane showed improvements in cognitive function tests, (2) dosing followed by the questionnaire and cognitive tests
within 4 months in both healthy older adults and in older adults 4 h later, (3) a questionnaire and cognitive tests at 7 days, and (4) a
with MCI. These studies also noted no adverse effects, suggesting questionnaire and cognitive tests at 14 days. Self-reported anxiety
that lion’s mane is a safe treatment. and stress were significantly reduced in the treatment group by
14 days. The treatment group reported significantly lower levels
3.2.6 Rhodiola rosea L. of anger, depression, and confusion and significantly improved
overall mood. Sleep or sleepiness was not significantly different
Rhodiola rosea is a plant found in the mountainous regions of
between the control and treatment groups. Cognitive performance
the Arctic, Europe, Asia, and North America with roots that have
did not change for either group. The results demonstrate that Vitano
long been used in traditional medicine [202]. The plant has been
was effective at reducing anxiety and stress and improving mood
used in the treatment of anxiety, depression, and fatigue and offers
in healthy university students but did not significantly improve
promise in improving cognition and mental performance due to cognitive performance compared to the control. Further research
its neuroprotective properties [203]. The plant’s roots contain in this area would benefit from utilizing a placebo control group.
biologically-active compounds such as flavonoids and glycosides In another study, 12 weeks of Rhodiola rosea extract combined
(e.g., salidroside) that help the body resist biological stressors and with a vitamin and mineral supplement (Vigodana) was assessed
avoid damage, hence earning its title as an adaptogen [204]. Several on the cognitive function of adults aged 50 to 89 with physical and
mechanisms may explain Rhodiola rosea’s possible neuroprotective cognitive disabilities (n=120) [70]. Vigodana contains vitamins E,
and cognition-promoting properties. The plant may interfere with B6, and B12, folate, magnesium, and Rhodiola rosea root extract.
the secretion of stress-response compounds such as the hormone All subjects had a self-perceived cognitive or physical disability
cortisol within the hypothalamic-pituitary-adrenal system [205]. and had total error scores ≥8 on the Orientation-Memory-
In addition, Rhodiola rosea may interact with p-JNK, which are Concentration Test. Subjects with AD, Creutzfeldt-Jakob disease,
protein kinases involved in stress signaling pathways implicated in Parkinson’s, brain trauma, and cerebral tumor were excluded from
Aꞵ accumulation associated with AD [206]. Finally, Rhodiola rosea the study. Group 1 (n=60) took 2 capsules after breakfast, and
has antioxidant properties and may act as a free-radical scavenger to group 2 (n=60) took 1 capsule after breakfast and 1 after lunch,
combat oxidative stress that may be associated with AD. and subjects were assessed at baseline, 6 weeks, and 12 weeks.
In a placebo-controlled double-blind study, the effect of a Physical and cognitive performance was assessed through a
daily low-dose regimen of 170 mg SHR-5 Rhodiola rosea extract digit connection test, a 4-point rating scale, and evaluation of
(4.5 mg of salidroside) was tested versus placebo on the mental efficacy and tolerability by the patient and a physician. The digit
performance of healthy young physicians aged 24 to 35 (n=56) connection test evaluated mental vitality by assessing the time it
with nonspecific fatigue during night shifts [68]. Subjects were took subjects to complete the test. The 4-point rating scale was used
randomly assigned to group A (n=26) that received a daily dose to assess symptoms of physical impairment such as exhaustion,
of SHR-5 for 2 weeks or group B (n=30) that received a daily decreased motivation, daytime sleepiness, decreased libido, and
dose of placebo for 2 weeks. After a 2-week wash-out period, sleep disturbances and symptoms of cognitive impairment such
subjects were crossed over to receive the treatment that they had as concentration impairment, forgetfulness, memory deficiency,
not received before for 2 weeks (i.e., group A received the placebo susceptibility to stress, and irritability. Results revealed that both
and group B received the SHR-5). Five tests were used to measure groups had significantly better physical performance at 12 weeks
visual and audial perception speed, attention capacity, and short- compared to baseline and highly significant improvement in
cognitive performance compared to baseline. Group 1 showed rosemary (750, 1,500, 3,000, or 6,000 mg) or placebo on 5 separate
consistently higher improvements in both physical and cognitive 1-day treatment sessions every week for 5 weeks [72]. Cognitive
performance by week 12 when compared to group 2, indicating performance was assessed immediately after consumption and at
that the dosage for group 1 seemed to be more effective than that 1, 2.5, 4, and 6 h post-consumption. The 750 mg dose resulted in a
of group 2. Physicians assessed the efficacy of the supplement as significant improvement in speed of memory compared to placebo,
“very good” or “good” for 81% of patients, and 80% of patients while 6,000 mg resulted in impairment. Compared to baseline, all
assessed the efficacy of the supplement as “very good” or “good” doses resulted in significant impairment, other than the 750 mg
for themselves. Thus, this study demonstrated that Vigodana dose. Continuity of attention was significantly impaired compared
seemed to improve the cognitive and physical performance of to placebo at every dose other than 750 mg, and quality of
subjects at 12 weeks compared to baseline with no adverse effects. working memory was significantly impaired compared to placebo
A limitation of this study was that it was not placebo-controlled, at every dose other than 3,000 mg. Subjective feelings of alertness
which would be a next step in this line of research. were significantly improved for the 750 mg dose, and alertness
The effect of a dose of ADAPT-232 (containing a standardized was significantly decreased for the 6,000 mg dose, compared
extract ratio 2.8:1 Rhodiola rosea, 1.4:1 Schisandra chinensis to placebo. Therefore, the lower dose of rosemary appeared to
(Turcz.) Baill., and 10.5:1 Eleutherococcus senticosus Maxim) on improve speed of memory and alertness, preventing time-related
the mental performance of healthy females aged 20 to 68 (n=40) performance decrements, which may be attributed to fatigue. In
with chronic stress was assessed in a randomized, double-blind, contrast, the higher doses negatively affected performance and
placebo-controlled, and parallel-group trial [71]. The subjects were subjective feelings of alertness.
randomly divided into a group (n=20) that received a single dose In another study, 76 young adults with low energy were
of 270 mg of ADAPT-232 or another group (n=20) that received randomized to a 1-time consumption of either a dose of 1.7 g
a placebo dose. The d2 Test of Attention and the Stroop Test were of rosemary (n=26), black pepper (n=26), or placebo (n=24),
used to assess mental performance during stressful cognitive tests measuring task performance before and 60 and 90 min after
(specifically their attention, speed, and accuracy). The first day consumption [73]. The results showed that rosemary decreased
was the baseline assessment. On the second day, subjects were mental fatigue on a visual analog scale at 60 min and reduced
tested again once in the morning and once in the afternoon. On the false alarms during the primary cognitive task at 90 min, although
third day, subjects took their doses of either ADAPT-232 or placebo these changes were statistically insignificant and transient. Thus,
rosemary does not induce consistent acute improvements in
and then were assessed 2 h later. The treatment group performed
cognitive performance, at least at the dose used in this study.
significantly better than the control group on attention, speed, and
In a study of healthy adults, 80 subjects were randomized
accuracy on the d2 test. No major adverse effects were reported,
to receive either 250 mL of water infused with rosemary
although a few instances of sleepiness and cold extremities were
(n=40) or plain water (n=40) with a 20-min absorption period
observed in both the treatment and placebo groups. This study
before cognitive assessment [74]. Those who drank rosemary
suggests that ADAPT-232 was effective at improving subjects’
had small to moderate beneficial effects for performance on
mental performance and attention, speed, and accuracy under
several tasks: The Corsi blocks mean span length, serial threes
stressful conditions. It is unclear how much Rhodiola rosea is
and serial sevens correct responses, RVIP correct responses
responsible for this improvement in performance, as ADAPT-232
and errors, and immediate and delayed word recall. Curiously,
contains a combination of plant compounds.
the effect of rosemary on fatigue of a visual analog scale was
Rhodiola rosea offers promise as a treatment for anxiety,
slightly negative. Those who received rosemary also had a
stress, and fatigue in healthy adults and as a possible enhancer of significant increase in deoxygenated hemoglobin compared
mood, mental performance, and cognition. Rhodiola rosea also to placebo. However, this effect became insignificant with
appears to be safe for human consumption with little to no adverse a Bonferroni correction. The overall main effect of time on
effects. However, further research should be conducted regarding deoxygenated hemoglobin was also significant, as it decreased
its effect on the cognition of older adults with cognitive decline in the middle of the testing period and increased toward the end.
and neurodegenerative diseases such as AD, and trials should be Therefore, treatment with rosemary water improved cognitive
placebo-controlled and include larger sample sizes. task performance and cerebral oxygen extraction. However, the
3.2.7. Rosemary (Rosmarinus officinalis L.) performance on several of the cognitive tasks was unchanged,
putting into question whether the noted improvements were a
Rosemary has long been theorized to stimulate the brain direct result of the increases in oxygen extraction, warranting
and assist in memory, with this thought dating back to ancient further exploration of this relationship.
Greece [207]. Studies have shown that rosemary extract can In addition to oral consumption, the effects of aromatherapy
scavenge reactive oxygen species [208] and exert a neuroprotective rosemary have been investigated as well. Aroma inhalation with
effect on dopaminergic neurons [209]. Therefore, it has been rosemary has been found to stimulate arousal, producing effects
investigated as a treatment to improve cognitive function. on both subjective mood and EEG [210]. It is well established that
In a crossover study, 28 healthy elderly individuals (65 – arousal affects task performance, following the inverted-U curve
90 years of age) received in random order one of 4 doses of dried of performance versus arousal [211].
Therefore, 144 healthy individuals were randomized to receive be important for the treatment of mood disorders that typically go
a 1-time administration of either ambient aromatherapy with hand-in-hand with cognitive difficulties. Nonetheless, despite the
4 drops of rosemary essential oil (n=48), lavender essential oil potent properties of the plant and the initial promising findings,
(n=48), or an odorless control (n=48), to assess subjective mood saffron has only been evaluated so far in a handful of clinical
and cognitive task performance before and after treatment [75]. trials [222].
The rosemary treatment had significantly higher scores on a In a study conducted in mild to moderate AD patients, subjects
secondary memory subfactor (indicating better accuracy during (n=46) were randomized for 16 weeks to receive either 30 mg/
memory-related tasks) and subjective feelings of alertness and day of saffron (n=23) or placebo (n=23) to determine its effects
contentedness compared to control. However, the control treatment on cognitive function with the MMSE, ADAS-cog, and the CDR
had significantly quicker responses (speed of memory factor and scale-sums of boxes (CDR-SB) at baseline and every 2 weeks [76].
speed of attention factor) than the rosemary treatment. These At the end of 16 weeks, the saffron group showed statistically
results support the concept of ambient aroma altering mood and significant improvements in cognitive function according to the
significantly affecting aspects of cognitive performance. However, ADAS-cog and CDR-SB compared to the placebo group, and
rosemary may cause a speed-accuracy trade-off, where greater no severe adverse effects were reported. In a follow-up trial
accuracy is accompanied by slower responses in comparison to conducted by the same group of researchers, 54 patients with mild
control. Furthermore, rosemary appeared to improve performance to moderate AD were randomized for 22 weeks to receive either
on more demanding tasks related to memory consolidation and 30 mg/day of saffron (n=27) or 10 mg/day of donepezil (n=27),
retrieval, but not less demanding attentional tasks. It is possible an FDA-approved AChEI [77]. The same assessment battery was
that rosemary aroma increases arousal excessively for less administered every 2 weeks as in the previous study. The ADAS-
demanding tasks but optimally for those that are more demanding. cog and CDR-SB improved similarly for both groups, and no
Thus, it appears rosemary aromatherapy may improve cognitive serious adverse effects were noted throughout the study. Thus,
performance, but its effectiveness greatly depends on the nature saffron may offer similar short-term improvement as donepezil
of the task. without the possibility of untoward effects.
The dose of rosemary greatly impacts its effects on cognitive In a study design similar to the previous one, patients with moderate
function, and it has even been shown to impair performance to severe AD (n=68) were randomized for 12 months to receive either
between 1,500 and 6,000 mg/day. Rosemary was also shown 30 mg/day of saffron (n=34) or 20 mg/day of memantine (n=34), a
to have a deleterious effect on speed of memory. Nonetheless, commonly used drug to treat symptoms of AD [78]. Every month,
other research shows that rosemary can be beneficial for subjects were evaluated with the Severe Cognitive Impairment Rating
cognitive function, creating overall conflicting results that Scale and the Functional Assessment Staging in addition to adverse
are difficult to interpret, questioning its clinical significance. events. The changes from baseline to 12 months in both cognition
Thus, supplementation beyond normal culinary use may not be assessments were similar for both groups, demonstrating that saffron
advantageous for cognitive function. was as effective as memantine in the prevention of further cognitive
decline in these patients. In addition, the number of adverse events
3.2.8. Saffron (Crocus sativus L.) was not different between the 2 groups.
Saffron is a spice derived from the dried stigmata of the plant Finally, in another study of patients with amnestic MCI, 35
Crocus sativus (from the Iridaceae family). The stigmata of Crocus subjects were assessed and diagnosed and then were randomized
sativus have been used for centuries in traditional medicine, and for 12 months into a wait-list control no-treatment condition
saffron has been shown to have 3 main metabolites: picrocrocins, (n=18) or to saffron extract (n=17) [79]. Subjects were assessed at
safranal, and crocins [212]. baseline and 12 months on the MoCA, the MMSE, the Geriatric
Based on what is currently known about saffron, it may Depression Scale, the Functional Rating Scale of Symptoms of
be beneficial for AD patients mainly due to its antioxidant Dementia for ADL, and the Neuropsychiatric Inventory. The results
properties. However, its crocins, water-soluble carotenoids indicated that the subjects who received saffron had significant
that are the primary metabolites involved in saffron’s memory cognitive improvement according to the MMSE, while the wait-
and cognition-enhancing effects, were shown to be effective in list control condition subjects had worsening cognitive decline. All
stopping Aβ plaque formation, crucial for preventing AD and other assessments were non-significantly different. Thus, overall
perhaps for treatment of those with the disease [213,214]. Crocins saffron shows promising findings for improvement in cognitive
were also shown in separate studies to prevent the formation functioning in adults with various stages of cognitive dysfunction,
of neurofibrillary tangles [214-216]. The findings from these 3 from MCI to severe AD. It also appears to have minimal, if any,
studies are important because Aβ aggregation and neurofibrillary adverse effects up to at least 1 year of consumption.
tangles are 2 of the main histopathological findings in AD. 3.2.9. Tart cherries (Prunus cerasus L.)
Another proposed mechanism of action for saffron’s ability to
prevent cognitive decline is through a moderate (up to 30%) Tart cherries are rich in phytochemicals, such as
inhibitory activity on AChE [217,218]. Finally, saffron has also anthocyanins [223,224]. They have been found to decrease
been shown to be as effective as fluoxetine and imipramine in the inflammation [223] and oxidative stress [225] and improve
treatment of mild to moderate depression [219-221], which could vascular function [226]. Anthocyanins have also been found
to have neuroprotective effects, as they can shield neurons warrants further investigation, perhaps using juice consumption
from inflammation, enhance neuronal function, increase over a long period of time and/or a greater absorption period.
cerebral blood flow, and stimulate neurogenesis in areas of
the brain necessary for cognition [227]. Impaired cerebral 3.2.10. Turmeric (Curcuma longa L.)
blood flow is hypothesized to contribute significantly to the The lynchpin physiologically-active compound of turmeric is
decline in cognitive function that occurs with advancing age curcumin [229], which has been shown to have a host of biochemical
and neurodegenerative disease [228]. Therefore, tart cherries actions, including anti-carcinogenic, anti-proliferative, anti-
have the potential to be an intervention for neurodegenerative inflammatory, antioxidant, antiviral, and antibacterial, among
disorders, such as dementia. others, and it has been shown to act on transcription factors,
In a study, 49 older adults (>70 years of age) with mild-to- enzymes, growth factors, cytokines, and neurotransmitters
moderate dementia were randomized for 12 weeks to receive [230,231]. Thus, its metabolic capacity is quite diverse and
either 200 mL/day of cherry juice (n=24) or a control juice extensive, but most oral applications are typically hindered by low
lacking anthocyanins (n=25) [80]. The cherry juice group saw bioavailability due to poor solubility, rapid metabolism, and swift
significant improvements in cognitive performance at 6 and elimination [230], making it challenging to create a therapeutic
12 weeks using the category verbal fluency task, AVLT total, delivery method, although technical formulations are utilized, e.g.,
AVLT delayed recall, and AVLT 20-min delayed recall tasks, nanoencapsulation with liposomes and micelles and emulsions
while the control group did not. Effect sizes were largest for [232]. Because of the oral delivery limitations, the results of clinical
the first 3 aforementioned tasks and were moderate for the last.
trials have either been inconsistent, unsupportive of preclinical or
Systolic blood pressure significantly improved and diastolic
animal data, or lacking in ultimate efficacy [233]. Nonetheless,
blood pressure modestly decreased in the cherry group, with no
extensive research demonstrates curcumin’s potential for being a
changes in the control. Therefore, consumption of anthocyanin-
key neuroprotective agent and beneficial for cognitive function
rich cherry juice was beneficial for multiple measures of cognitive
in healthy adults and those with AD or dementia, based on its
function in individuals with AD with additional improvements in
ability to inhibit AChE, protect against Aβ toxicity and/or limit
vascular function.
its production, reduce the effects of oxidative stress, and decrease
However, tart cherries do not appear to have immediate effects
inflammation, among others [233-236].
on cognitive performance compared to their long-term effects, as
In a study of 60 healthy adults aged 60 – 85 years, participants
shown in the previous study. Young healthy adults (18 – 35 years
were randomized to receive either 400 mg (~80 mg curcumin) of
of age; n=6), older adults (at least 55 years of age; n=5), and older
Longvida (a solid lipid curcumin formulation; n=30) or placebo
adults with dementia (n=5) were randomized in a crossover design
to a 1-time consumption of anthocyanin-rich cherry juice in one (n=30) to examine acute (1-h and 3-h post-treatment), chronic
of 2 dose schemes: (1) a single 300 mL dose at 0 h or (2) 100 mL (4 weeks), and acute-on-chronic (1-h and 3-h post-treatment
doses at 0, 1, and 2 h with cognitive tasks at baseline and 6 h [81]. following chronic treatment) effects on cognitive function and
Regardless of dose-timing, juice consumption did not improve mood [83]. Outcome measures were assessed at baseline and 28-
acute cognition, as measured by the AVLT, pattern and letter day follow-up, and cognition was assessed by the Computerized
comparison, or task-switching tests. In another crossover study, 27 Mental Performance Assessment System. At 1-h post-treatment,
middle-aged (45 – 60 years of age) individuals were randomized the curcumin group had improved performance on sustained
to a 1-time consumption of either 60 mL of tart cherry concentrate attention (the digit vigilance task) and working memory (the serial
or placebo, a 1-h absorption period, and then assessment of threes subtraction task) compared to placebo. Chronic curcumin
cognitive performance, blood pressure, and prefrontal cortex treatment significantly improved working memory (the serial
cerebrovascular response at baseline and 1, 2, 3, and 5 h after threes subtraction task), mood, and fatigue compared to baseline
consumption [82]. Those who received the tart cherry concentrate and placebo. The acute-on-chronic treatment effect was significant
had a significant decrease in systolic blood pressure at 1, 2, and for alertness and contentedness in the curcumin group. Thus, low-
3 h compared to placebo. This group also saw significantly higher dose (80 mg) curcumin had significant positive acute and chronic
concentrations of oxygenated hemoglobin during the 30-40 min effects on cognition and chronic effects on mood and fatigue.
epoch of the absorption period, compared to placebo, as well as In a second study by the same group of investigators, 89 healthy
during each period of task performance 1 h after consumption. older adults aged 50 – 80 years were randomized for 12 weeks
The cherry group also had higher total hemoglobin concentrations to receive either 400 mg (~80 mg curcumin) of Longvida (n=46)
during each period of task performance after 1 h. However, or placebo (n=43) on cognitive function and overall health [84].
cognitive performance was not significantly different between Cognitive performance was assessed at baseline and 4 and
the groups. Therefore, while tart cherry consumption resulted 12 weeks and was measured by serial threes and serial sevens,
in acute improvements in blood pressure and in cerebral blood virtual Morris Water Maze, Divided Attention Tracking Task, and
flow to the prefrontal cortex during task performance, this did not Arrow Flankers Task. Compared to placebo, the curcumin group
significantly affect performance on cognitive tasks. Regardless, had better working memory performance on the virtual Morris
the changes in cerebral blood flow have strong implications for Water Maze and on serial threes and serial sevens at 12 weeks.
tart cherry as an intervention for neurogenerative diseases, which Thus, treatment with Longvida appeared to improve working
memory in healthy older adults, which was consistent with the patients. In a study, 31 healthy adults (20 – 81 years of age) were
previous study. randomized for 12 weeks to receive either 50 mg/day of diosgenin-
In another study, 160 community-dwelling, cognitively healthy rich yam extract (n=18) or placebo (n=13) [87]. Those who
older adults were randomly assigned for 12 months – 500 mg received yam extract saw a significant age-dependent increase in
3 times/day Biocurcumax, a curcumin formulation (n=80), or the Repeatable Battery for the Assessment of Neuropsychological
placebo (n=80) for the prevention of cognitive decline [85]. Clinical Status total score compared to placebo, with older subjects
and cognitive assessments were conducted at baseline and 6 and (>47 years of age) achieving greater improvement. On the
12 months. Frequency of errors in prospective and retrospective Repeatable Battery for the Assessment of Neuropsychological
short- and long-term memory was measured by self-report on the Status subtests, semantic fluency significantly improved in the
Prospective and Retrospective Memory Questionnaire. General yam extract group compared to placebo. Therefore, diosgenin
cognition was assessed with the MoCA. Verbal learning and yam extract was able to improve cognitive function in adults over
memory were assessed with the AVLT. Verbal fluency was assessed a wide range of ages, but with more pronounced effects occurring
with the COWA. Perceptual motor speed was assessed with the in individuals over 47 years of age. However, a mechanistic
Wechsler Digit Symbol Scale from the WAIS-R. The computerized explanation for diosgenin-rich yam’s effect remains unknown, as
CogState was administered and included a battery of cognitive the relationship between morphological changes in the brain and
tasks. A significant interaction effect for performance on the MoCA cognitive function in neurodegenerative disease progression was
was related to a decline in cognitive function at 6 months in the not explored.
placebo group that did not occur in the Biocurcumax group, and no
3.2.12. Withania somnifera (L.) Dunal - Ashwagandha
other difference between groups was significant. Thus, the results
of the study showed limited efficacy of Biocurcumax for delaying Withania somnifera, commonly known as ashwagandha, is an
cognitive decline in older healthy adults. Ayurvedic plant that has been used medicinally for over 3,000 years
Another study was conducted in cognitively healthy middle [239]. It is an adaptogen that helps the body respond more effectively
age and older adults (51 – 84 years of age) to determine the effects and resiliently to stress, promotes immunity, and combats oxidative
of a nanoencapsulated formulation of curcumin (Theracurmin) on stress and cellular damage due to its antioxidant properties. The
cognitive function and brain Aβ and tau accumulation according bioactive C28-steroidal lactones found in the leaves of Withania
to positron emission tomography scans [86]. Participants (n=40) somnifera (such as Withaferin A and sitoindosides VII-X) have
were randomized for 18 months to receive 90 mg of highly been shown to have antioxidant, anti-inflammatory, anxiolytic,
bioavailable curcumin twice/day (n=21) or placebo (n=19). and neuroprotective properties. In addition, the roots of Withania
Cognitive assessments included verbal (SRT) and visual (Brief somnifera contain Withanoside IV and its metabolite sominone,
Visual Memory Test-Revised) memory and attention (TMT A), which have been demonstrated to induce neuronal outgrowth and
and positron emission tomography scans were performed in the synaptogenesis. Furthermore, the plant has been shown to inhibit
amygdala, hypothalamus, medial and lateral temporal, posterior AChE and protect against cognitive impairment in rats [240].
cingulate, parietal, frontal, and motor (reference) regions. The In an 8-week randomized, double-blind, placebo-controlled,
SRT Consistent Long-Term Retrieval, SRT Total, visual memory, parallel-group trial, the effect of 300 mg twice/day of
and attention all significantly improved in the curcumin group ashwagandha root extract (KSM-66 Ashwagandha; n=25) versus
compared to placebo. Brain Aβ and tau accumulation decreased placebo (n=25) in adults aged 35+ with MCI was assessed [88].
significantly in the amygdala in the curcumin group compared to The KSM-66 Ashwagandha was a 100% aqueous extract of the
placebo, and while they did not change in the hypothalamus of roots of Withania somnifera and contained 5% withanolides.
the curcumin group, they increased in the placebo group. Thus, Subjects were evaluated at baseline, 4 weeks, and 8 weeks
this is the first study documenting improvements in memory and on memory, visuospatial capabilities, executive function, and
attention in older adults after bioavailable curcumin treatment that attention. The WMS-III was used to assess immediate, general,
was related to improvements in plaque and tangle accumulation and working memory. In addition, WMS-III Visual Reproduction
in certain brain regions. Overall, the results of curcumin in I and II subtests were used to assess visual memory, and the
clinical trials are not as conclusively impressive as in preclinical Shepard Mental Rotation Task was used to assess the subject’s
and animal studies, which point to research design issues and cognitive rate of spatial processing. The Wisconsin Card Sort Test
limitations based on curcumin’s typical low bioavailability and and Eriksen Flanker Task were also used to assess the subjects’
resultant limited therapeutic doses. executive function. Finally, TMT A and the Mackworth Clock
Test were used to assess attention and information-processing
3.2.11. Wild yam (Dioscorea villosa L.)
speed. The treatment group performed significantly better on
Diosgenin is a compound found in many species of yam, which the tests that assessed immediate and general memory, executive
has been found to repair axonal atrophy and synaptic degeneration, function, attention, and information-processing speed after
improving memory dysfunction in a mouse model of AD [237] 8 weeks compared to the placebo group. However, the effects of
and in normal mice [238]. Therefore, diosgenin may potentially treatment on working memory and visuospatial processing were
strengthen cognitive function in both healthy adults and AD inconclusive, as the difference in performance between the 2
groups during these tasks was insignificant. No adverse effects creative thinking, event-based prospective memory, time-based
were reported in the study, deeming the treatment tolerable. prospective memory, and action-based prospective memory).
This study demonstrates that Withania somnifera offers promise Therefore, caffeine appeared to successfully improve executive
as a safe and effective treatment for improving immediate and functioning and Stroop reaction time.
general memory, executive function, attention, and information- In a similar study of healthy adults, 128 subjects were
processing speed in patients with MCI. randomized to a 1-time consumption of either caffeinated (65 mg;
In another randomized, double-blind, and placebo-controlled n=64) or decaffeinated coffee (n=64) before performing cognitive
study of subjects with bipolar disorder (aged 18-65; n=60), tasks [91]. Those who received caffeine had significantly faster
Withania somnifera extract was assessed for its effect on cognitive simple reaction times, indicating increases in speed of encoding
dysfunction [89]. Subjects were randomly assigned for 8 weeks to and response to a novel stimulus. However, caffeine exerted no
either 500 mg/day of Withania somnifera in the form of a tablet significant effects on working memory tasks. Interestingly, caffeine
called Sensoril, which contains a minimum of 8% withanolides, had differential effects on extroverts and introverts, as extroverts
32% oligosaccharides, and a maximum of 2% Withaferin A performed better after caffeine in the running memory task, and
(n=30) or placebo (n=30) and were tested at baseline and at post- introverts performed worse. Similarly, the effect of caffeine intake
intervention. The subjects continued taking their medications and trait anxiety interacted, as caffeine improved performance in
as usual. The Set Shifting Test, Strategic Target Detection Test, the mental rotation task for those with high anxiety and hindered
Flanker Test, Auditory Digit Span, Word List Memory, and Finger performance in those with low anxiety. Therefore, the beneficial
Tapping Test were used to evaluate executive function, processing effects of caffeine not only depended on the nature of the task
speed, attention, working memory, memory, and psychomotor (improving reaction time rather than working memory), but also
speed, while the Penn Emotional Acuity Test was used to evaluate the nature of the individual (more effective in extroverts and high-
social cognition. Subjects in the treatment group performed anxiety individuals for certain tasks).
significantly better on the Flanker Test (neutral mean response In a crossover study, 72 young adult regular coffee drinkers were
time), Auditory Digit Span (mean digit span backward), and Penn randomized to a 1-time consumption of either caffeinated (100 mg)
Emotional Acuity Test (mean social cognition response rating) coffee, decaffeinated coffee, or coffee-flavored placebo water at each
compared to placebo at the end of the study. No other cognition of 3 study visits before performing cognitive tests [92]. The regular
tests differed significantly between the treatment and placebo coffee group had significantly better digit vigilance accuracy and
reaction time, compared to the decaffeinated coffee and placebo
groups. Adverse effects were mild, with no difference between the
groups, respectively. The regular coffee group also had significantly
treatment and placebo groups. These results indicate that Withania
faster RVIP reaction time compared to the placebo group. Both
somnifera extract may safely improve aspects of cognition such
caffeinated and decaffeinated coffee significantly improved
as verbal working memory, response time, and social cognition
subjective feeling of alertness, compared to placebo, and caffeinated
response in subjects with bipolar disorder. However, the effect
coffee decreased feelings of tiredness and headaches compared to
of Withania somnifera extract on other aspects of cognition is
both other groups. Overall mood and mental fatigue ratings were also
inconclusive and warrants further investigation.
significantly better for the regular coffee group compared to placebo.
3.2.13. Xanthines However, regular coffee increased feelings of jitteriness compared to
placebo in young females and compared to decaffeinated coffee in
Antioxidant xanthines are abundant in natural sources (e.g., older males. Therefore, caffeine increased reaction time and accuracy,
tea, coffee, and chocolate) in molecular forms such as caffeine enhanced alertness and overall mood, and mitigated feelings of
(1,3,7-trimethylxanthine) [241]. Caffeine is widely consumed for its tiredness, headaches, and mental fatigue. However, these positive
adenosine antagonistic effects, which provide excitation and CNS findings were not without feelings of jitteriness, although age and sex
stimulation [242] by modulating neurotransmitter release (e.g., appeared to influence the extent of jitters.
dopamine, acetylcholine, norepinephrine, and serotonin) [243], In addition to improvements in performance, caffeine has also
thus altering attention and mood [244]. Therefore, studies demonstrated physical neuroprotective effects during cognitive
have found that caffeine is successful in improving cognition tasks. Changes in regional cerebral blood volume have occurred in
by improving alertness [245], reducing reaction times [246], the frontal region of the brain during cognitive tasks [249], but it
improving concentration and accuracy [247], and even enhancing is unknown whether they occur specifically in the associated area
short-term memory [248]. Thus, many studies have investigated in the prefrontal cortex, which is related to mental work [250].
the acute effects of coffee consumption on cognition. Caffeine has been found to constrict blood vessels in the brain,
Forty-three regular caffeine users were randomized to receive explaining its ability to reduce headaches [249], so it may also
either caffeinated (~50 mg caffeine) or decaffeinated coffee before reduce regional cerebral blood volume.
performing several cognitive tests [90]. The treatments were In a crossover study, 14 subjects were randomized to 1-time
offered at 2 time points, 1 week apart. Those who had caffeine consumption of either caffeinated (180 mg) or decaffeinated
had a significantly faster mean reaction time on the Stroop Test coffee and then consumed the other beverage after at least
and performed significantly better on the Jansari Assessment 1 week. After each consumption, subjects performed the
of Executive Functions (average performance, planning, Uchida-Kraepelin psychodiagnostics test to compare the
effects of mental work on prefrontal cortex regional cerebral times between 10 and 90 min post-consumption. However,
blood volume with and without caffeine [93]. On average, the caffeine had an acute quadratic effect following the first drink (1
number of answers per session increased in the caffeine group cup was superior for reaction time) and a linear dose-response
and decreased in the decaffeinated group, likely due to mental effect following the third drink (2 cups slowed reaction time).
fatigue. Regional cerebral blood volume in the inferior frontal Therefore, compared to water, caffeine had a significant acute
cortex increased with each mental work task, though this effect on arousal, particularly at lower doses. Furthermore, at
occurred to the same degree before and after caffeine intake. the same caffeine dose, tea and coffee are superior at acutely
Thus, improvements in performance with caffeine were not enhancing performance for different tasks. Tea improved critical
reflected in the regional cerebral blood volume in the inferior flicker fusion (a measure of alertness), while coffee improved
prefrontal cortex. However, in the caffeine group, regional choice reaction time (a measure of reaction time), but the effects
cerebral blood volume decreased during rest periods between of coffee on reaction time were not stable. Therefore, the exact
tasks due to vasoconstriction. This indicates that in addition to differential effects of tea and coffee on cognition remain unclear
caffeine’s ability to activate prefrontal cortex neurons to improve and warrant further investigation.
cognition, the vasoconstrictive capacity of caffeine protects Additional studies have been performed on the effects of
against potential hyperemia induced by mental work. Overall, tea on cognition. In a 2-part crossover study, participants were
the beneficial effects of caffeine on cognitive function seem to randomized in study 1 (n=26) to receive 2 servings of either black
clearly extend far beyond its properties as a stimulant. tea (50 mg caffeine and 23 mg theanine/serving) or placebo tea
While both coffee and tea contain caffeine, the effects of tea on over 60 min, and in study 2 (n=32) they received either 3 servings
cognition and human performance are less widely studied. While of black tea (30 mg caffeine and 12 mg theanine/serving) or
coffee and tea, when matched for caffeine, have similar effects on placebo tea over 90 min before performing cognitive tasks
alertness, tea has been found to produce more consistent levels [95]. In study 1, those who received black tea had more correct
of arousal throughout the day [251]. This could be due to the responses on intersensory attention subtasks (auditory and visual)
components of tea, such as flavonoids or theanine, that coffee lacks. and responded faster (visual) compared to placebo. They also had
When ingested alone, theanine has been found to induce calmness more correct responses for task switching and felt significantly
and synchronicity of brain activity [252], but when combined with more alert but less calm compared to placebo. In study 2, the
caffeine it induces even greater synchronization [253], providing number of correct responses or reaction times for intersensory
improvements in attention [254]. attention did not differ between groups, but those who received
Therefore, in a crossover study, 30 habitual caffeine drinkers black tea had more correct responses for task switching, felt
were randomized to receive either caffeinated black leaf tea significantly more alert, and trended toward greater feelings
(either 37.5 mg/1 cup or 75 mg/2 cups), caffeinated black coffee of contentedness compared to placebo, with no difference in
(75 mg/1 cup or 150 mg/2 cups), or bottled water at 4 different feelings of calmness. Therefore, both studies showed that black
time points throughout the day before performing cognitive tea improved overall attention for the intersensory attention
tasks to compare the acute effects of coffee and tea on cognitive tests and accuracy for novel stimuli on the task-switching tests.
and psychomotor performance [94]. For the critical flicker The greater improvements in reaction time and accuracy and
fusion task, the analysis revealed that water was associated enhanced measures of self-reported mental state occurred with
with decreased performance over time, while the caffeinated the stronger tea in study 1, likely due to the combined effects of
beverages maintained performance throughout the day, with caffeine and theanine.
the best results shown for 1 cup of tea. After the first drink, a In another study, 23 subjects were randomized to receive either
significant interaction between treatment and time was found, as matcha tea, a matcha snack bar (each containing 4 g matcha
caffeine maintained alertness, while water was associated with a powder with 67 mg theanine and 136 mg caffeine), placebo tea,
decline. Furthermore, at the same dose of caffeine, tea produced or placebo snack bar, while performing cognitive tasks at both
a rapid increase in the critical flicker fusion threshold between 30 baseline and post-consumption [96]. The treatments were offered
and 90 min post-consumption compared to coffee. Performance for 4 days, and each day cognitive function was assessed before
did not differ significantly between doses. For the line analogue and after consumption. Response speed for the simple reaction
rating scales for sedation, 1 cup of tea was associated with higher time task was faster in those who received matcha tea compared
subjective feelings of alertness throughout the day, which is to the placebo drink. For choice reaction time, those who received
consistent with its effects on critical flicker fusion performance. either type of matcha had significantly improved response speeds
Only the first drink influenced the line analogue rating scales compared to either placebo. For the speed of attention factor, the
for sedation, with significantly higher levels of alertness for interaction between format and condition was significant, although
caffeinated beverages compared to water. The second drink the significance disappeared using multiple pairwise comparisons.
showed a significant treatment effect for the recognition reaction For delayed picture recognition accuracy, spatial working memory
time component of the choice reaction time task, where water accuracy, and the working memory factor, both drink formats
slowed reaction time and the caffeinated beverages maintained yielded better accuracy compared to the bar format. Therefore,
baseline performance. At the same caffeine dose, compared consumption of matcha in both tea and bar forms slightly improved
to tea, coffee was associated with significantly faster reaction cognitive performance on a few specific attentional tasks, and the
drink form outperformed the bar form on accuracy of delayed higher number of correct answers on the modified Stroop Test at
picture recognition and spatial working memory. Both forms 30 days compared to baseline, while white chocolate intake had
consistently affected attention abilities but had more significant no impact. These numbers remained marginally higher at follow-
effects on working memory. These results appear more similar to up in the dark chocolate group compared to the white chocolate
the effects of caffeine alone, rather than the synergistic effects of group, and the dark chocolate group performed better overall. For
caffeine and theanine, suggesting further research is warranted. the digital cancellation test (3 trials), dark chocolate significantly
Xanthines are also found in chocolate; in addition to caffeine, increased total performance numbers at 30 days compared to
cocoa products have an extremely high concentration of a metabolite baseline for trial 3 (but not trials 1 or 2), whereas white chocolate
of caffeine called theobromine (3-7-dimethylxanthine) [255]. The had no effect. Total performance in the dark chocolate group
effects of theobromine on the CNS have been found to be weak, remained significantly higher compared to the white chocolate
but in large doses, it has been found to cause increases in energy, group at follow-up. However, omission ratio significantly
motivation, and alertness in some individuals [256]. decreased at 30 days in trials 1 and 2 for the dark chocolate group
In a 2-part study, the effects of chocolate consumption on compared to baseline. The NGF level increased at 30 days for
cognition were investigated [97]. In the first study, 20 individuals the dark chocolate group but returned to the baseline value at
were randomized to 1-time consumption of either chocolate with follow-up. In the white chocolate group, NGF did not change
cocoa powder, chocolate containing 250 mg theobromine and at all. Plasma theobromine concentration increased significantly
19 mg caffeine, or a placebo. The cocoa powder and caffeine groups throughout the intervention period in the dark chocolate group,
had significantly faster simple reaction time response speeds, and returning to baseline at follow-up, whereas it did not change in the
the caffeine group had significantly better performance on the white chocolate group. However, plasma caffeine levels did not
RVIP task compared to placebo with cocoa powder marginally change in either group at any point. Therefore, 1 month of dark
better. The cocoa powder and caffeine groups also had significantly chocolate consumption yielded a transient increase in NGF and
higher self-reported energetic arousal, and the caffeine group had plasma theobromine, which may promote more lasting neuronal
significantly improved hedonic tone (cocoa powder was marginally plasticity and subsequent improvement in cognition.
better) compared to placebo. Feelings of hunger decreased only Thus, these results using coffee, tea, and chocolate as sources of
after cocoa powder consumption, but not caffeine, compared to various xanthines are promising for improving cognitive function.
placebo, and headache symptoms decreased only after caffeine, but In addition, these foods may have other naturally occurring
not after cocoa powder. Therefore, the cocoa powder and caffeine phytochemicals that interact with the xanthines to produce positive
treatments showed similar effects, although cocoa powder was cognitive effects.
slightly less effective. In the second study, 22 individuals were
randomized to 1-time consumption of 3 different treatments with 4. Discussion
varying levels of methylxanthines (i.e., caffeine and theobromine):
zero methylxanthine, low methylxanthine (8 mg caffeine and With the rising burden of chronic illnesses, the increasing
100 mg theobromine), and high methylxanthine (20 mg caffeine and morbidity and mortality of AD and other neurocognitive disorders
250 mg theobromine) or placebo (water). These treatments match have spurred great interest in brain health, both among medical
the methylxanthine contents of white, milk, and dark chocolate, providers and the public. In part due to a lack of effective treatment
respectively. High methylxanthine significantly increased reaction or preventive options, improvement of cognitive function using
speed compared to zero methylxanthine for the simple reaction various dietary supplements has emerged as a particular area
time task, and both low and high methylxanthine improved RVIP of focus. At present, the FDA-approved medications for the
performance compared to zero methylxanthine. Mood scores treatment of dementia can only briefly slow cognitive decline,
for energetic arousal and hedonic tone showed a similar effect while also causing significant adverse effects, and robust
to the simple reaction time and RVIP, with higher scores for evidence for effective preventive strategies is also lacking [2].
methylxanthine-containing treatments. Therefore, the effects of milk Although regular physical exercise and a healthy dietary pattern
and dark chocolate due to methylxanthine content do not appear to that avoids nutritional deficiency currently form the basis
be significant. Overall, both studies exhibited some improvements for prevention of neurodegenerative disease [257], targeted
in cognition and mood. Each treatment arm contained around or nutritional supplementation tailored to the health status of the
below the lower range of caffeine doses found to have detectable individual patient may offer additional benefit in the prevention
stimulant effects, suggesting that these psychoactive changes were and management of cognitive decline.
likely due to the methylxanthine content. This narrative review of clinical trial data suggests that
In another study, subjects were randomized to receive either certain nutrients and phytonutrients are capable of significantly
dark chocolate (26.8 mg caffeine and 197.5 mg theobromine/day; modulating cognition in different adult populations with varying
n=10) or white chocolate (non-detectable methylxanthine; n=8) health conditions that cause cognitive impairment. The populations
daily for 30 days to investigate the effects of methylxanthine- in this review included AD and MCI, MS, traumatic brain injury,
rich chocolate intake on cognition [98]. Cognitive function was stroke, psychotic disorders, and healthy adults.
measured at baseline, after 30 days, and 3 weeks after the end of In AD and MCI, numerous nutrients and phytonutrients
the intervention. Dark chocolate intake resulted in a marginally have been studied for their effects on cognitive function.
A reduced rate of cognitive decline was exhibited in trials using further investigate its potential for cognitive enhancement. Tart
α-lipoic acid as an adjunct treatment to traditional medications cherry juice may also modestly improve cognitive function after
[3,4]. Likewise, Bacopa monnieri has shown improvements chronic consumption [80], while a similar acute improvement in
in some aspects of cognitive function, perhaps due to anti- cognition has not been observed [81]. Saffron has shown promise
inflammatory and antioxidant effects [35,36]. In contrast, in patients with varying degrees of cognitive impairment, and
B vitamin supplementation in AD was not shown to improve small studies suggest it may offer benefits comparable to AChEI
cognitive function or delay decline [11]. However, in patients medications [76-79]. Finally, in a study, Withania somnifera
with MCI and high homocysteine [14], B vitamin treatment demonstrated promising results as a safe and effective treatment
may slow the decline in cognitive function, suggesting that for improving immediate and general memory, executive
the effects of B vitamin treatment may depend on the baseline function, attention, and information-processing speed in patients
nutritional status. Cholinergic precursors including choline, with MCI, but was inconclusive in its effect on working memory
lecithin, and phosphatidylserine have been studied in several and visuospatial processing [88]. Overall, in AD and MCI,
trials of individuals with AD, MCI, or age-related cognitive numerous dietary supplements and plant extracts have shown
impairment with inconsistent results [15,18-21]. Overall, the promise in individual trials for improving cognitive functioning.
reviewed studies indicate that cholinergic precursors may However, the totality of evidence for any one nutrient or
improve some aspects of cognitive function without adverse phytonutrient is inconsistent at best, and larger-scale trials with
effects, although methodological issues and heterogeneity of better methodological designs are needed to make definitive
the studies make definite conclusions about benefit impossible recommendations about their use.
at this time. Vitamin D has shown promise in AD and MCI, Nutrients and phytonutrients have also been evaluated in
where improvements in cognitive function were noted, psychotic disorders including schizophrenia and psychosis.
along with improvements in blood lipids and Aβ-related A very small study in subjects with EEG similarities to those with
biomarkers [23,24]. On the other hand, vitamin E has shown schizophrenia examined the effect of citicoline supplementation
inconsistent results. Some studies have indicated that vitamin E with preliminary findings of improved executive function [17].
may modestly delay the progression of dementia [6], but another American ginseng has also been studied with promising results,
study raised the question of differential effects in responders and showing improvement in working memory and reduction in
non-responders [7]. Responders with a reduction in oxidative extrapyramidal effects, which often greatly impair quality of life
stress saw maintenance of cognitive function, while non- and functioning in patients with schizophrenia [65]. In a study,
responders who showed no reduction in oxidative stress actually NAC was also able to improve multiple cognitive symptoms
saw a decrease in cognitive function, possibly through vitamin (excluding positive symptoms) found in schizophrenia [8],
E acting as a pro-oxidant [7]. Ginkgo biloba is an herb that has while another study using NAC found an improvement in
been widely studied with conflicting results. Some research working memory in patients with psychosis after 24 weeks of
showed promise through modest improvements in various supplementation [9]. Withania somnifera showed significant
aspects of cognitive function [42,43,49,51-53,55,57], although improvements in neutral mean response time, mean digit span
the effects were typically small and not always clinically backward, and mean social cognition response rating in subjects
significant. The design and quality of studies were also variable, with bipolar disorder, but not other aspects of cognition [89].
with some trials lacking blinding or placebo control, and some Overall, nutrients and phytonutrients have rarely been evaluated
experiencing significant attrition. Other research showed no for their effects on cognition in this patient population, but the
significant effect of Ginkgo biloba after treatment [48,50]. results of these few studies warrant further investigation in the
American and Panax ginseng have also been evaluated for their treatment of psychotic disorders, where conventional medical
effects on cognitive impairment. As with Ginkgo biloba, ginseng treatment is typically lacking in efficacy.
has shown modest improvements in some facets of cognition In MS, an aloe polysaccharide multinutrient supplement was
[59-61,63], while being limited by similar methodological assessed in a small trial, showing improved cognition, mood,
concerns. Lion’s mane mushroom demonstrated improvement and functioning symptoms and quality of life over the course
in cognitive function in older Japanese adults with MCI, with of the 12-month intervention [34]. Vitamin D3 supplementation
the improvement increasing over the course of 16 weeks and was also found to improve cognitive performance in 25(OH)D
declining after 4 weeks of washout [66]. Ω-3 fatty acids have deficient patients with relapse-remitting MS [22], while a Ginkgo
also been studied with inconsistent results. While some research biloba extract did not improve cognitive function over a 12-week
showed modest improvement in clinical status and an attenuated period [54]. Once again, few nutrients and phytonutrients have
decline in cognitive ability [5,27], possibly through reductions been studied for their effects on cognitive functioning in this
in inflammation and oxidative stress, another study did not patient population.
reveal any benefit in the prevention or treatment of AD [159]. Although nutrients and phytonutrients have most often shown
A less studied compound is aloe polymannose, a polysaccharide benefit in chronic disorders, acute conditions may also improve
that showed statistically and clinically significant improvements from their use. In particular, NAC appears to be beneficial in the
in cognition and multiple immune and inflammatory markers in treatment of cognitive symptoms of blast exposure-induced mTBI,
an open-label study [33], warranting larger controlled studies to with earlier administration leading to improved outcomes [10]. The
risk of cognitive dysfunction after stroke is elevated, so treatments function certainly warrant continued study. These primarily
to lessen post-stroke complications are needed. Citicoline has supplemental products have the potential to serve as relatively
shown promise in improving some domains of cognitive function inexpensive preventive and treatment strategies for cognition,
over 12 months of treatment after stroke without any noted and encouragingly almost all of these nutrients and phytonutrients
significant adverse effects [16]. were well-tolerated with minimal documented adverse effects.
In addition to various diseases and disorders, nutrients and In addition, many of them, e.g., caffeine, curcumin, and saffron,
phytonutrients have been examined for their efficacy on cognitive have a long history of culinary use and are found in plants that
function in healthy adults. For example, Bacopa monnieri has been are known to be healthful, adding to the safety profile of long-
studied in a few instances in healthy populations of various ages and term consumption. However, amounts greater than those used
shows promise in improving several domains of cognitive function in food preparation should continue to be evaluated for safety
with minimal recorded adverse effects [35,37-40]. Lion’s mane also where they are not already well-documented, e.g., rosemary in
showed a significant improvement in cognitive function in older supraphysiological doses revealed negative effects on cognitive
adults after 12 weeks of consumption [67]. Furthermore, Rhodiola performance, but no serious adverse events were recorded [72].
rosea has shown hopeful results in improving mental capacity for Trying to generalize the results of such a large number of
work, fatigue, anxiety, mood, and cognitive performance in healthy articles on 21 nutrients and phytonutrients is not simple. The
adults [194-198]. However, several vitamins have thus far failed heterogeneity of study design and methodological quality pose
to show consistent benefits. In adults with elevated homocysteine primary limitations to generalizability. While many of the studies
but intact cognitive function, B vitamin supplementation has been were randomized, double-blind, placebo-controlled trials, others
inconsistent in improving cognition [12,13]. Likewise, vitamin D were limited by small samples and lack of blinding, placebo, or
supplementation does not appear beneficial for improving control group. Treatment amount and type and follow-up time
cognition in healthy adults, although those with the lower baseline across studies also differed significantly, making it difficult to
25(OH)D levels may experience some improvement in nonverbal predict any long-term risks for certain nutrients and perhaps
memory [25,26]. The effects of zinc supplementation on cognition preventing the detection of benefits that may only manifest with
are similarly very limited [28]. Ginkgo biloba has also been studied ingestion of a nutrient or phytonutrient for years. Cognition
in healthy adults with conflicting results. Some research has shown is assessed with a multitude of neuropsychological tests, so it
no benefit [48], while other studies suggest modest benefits on is difficult to determine how, e.g., changes on the ADAS-cog
specific cognitive domains [43,45-47]. Working memory appears compare to changes on the many versions of the WAIS. Most of
to be enhanced by both American and Panax ginseng [58,62,64]. these studies tested only 1 nutrient or phytonutrient, but across
Supplementation with aloe polysaccharides has shown memory the board they did not include dietary analysis of the subjects,
benefits [30,32], although the results are equivocal [31]. so it is unknown if and how food intake and nutritional status
Some plant extracts well known in culinary use have also could have affected the results, particularly for the vitamins and
been studied for their potential cognitive benefits in healthy minerals included in this review. Bioavailability and absorption of
individuals. Rosemary has been evaluated as an oral supplement the active ingredients studied are additional key considerations for
and in aromatherapy with largely underwhelming results. Modest assessing the clinical outcomes. For example, curcuminoids are
improvements in cognition and mood were noted in some studies, known to have very low naturally occurring bioavailability and
although others showed either no significant effects or negative absorption, and the way they are formulated in a test product could
effects on performance with elevated doses [72-75]. However, have dramatic effects on study outcomes [231]. Sun exposure
curcumin showed more promise in several studies, showing should be measured for any study assessing supplemental
improvements in cognition and attention [83-86], while yam vitamin D consumption but was not included in the study design
extract was able to improve measures of cognitive performance of those studies. Every growing season has the potential to modify
with more pronounced effects in older individuals [87]. The effect the nutrient profile of a plant, so its levels of active ingredients
on cognition of xanthines, antioxidants found in foods such as in a supplemental product could subsequently be affected, which
coffee, tea, and chocolate, has also received considerable research ultimately impacts its clinical efficacy. Due to these limitations,
interest. Various studies suggest that xanthines such as caffeine additional large, well-controlled studies are needed to investigate
may improve cognition, including alertness, accuracy, and reaction the safety and efficacy of these nutrients and phytonutrients in
time [90-98]. Thus, several plant extracts or components have the context of treating and preventing various neurocognitive
shown promise in improving cognitive function among healthy disorders.
adults, although the evidence stems largely from small trials with This type of narrative review has several inherent limitations.
various methodological differences and limitations. We did not synthesize or pool data for each nutrient or
Overall, the reviewed clinical trials have displayed a wide phytonutrient and disease or disorder. Thus, it is difficult to make
range of results on cognitive function, going from negative (high any conclusions about the overall efficacy of these nutrients and
doses of rosemary) to null (several vitamins) to promising (aloe phytonutrients. Furthermore, we did not compare the efficacy
polysaccharides, Bacopa monnieri, curcumin, Rhodiola rosea, of different dosages among studies, so in most cases, the ideal
saffron, Withania somnifera, and xanthines). The nutrients dose of any nutrient or phytonutrient is not clear. It is also not
and phytonutrients showing promise in improving cognitive certain how dosages may need to differ depending on the disease
or disorder. In addition, we did not limit our review to a certain Baldauf-Wagner S, et al. A Randomized Placebo-controlled
treatment duration, so it is difficult to determine how outcomes Pilot Trial of Omega-3 Fatty Acids and Alpha Lipoic Acid
translate to improvements in lifespan, even for studies that in Alzheimer’s Disease. J Alzheimers Dis 2014;38:111-20.
evaluated a year-long intervention. [6] Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M,
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The effects of twenty-one nutrients and phytonutrients on cognitive

ARTICLE INFO ABSTRACT

Res 2011;32:67-72. and Safety of Saffron Supplementation: Current Clinical

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