Systematic Reviews

Adele E. Cave1, Dennis H. Chang1, Gerald W. Münch1,2 and Genevieve Z. Steiner‑Lim1,3*

Background Subjective cognitive impairment (SCI) substantially increases dementia risk and is often conceptual‑ ised as the preclinical asymptomatic phase of the cognitive decline continuum. Due to the lack of pharmacological interventions available to treat SCI and reduce dementia risk, and the popularity of herbal and nutritional medicines, the primary aim of this review was to investigate the efficacy on cognitive function and safety of herbal and nutri‑ tional medicines (relative to a control) for older adults with and without SCI. The secondary aims were to describe the study characteristics and assess the methodological quality of included studies. Method Five databases (Cochrane, MEDLINE, CINAHL, PsycInfo, and EMBASE) were searched from database inception with weekly alerts established until review finalisation on 18 September 2022. Articles were eligible if they included the following: study population of older adults with and without SCI, herbal and nutritional medicines as an interven‑ tion, evaluated cognitive outcomes and were randomised control trials. Results Data were extracted from 21/7666 eligible full‑text articles, and the risk of methodological bias was assessed (with SCI = 9/21; without SCI = 12/21). Most studies (20/21) employed parallel, randomised, placebo‑controlled designs and were 12 weeks in length. Herbal supplements were widely used (17/21), namely a form of Ginkgo biloba (8/21) or Bacopa monnieri (6/21). Measures of cognition varied across studies, with 14/21 reporting improvements in at least one domain of cognitive functioning over time, in the intervention group (compared to control). A total of 14/21 studies were deemed as having an overall high methodological risk of bias, 6/21 had some concerns, and only one study (using an SCI population) was assessed as having a low risk of methodological bias. Conclusions Overall, this review found that there is a low quality of evidence regarding the efficacy of cognitive function and safety of herbal and nutritional medicines for older adults with and without SCI, due to a high risk of bias across studies. Additionally, further work needs to be done in classifying and understanding SCI and selecting appropriate trial primary outcomes before future studies can more accurately determine the efficacy of interventions for this population.

*Correspondence: Genevieve Z. Steiner‑Lim [email protected] Full list of author information is available at the end of the article

© The Author(s) 2023.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visithttp://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Keywords Cognition, Complementary medicine, Herbal medicine, Nutrition, Subjective cognitive impairment (SCI), Mild cognitive impairment (MCI), Dementia, Alzheimer’s disease, Systematic review

Subjective cognitive impairment (SCI) is a self-perceived worsening of cognitive functioning, particularly in the area of memory, that cannot be verified by neuropsychological tests [1, 2]. SCI lies on a continuum of healthy cognitive ageing and is conceptualised as the preclinical phase of dementia (healthy cognitive ageing, to preclinical SCI, followed by prodromal mild cognitive impairment (MCI), then dementia) [2–4]. SCI is estimated to double the risk of future objective decline (MCI or dementia) [5, 6], carries an increased prevalence of Alzheimer’s disease biomarkers and impacts mental health (1 in 3 people) and functional ability (1 in 2 people) [7], making it an important area of focus for secondary prevention research and care.

It is estimated that the prevalence of SCI is 1 in 4 older adults aged 60 years and above, worldwide, with these numbers increasing rapidly each year [2]. Currently, there are no approved pharmacological interventions available, with many older adults experiencing SCI seeking alternative treatments [8]. Difficulty also lies with the assessment of SCI, as current diagnostic tools have been developed for MCI or dementia [8, 9]. Furthermore, inconsistencies in the categorisation of SCI (namely the division between healthy adults without SCI and those with SCI) are apparent in research [8, 9]. Due to the increased risk of dementia and high prevalence of SCI, high-quality research into effective treatments to improve cognitive functioning and prolong further decline is needed.

A review and meta-analysis conducted in 2018 investigated a variety of interventions (group psychological, cognitive, lifestyle and complementary and alternative medicines) for the treatment of SCI and their efficacy on psychological well-being, metacognition and objective cognitive performance [9]. The authors found that studies were generally of low quality; hence, no firm conclusions could be made about the efficacy of the interventions employed [9]. Whilst this review/meta-analysis is of great importance to furthering SCI treatment research, it did not explore the efficacy of single interventions on cognitive functioning, nor did they investigate this usage and efficacy in older adults without SCI.

Complementary medicines (CMs) are defined as a broad range of health care approaches that are not thought to be part of conventional medical care [10, 11]. CMs are classified into three primary categories of delivery: nutritional (e.g. herbs, dietary supplements), psychological (e.g. meditation, relaxation therapy) and

physical (e.g. acupuncture, massage) [10]. CMs are becoming more widely available and used by older adults, particularly herbal and nutritional medicines for the treatment of chronic health conditions including, cardiovascular disease [12], diabetes [13] and dementia [14, 15]. Herbal medicines contain herbal substances or herbal preparations, with nutritional supplements/medicines containing vitamins, minerals and in combination formulas and herbal substances/preparations as well [11, 16]. The natural properties of these medicines make them attractive to individuals wanting to improve their general health and well-being [11].

The primary aim of this review was to investigate the efficacy of cognitive function and safety of herbal and nutritional medicines (compared to an appropriate control group) for older adults with and without SCI. The secondary aims were to describe the study characteristics and assess the methodological quality of included studies, utilising the Cochrane risk of methodological bias (ROB 2) tool. This is the first review, to our knowledge, that has investigated the use of herbal and nutritional medicines for older adults with and without SCI, in depth.

This review is structured according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [17] and registered with the PROSPERO international database of systematic reviews on 7 May 2021 (#CRD42021244631). A protocol was not published for this review.

Eligibility criteria

A scoping review was conducted in line with the study eligibility criteria which were determined as per the PICOS principles for systematic reviews [18]:

1. 1. Population: older adults1 with and without subjective cognitive impairment (subjective cognitive impairment is a self-perceived worsening of cognitive functioning) [1, 2]
2. 2. Intervention: herbal and nutritional medicines (herbal medicines containing herbal substances or herbal preparations, and/or nutritional supplements/

1 Older adults (with and without SCI) were defined as aged 45 years and older, in accordance with the US Centers for Disease Control and Prevention (CDC) population-based statistics on Subjective Cognitive Decline and Aging [7].

1. Table 1 Keywords forming the search strategy of the review utilised for the five databases

Area and search number Search terms Subjective cognitive impairment (S1) “subjective cognitive impairment” OR “SCI” OR “sub‑

jective cognitive complaint*” OR “SCC” OR “subjec‑ tive memory complaint*” OR “SMC” OR “cognitive decline” OR “preclinical dementia” OR “preclinical Alzheimer*” OR “age associated cognitive decline” OR “age related cognitive decline” OR “age associ‑ ated memory impairment”

Older adults without subjective cognitive impairment (S2) “healthy ageing” OR “healthy aging” OR “older adult*” Intervention (S3) “herbal medicine” OR “Chinese medicine” OR “com‑

plementary medicine” OR “alternative medicine” OR “natural medicine” OR “vitamin* OR nutraceu‑ tical” OR “nutritional supplement” OR “Chinese herbal medicine” OR “traditional Chinese medicine” OR “ginkgo” OR “ginseng” OR “alpha‑lipoic acid” OR “lipoic acid” OR “bacopa monnier*” OR “brahmi”

(S4) S1 OR S2 AND S3

*indicates truncation

medicines containing vitamins, minerals, fatty acids etc., separately or in combination formulas) [11, 16]

1. 3. Comparisons: appropriate control group (non-active orally ingested placebo, orally ingested active control)
2. 4. Outcome: measures of cognition (both standardised/ validated and non-standardised/non-validated testing measures)
3. 5. Study design: randomised control trials (parallel or cross-over)

The following are the inclusion criteria: chronic dosing studies over a period of 2 weeks or more, peer-reviewed articles fully accessible online and written in English that met the above PICOS criteria. The following are the exclusion criteria: reviews, case studies, editorials, conference proceedings, preclinical studies (both in vitro and in vivo), trial protocols, trial registrations, book chapters, abstracts only, peer-reviewed articles in which the study population had a diagnosis of mild cognitive impairment or dementia, did not include cognition as a primary or secondary endpoint, or employed a co-intervention such as cognitive training.

Search strategy

Two researchers (AEC, GZS) reviewed the search strategy in consultation with an experienced librarian, prior to the commencement of scoping. Four databases were searched for peer-reviewed articles: Cochrane, MEDLINE, CINAHL and PsycInfo from inception to 4 August 2018, and a further fifth database, EMBASE, was searched on 14 September 2022. Weekly alerts were established across the five databases until review finalisation on 18 September 2022. A full list of keywords is detailed below in Table 1. The only modification to the

search strategy was the exclusion of non-randomised controlled trials from the Cochrane database to reduce the number of records for screening. Reference lists of included studies were also searched to identify any further eligible studies. Studies that included multiple age groups were also included if they reported demographics and outcomes separately for older participants in line with the eligibility criteria.

Data extraction and appraisal

All titles and abstracts were first screened by one author (AEC) for inclusion or exclusion from the review. If there were uncertainties regarding suitability for inclusion, the second reviewer (GZS) would assist to collaboratively make a final decision. Full-text articles were reviewed by the two authors with disagreements of acceptability resolved by discussion. Study characteristics were then extracted for each full-text article. These characteristics included author(s) and study location, aim, study population (group, sex, mean age, standard deviation and range), diagnosis criteria/global cognition measure, study design and outcome measurement frequencies, intervention, dose and duration, measures of cognition and results (cognition, retention, adherence and adverse events).

A methodological risk of bias assessment was conducted in accordance with the Cochrane Review Process for Randomised Trials (ROB 2) [19]. The quality of trial design, conduct and reporting of the included studies was assessed. Separate risk of bias assessments was conducted for parallel [20–39] and cross-over design studies [40]. The risk of bias tool evaluates five domains: bias arising from the randomisation process, deviations from intended interventions (effect of assignment and

adherence to intervention), bias due to missing outcome data and in the measurement of the outcome, and bias in the selection of the reported result [19]. The sixth domain of bias arising from period and carryover effects was also evaluated for the cross-over study [19]. One author (AEC) independently conducted the risk of bias assessment, with the second author (GZS), reviewing the outcomes.

Individual studies were assessed as low risk, some concerns regarding methodology and high risk based on each of the above-mentioned domains. Studies with one or more domains assessed as high risk or with some concerns for multiple domains were deemed overall as high risk. Those with at least one domain with some concerns were evaluated in this category. The risk of bias process was conducted to assess the methodological quality of studies in their published form; study authors were not contacted for further information. A qualitative synthesis approach to this review was taken due to the large variation of interventions and cognitive assessments utilised across the studies, for each of the populations.

Study selection

Figure 1 outlines the study selection process, with twenty-one studies meeting the eligibility criteria [20– 40]. Nine studies involved older adults with SCI [20–22,

1. 26, 28, 33, 35, 37, 38], and the remaining twelve, older adults without SCI [23–25, 27, 29–32, 34, 36, 39, 40].

Fig. 1 PRISMA flow diagram illustrating the study selection process

Study characteristics

1. Table 2 details a summary of the characteristics of the nine [20–22, 26, 28, 33, 35, 37, 38] SCI studies, and
2. Table 3 details the twelve studies in older adults without SCI [23–25, 27, 29–32, 34, 36, 39, 40]. Both tables outline the study aim, population (group, sex, mean age, standard deviation and range), diagnosis/global cognition measure, design, intervention and dose, duration, measures of cognition and results (cognitive outcomes, retention and adherence, and adverse events).

Across both populations, all studies were randomised, double-blind, placebo-controlled trials [20–40]. Twenty studies employed a parallel design [20–39], and one study utilised a cross-over design [40]. Three studies utilised the same intervention with two different doses (three comparison groups in total, including placebo) [20, 22, 28], and one study utilised two different interventions compared to a single control [29].

Eight studies were conducted in the USA [24, 25, 27–31, 36], three each in Australia [23, 32, 38] and Italy [26, 33, 39], two in India [21, 35] and one each in Korea [20], the Netherlands [22], the UK [34], China [37] and

Japan [40]. Two studies were published from 1995 to 1998 [22, 33], ten published between 2000 and 2010 [21, 23–25, 27, 30–32, 35, 36], with the remaining nine between 2012 and 2020 [20, 26, 28, 29, 34, 37–40].

Fifteen studies reported methods of recruitment [20, 22–26, 28, 29, 32, 35–40], with twelve studies conducted in community settings (audio, visual, and print media, universities) [20, 23–25, 28, 29, 32, 35–38, 40] and three in clinical settings (general practice and outpatient clinics) [22, 26, 39].

Participants

Across the included studies, the total sample size (at baseline) was N= 1891, with 19/21 studies reporting participant sex (N= 1798; 61% were female) [20– 25, 28–40]. The mean age of participants reported across 20/21 studies was 65.43 years [20–34, 36–40], SDpooled= 13.95 (for 17 studies) [20–23, 25, 27–33, 36–40]. Individual studies ranged from 28 [40] to 262 participants [31]. A total of 755 participants were from the nine SCI studies [20–22, 26, 28, 33, 35, 37,

1. Table 2Summary of characteristics for studies involving older adults with subjective cognitive impairment

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

Retention/adherence:

nificant improvement

compared to placebo

to placebo with a sig‑

completed the study:

reported and no par‑

adherence rate in all

memory and execu‑

no serious AE’s were

Cognition: improve‑

93.3%, with a > 90%

ment in short‑term

in both HD and LD

ticipants withdrew

69/75 participants

groups compared

90% and placebo

in the HD group

Adverse events:

HD 93.3%, LD

tive function

due to AE’s

groups

alone

span task (CANTAB),

executive function

8 weeksImmediate recall

tern recognition

and the spatial

from the pat‑

memory task

(WCST)

2) LD = 600 mg daily

3) Matched placebo

(species of fungus)

(2 capsules, 3 × per

(2 capsules, 3 × per

day) N.R = placebo

Tremella fuciformis

daily (2 capsules,

1) HD = 1200 mg

3×per day)

ingredients

day)

trial, outcomes at 0

placebo control

double‑blind

scale ≤ 0.5 Randomised,

and 8 weeks

MMSE (≥ 25), clinical

dementia rating

(65F:10 M) with sub‑

complaints aged

jective cognitive

in the HD group

53.83 (± 5.5)m

in the LD group

dwelling adults

in the placebo

with 26F:4 M

and 26F:4 M

and 13F:2 M

Community

years, range

40–65 years

group

tion ofTremella fuci-

[20] To examine the effi‑

in individualsformis

of oral administra‑

cognitive impair‑

cacy and safety

with subjective

ment

Ban et al. 2018Korea

Table 2(continued)

Retention/adherence:

then excluded as out‑

placebo in: digit span

Cognition: significant

tion were considered

paired associates dis‑

liers, participants tak‑

group × time interac‑

ing ≥ 85% of medica‑

or moderate adverse

similar delayed recall

backward, list learn‑

and visual retention

tion (improvement)

for interventionc.f.

ing delayed recall,

the study with 15

59/65 completed

events reported

no serious, mild

Adverse events:

by participants

compliant

cognition Results

(based on pictures),

digit symbol (WAIS)

(based on designs),

Digit Span Forward

and delayed recall,

pairs—immediate

(WMS‑1) immedi‑

Serial Subtraction

associates—simi‑

Cancellation Test,

visual retention 1

visual retention 2

lar and dissimilar

(RAVLT) immedi‑

Test, list learning

ate and delayed

ate and delayed

recall, passages

and Backward

control and dose DurationMeasures of

recall, paired

(WAIS), Digit

12‑week interven‑

tion period then

a 12‑week with‑

drawal period

only states ‘matched

with bioactive con‑

®BacoMind(stand‑

ofBacopa monnieri

stituents) 1 × 450‑

Matched placebo

mg capsule daily

1×capsule daily,

ents in placebo,

without actives’

ardised extract

measure DesignIntervention/

N.R = ingredi‑

outcomes at 0, 12

double‑blind pla‑

cebo control trial,

and 24 weeks

MMSE (≥ 24)Randomised,

study location AimStudy populationDiagnosis criteria/

global cognition

nitive deficits (AAMI)

with no major cog‑

range 50–75 years

Adults with mem‑

aged=64.98m

ory complaints

with 23F:42 M

(± 9.37) years,

for 1 year

the clinical efficacy,

®Mindon impaired

memory in elderly

safety and toler‑

ability of Baco‑

2008[21]India To evaluate

individuals

Barbhaiya et al.,

Author and

Table 2(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

participants withdrew

cebo = 15 (total reten‑

Retention/adherence:

headache and sleepi‑

complaints, dizziness,

1 and 2 tests. Within‑

on the EMCT or Rey

increase in the low‑

ing but not limited

to gastro‑intestinal

with an adherence

Adverse events: 25

group, Benton test

due to AEs includ‑

dose = 14 and pla‑

ments across time

tion rate of 81.7%)

nificant between‑

Cognition: no sig‑

total withdrawals

scores increased

group improve‑

with the largest

group = 15, low

from high dose

ness (across all

rate of 93.98%

in all 3 groups

dose group

groups)

visual memory), Rey

memory and learn‑

revised (short‑term

of visual retention‑

(short‑term verbal

test parts 1 and 2

tion), Benton test

and concentra‑

treatment EMCT (measur‑

ing, long‑term

ing attention

memory)

4 weeks washout

then 24 weeks

leaf, folium, ethanol,

both solutions were

chlorophyll was dis‑

soluble chlorophyll

flavone glycosides)

drops, 1.9 ml undi‑

tion:Ginkgo biloba

powder dissolved

extract (composi‑

solved in alcohol)

1) High dose (40

3×daily) (water‑

extract with pla‑

taste and colour

(water insoluble

mixed together,

2) Low dose (40

of all 3 dosages

luted 3 × daily)

water mixture,

cebo 3 × daily)

3) Placebo (40

alcohol/water

in an alcohol/

Ginkgo biloba

drops (1.9 ml

drops, 1.9 ml

similar

outcomes at 0, 6, 12

double‑blind pla‑

cebo control trial,

and 24 weeks

of known origin Randomised,

and memory loss

MMSE (≥ 20)

group and 47F:35 M

with self‑reported

=68.96 (± 7.77)m

group, 50F:32 M

tion complaints

and 46 females

in the placebo

in a high‑dose

with 31 males

memory and/

or concentra‑

in a low‑dose

Elderly adults

years, range

55–86 years

group

of an alcohol/water

with memory and/

cebo in the elderly

versus pla‑biloba

extract ofGinkgo

or concentration

of two dosages

and tolerance

[22]lands To determine

the efficacy

complaints

1998The Nether-

Brautigam et al.,

Table 2(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

with 95% adherence

ment in MMSE score

Adverse events: one

8 weeksMMSECognition: improve‑

after active product

ence: no withdraw‑

and 90% in the pla‑

in the active group

in the active group

reported aftertaste

Retention/adher‑

als from the trial,

cebo group

intake

mcg, vitamin B12 33

1×capsule per day,

dry extract 320 mg,

capsule form and 1

9.5 mg, Biotine 450

ofBacopa monnieri

mcg, copper 2 mg,

mcg, folic acid 400

mcg, vitamin D 25

Matched placebo,

30 mg, vitamin B6

‑Teanina 100 mg,

N.R = placebo

Crocus sativus

Combination

ingredients

per day

trial, outcomes at 0

placebo control

double‑blind

Randomised,

and 8 weeks

cognitive decline

diagnosis of cog‑

without a known

MMSE (20–27),

self‑perceived

nitive decline

or dementia

of age) (N.R = range,

perceived cognitive

(=66 (± 3) yearsm

30 older adults

sex), with self‑

decline

of a rational assem‑

functions in a sam‑

blage of nutraceu‑

ticals on cognitive

ple of 30 elderly

[26]Italy To evaluate

the effects

subjects

Cicero et al., 2016

Table 2(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Retention/adherence:

and 600 mg interven‑

group due to adverse

Adverse events: three

participants reported

drew (1 from the pla‑

spearmint group sig‑

deemed ‘not related’

(900 mg) adherence

events with a 98.1%

in both the placebo

in working memory

and spatial working

(600 mg) and 100%

3 participants with‑

nificantly improved

myalgia, headache,

Cognition: 900 mg

and heartburn. All

memory accuracy

cebo group and 2

worsening of oily

tion of heartburn

scalp, cystic acne

from the 600 mg

(placebo), 99.1%

with the excep‑

AE’s: knee pain,

tion groups

and tracking (motor

investigating atten‑

90 daysCDR − with 11 tasks

episodic and work‑

executive function

tion and informa‑

tion processing,

ing memory,

control)

crystalline cellulose/

3) Placebo capsules

(L.)/Mentha spicata

(L.)/Mentha spicata

matched on taste,

spearmint extract

spearmint extract

contained micro‑

day (2 × capsules

day (2 × capsules

day (2 × capsules

total), N.R = if

appearance

1) 600 mg

2) 900 mg

and smell

total)

total)

(participants arrived

equiv. to the overall

on testing day fast‑

and 90 days (aver‑

ing from product/

score for that day)

across testing day

outcomes at 0, 45

Average of scores

double‑blind pla‑

cebo control trial,

age on each day)

tion of interven‑

assessed 15 min

and 2, 4 and 6 h

tion or placebo,

after ingestion.

food and were

prior to inges‑

Randomised,

then 30 min

MAC‑Q (≥ 25), WMS

(≤ 29 on VPA‑1)

and WMS (≤ 9

MMSE (≥ 24),

on VPA‑2)

50–70 years with 30

participants in each

spearmint), (overall

(± 0.6) years, range

Institute of Mental

Adults with AAMI

mint and 900 mg

group (placebo,

on the National

Health criteria)

600 mg spear‑

aged=59.4m

30 M:60F)

(based

extract on cognitive

performance, sleep

the effects of sup‑

and mood in indi‑

viduals with AAMI

with a spearmint

2018[28]USA To investigate

plementation

Herrlinger et al.,

Table 2(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Retention/adherence:

pants < 80% excluded

nausea and vomiting,

ence was an average

1/56 non‑compliant)

of 97%, with partici‑

and one in placebo

cantly for the inter‑

ticipants withdrew

Adverse events = 1

from the trial (only

across time, com‑

developed a mild

working memory

Cognition: spatial

51/56 completed

the study. Adher‑

pared to placebo

tion experienced

improved signifi‑

vention group,

rash, both par‑

from interven‑

reaction time

participant

from study

ment battery (SUC‑

16 weeksSwinburne Univer‑

(word list learning)

sity computerised

cognitive assess‑

CAB) and CVLT‑2

with 46 ingredients,

seed), 1 tablet each

dry fruitmarianum

B2), 1 tablet taken

(St. Mary’s thistle),

and 2 mg of ribo‑

contained starch

tablet (combina‑

quantities being

Swisse Women’s

andVitis vinifera

dry seed (grape

with the largest

day with break‑

tablet matched

of intervention,

on appearance

flavin (vitamin

with breakfast

™Ultivite 50 +

Ginkgo biloba

fromSilybum

fast. Placebo

tion formula

trial, outcomes at 0

placebo control

and 16 weeks

double‑blind

Randomised,

with a medical prac‑

MMSE (≥ 24), mem‑

mine whether par‑

to screen for SMCs

and medical exam

ory questionnaire

titioner to deter‑

in good health

ticipants were

memory complaints

64–82 years with 28

participants in each

multivitamin group

(± 4.3) years, range

group (=70.3m

(=71.9 (± 4.8)m

Women report‑

years, placebo

ing subjective

group

tivitamin and herbal

mentation of a mul‑

tion in community‑

of 16‑week supple‑

formula on cogni‑

dwelling, elderly

2012[38]Australia To investigate

the effects

women

Macpherson et al.,

Table 2(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

increased in the treat‑

compared to placebo

Adverse events: none

(reported at 3‑month

ence: no withdrawals

reported in the study

ence rate as an aver‑

age across the dura‑

Cognition: memory

reported by partici‑

with a 92% adher‑

index significantly

Retention/adher‑

tion of the study

at the endpoint

ment group

intervals)

pants

recall and deferred

index, acquisition

9 monthsRMT − (memory

memory)

to study drug—two

capsules daily (one

capsules daily (one

bitartrate, minerals

seng extract G115

Placebo ‘identical’

(N.R = dose) (from

Standardised gin‑

and vitamins (not

), dimeth‑ginseng

the root ofPanax

one after lunch).

one after lunch),

specified)—two

ylaminoethanol

after breakfast,

after breakfast,

N.R = placebo

ingredients

MMSE (≥ 24)Randomised, dou‑

3, 6 and 9 months

ble‑blind placebo

comes at 15 days,

(only first and last

control trial, out‑

session analyses

conducted)

with AAMI, 21F:9 M

group and 21F:9 M

in the intervention

(=60.45 (± 3.9)m

in the placebo

51–65 years)

Older adults

years, range

group

well‑being—affec‑

interrelationships

domains of well‑

tive functioning

being and their

tion and cogni‑

(psychological

and perceived

(intervention)

on two major

quality of life)

[33] To determine

the influence

of treatment

Neri et al., 1995Italy

Table 2(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

patient withdrew due

ence: 87.5% retention

in the placebo group

ing the intervention

and 12 weeks), digit

nificantly improved

forward (12 weeks)

at each of the time

control (12 weeks),

rashes in the inter‑

and 12 weeks) sig‑

and 1 in the SBME

and paired associ‑

Cognition: mental

to maculopapular

(4 weeks, 8 weeks

Adverse events: 1

group withdrew),

Retention/adher‑

points listed dur‑

N.R = adherence

ated learning (8

logical memory

vention group

(2 participants

period

visual reproduction

ate learning (WMS)

and paired associ‑

logical memory,

digit backward,

of a placebo period Mental control,

digit forward,

following 4 weeks

12 weeks, then

Placebo twice daily,

of administration.

N.R = administra‑

125 mg of SBME

tion, ingredients

twice a day,

N.R = type

outcomes at 0, 4, 8,

double‑blind pla‑

cebo control trial,

12 and 16 weeks

aMemory (< 6) Randomised,

and WMS Logical

MMSE (≤ 24)

with 20 participants

with AAMI, range

(± SD), (3F:37 M)

N.R = mean age

in each group

55–70 years,

Forty adults

[35]India To study the effi‑

cacy of SBME

in subjects

with AAMI

Raghav et al., 2006

Table 2(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

Retention/adherence:

adverse event reports

and memory retrieval

group, both interven‑

completed the study,

group they withdrew

Cognition: no signifi‑

retrieval for placebo)

cant between group

across time—audio/

outcomes improved

98/101 participants

of participants due

across time. Within

upset, N.R = which

to gastrointestinal

abstracting ability

Adverse events: 2

tion and placebo

(except memory

with withdrawal

N.R = adherence

visual memory,

improvements

from

memory, abstract‑

ing and memory

12 weeksVisual/auditory

recall

dose measurements

,Catharanthus roseus

capsules with meals

capsules with meals

leaf), acetyl‑sinensis

placebo ingredients

p/day) or additional

‑carnitine, cola nutl

extract (),kola nitida

vitamin B6, vitamin

flour, N.R = specific

mainly containing

Matched placebo,

for active and pla‑

choline bitartrate,

and‑cysteine) (2l

Advanced (Phos‑

extract (Camellia

‑phenylalaninel

Huperzia serrata

‑pyroglutamicl

B12,‑tyrosine,l

acid, green tea

phatidylserine,

cebo (states 2

,Ginkgo biloba

(whole plant),

‑glutamine,l

BrainPower

daily

trial, outcomes at 0

placebo control

and 12 weeks

double‑blind

Randomised,

gorised as ‘severe SC

(moderate severe), 4

as ‘slight SC group’, 3

SC) or 2 (slight/mild

SC) were combined

for a Chinese popu‑

(severe) and 5 (very

or occasional slight

tion/concentration

lation, participants

group’, N.R = name

severe) were cate‑

or impaired atten‑

medical question‑

naire, constructed

of questionnaire

scoring 1 (no SC

of hypomnesis,

as determined

and validated

by a standard

forgetfulness,

memory loss

No reports

group and 34F:17 M

numbers calculated

(± 10.5) years, range

including 33F:14 M

in the intervention

unteers with SMCs

after withdrawals)

47.28–88.43 years

Community vol‑

and participant

in the placebo

aged67.1m

group (ages

the safety and effec‑

term administration

dietary supplement

a multi‑ingredient

tiveness of short‑

on SMCs in older

of BrainPower

[37]China To evaluate

Advanced,

adults

Zhu et al., 2016

AAMIAECANTABCDRCVLT-2EMCTAge-associated memory impairment,Adverse event,Cambridge Neuropsychological Test Automated Battery,Cognitive drug research system,California Verbal Learning Task,Expended

SBMEBacopa monnieriSCSMCsVPAWAISWCSTWMSStandardisedextract,Symptom complaints,Subjective memory complaints,Verbal paired associates,Wechsler Adult Intelligence Scale,Wisconsin Card Sorting Test,

HDLDMAC-QMMSEN.RRAVLTRMTMental Control Test,High dose,Low dose,Memory Complaint Questionnaire,Mini-Mental State Examination,Not reported,Rey Auditory Verbal Learning Test,Randt Memory Test,

aRaghav et al. (2006) [35] reported on AAMI without any evidence of dementia or psychiatric disorder despite excluding individuals scoring > 24 on the MMSE

Weschler Memory Scale

1. Table 3Summary of characteristics for studies involving older adults without subjective cognitive impairment

Retention/adherence:

nificant improvement

adherence measured

reported by 2 partici‑

withdrew from study

pants who withdrew

13 participants with‑

storage and retrieval

in the ginkgo condi‑

and post‑treatment,

tasks for theBacopa

and digestive prob‑

ence: 6 participants

in placebo group, 9

drew between pre‑

Adverse events: 10

in the intervention

ment in long‑term

as ≥ 75% intake, all

with no difference

only in the ginkgo

flu like symptoms

tion due to head‑

participants were

Retention/adher‑

nificant improve‑

recall and Stroop

in RAVLT delayed

between groups

of 3.9 (out of 84)

group reporting

aches and sleep

in total, average

Adverse events:

groupmonnieri

Cognition: sig‑

Cognition: sig‑

tablets missed

disturbance

compliant

cognition Results

group

lems

(executive function),

12 weeksWoodcock‑Johnson

Psycho‑educational

Additionally, Stroop

and the WAIS letter

and decision time),

memory, cognitive

digit test of imme‑

irrelevant informa‑

processing speed,

score from RAVLT.

(vocabulary), self‑

(both movement

age and retrieval,

ordered pointing

crystallised abil‑

ability to ignore

inspection time

long‑term stor‑

battery‑revised

spot‑the word

delayed recall,

ity, short‑term

Delayed recall

task assessing

diate working

odd‑man‑out

control and dose DurationMeasures of

tion, the DAT

(fluid ability,

memory

6 weeks of placebo

ofBacopa monnieri

for the treatment

for control group

and 12 weeks

group

Matched placebo (3

extract, 300 mg/day

per meal), N.R = pla‑

tablets per day—1

of 40 mg each—1

Matched placebo

cebo ingredients

Bacopa monnieri

120 mg per day

()Ginkgo biloba

(1 tablet daily),

(3 tablets daily

measure DesignIntervention/

(1 tablet daily)

™Ginkgoforte

N.R = placebo

Standardised

ingredients

per meal)

trial, outcomes at 0,

trial, outcomes at 0

placebo control

placebo control

6 and 12 weeks

and 12 weeks

double‑blind

double‑blind

Randomised,

Randomised,

and names of medi‑

BOMC and no com‑

study location AimStudy populationDiagnosis criteria/

impairment, POMS,

N.R = BOMC cut‑off

cognition measure

POMS, N.R = global

plaints of memory

cal questionnaires

Medical question‑

global cognition

rent medications,

history and cur‑

naire—medical

independently aged

Healthy older adults

also included in this

study however ana‑

females (21 females

participants in each

N.R = range, S.D (27

50 males (26 males

range 55–79 years:

in ginkgo) and 43

65 years or older

54 healthy older

lysed separately

Younger adults

61.7 (± 5.5)m

women) living

=73.5 years,m

in placebo, 24

in placebo, 22

adults (60%

in ginkgo)

group)

ity in healthy elderly

safety and tolerabil‑

(whole plant stand‑

[23]Australia To extend on previ‑

ardised dry extract)

adults on cognitive

ofBacopa monnieri

on cognitive func‑

of 120 mg ginkgo,

tion and its affect,

mance of healthy

mine the efficacy

to benefit perfor‑

in order to deter‑

older and young

ous research

participants

2008[24]U.S.A To evaluate

the effects

outcomes

Burns et al., 2006

Calabrese et al.,

Author and

Table 3(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

nificant improvement

out, > 95% adherence

reports of headaches,

effects were reported

excluded from analy‑

strict task for the pla‑

Cognition: no signifi‑

in neuropsychologic

mon AEs being nau‑

pliance, N.R = adher‑

sis due to non‑com‑

with the most com‑

cant improvements

ence: 3 participants

ence: 3 participants

and flatulence, two

sea/stomach upset

17% of each group

only in list learning

no serious adverse

reported they had

rash and dizziness

for all participants

one AE attributed

from the placebo

Retention/adher‑

Retention/adher‑

from the Ginkgo

Adverse events:

Adverse events:

N.R = minor AEs

group dropped

by participants,

to the product

Cognition: sig‑

they ingested,

group and 8

cebo group

test data

ence

4 monthsBenton visual reten‑

tion, controlled oral

judgement of line

mental screening,

word association,

list learning strict

list learning easy,

and symbol digit

modified mini

orientation,

modalities

68 mg of,Gotu kola

containing 160 mg

daily multivitamin/

based supplement

day with meals. All

(100 mg) and vita‑

also given a once‑

plement (Nutrilite

multimineral sup‑

Matched placebo

participants were

as beta carotene,

of,Ginkgo biloba

180 mg of DHA,

day with meals,

three capsules/

three capsules/

a bioflavonoid

min A (300 IU)

‑Ginkgo biloba

N.R = placebo

concentrate

ingredients

Daily)

Making Test (parts

6 weeksSelective Remind‑

the WAIS‑3 Digit

Symbol‑Coding

ing Test, WMS‑3

(face 1 and face

2 subtests), Trail

A and B), SCWT

subtest

32 oz/day (2 × 16 oz)

Matched placebo

N.R = specific pla‑

cebo ingredients

beverage 32 oz/

containing 27%

cranberry juice

day (2 × 16 oz),

with sucralose

of a beverage

sweetened

trial, outcomes at 0

placebo control

and 4 months

double‑blind

MMSE (24–29)Randomised,

range 65–84 years),

(± 6.0) years, range

tively intact older

73.1 (± 4.8) years

group (21F:21 M

Healthy, cogni‑

placebo group

(15F:21 M, 72.1

adults: ginkgo

65–83 years)

mostasis, and is safe

alters primary hae‑

plement improves

cognitive function

and quality of life,

tively intact older

in healthy, cogni‑

if aGinkgo biloba

containing sup‑

[25]USA To determine

adults

Carlson et al., 2007

trial, outcomes at 0

placebo control

double‑blind

Randomised,

and 6 weeks

no history dementia

neurocognitive

and reporting

or significant

MMSE (≥ 24)

impairment

(± 5.80) (N.R = range,

cranberry group (25

(> 60 years of age):

placebo group (25

Cognitively intact

adults)=69.17m

adults)=69.39m

(± 7.11) years

older adults

sex)

efficacy of cranberry

[27]USA To conduct the first

functioning of cog‑

nitively intact older

known clinical trial

of the short‑term

juice on the neu‑

ropsychologic

adults

Crews et al., 2005

Table 3(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

from the final analysis

compliance reported

as 100% for nearly all

ticipant experienced

participant reported

and VFT across time,

oxidant group com‑

in TMT A and TMT B,

cant improvements

of sinusitis in active

event of hepatitis E

(1 adverse event, 1

due to withdrawal

ticipants excluded

non‑serious event

MoCA and RAVLT Cognition: signifi‑

Adverse events: 1

Retention/adher‑

pared to placebo

could not attend

group and 1 par‑

an acute serious

of exacerbation

study sessions),

and in the anti‑

participants

ence: 2 par‑

TMT, VFT, MMSE,

followed by 8 weeks

intake or interven‑

of what occurred

during this time)

tion or placebo

period (unclear

1‑week run‑in

once daily contain‑

containingBacopa

vegetable stearate

pene, astaxanthin

active substances

Matched placebo

and vitamin B12.

(5 mg) and non‑

Antioxidant mix

ing magnesium

, lyco‑monnieri

1 tablet daily

tablet taken

trial, outcomes at 0

placebo controlled

double‑blind

disorders Randomised,

and 8 weeks

and no neurological

MMSE (≥ 27)

Healthy older adults

(> 60 years of age):

years) N.R = range

=61.88 (± 1.36)m

=62.05 (± 1.55)m

group (28F:12 M,

group (27F:13 M,

antioxidants mix

years), placebo

to 8 weeks of treat‑

ment with an anti‑

oxidant mix com‑

pared to placebo

in healthy older

in the trail mak‑

ing test scores

from baseline

the changes

[39]Italy To evaluate

adults

Crosta et al., 2020

Table 3(continued)

Retention/adherence:

reported, N.R = adher‑

in the ginkgo synergy

from baseline to end‑

oral word association

with ulcerative colitis

for the Ginkgo group

point and in the OPC

Cognition: according

group from baseline

to time in the TMT‑B

joint aches and one

placebo participant

ing, one participant

nificantly increased

in the OPC synergy

shortly after enroll‑

retention numbers

reported insomnia

the Ginkgo group

showed improve‑

on the controlled

group diagnosed

line to 3 months,

ment from base‑

trial‑S scores sig‑

and heightened

Adverse events:

group reported

one participant

energy at night

inconsistently

to 3 months

cognition Results

ence

subtest of the WAIS

the Digit Symbol

A and B, COWA,

and the HVLT‑R

6 monthsMMSE, SCWT,

the TMT Parts

control and dose DurationMeasures of

cebo administration

lets/day to 700 mg/

®1) Ginkgo Synergy

method/type, dose

3) Placebo contain‑

and choline (4 tab‑

(2 capsules/day—

powder, N.R = pla‑

120 mg/day total)

®2) OPC Synergy

lactose and beet

(2 capsules/day)

measure DesignIntervention/

and Catalyn (4

ing cellulose,

tablets/day)

day total)

trial, outcomes at 0,

placebo control

3 and 6 months

double‑blind

Randomised,

study location AimStudy populationDiagnosis criteria/

disorders, not living

SPMSQ, WMS‑Story

A, no AD or related

in a nursing facility

global cognition

MMSE (≥ 23),

cebo group=70.3m

Healthy older adults

®Synergyplus Cata‑

(± 6.7) years, range

(± 8.3) years, range

lyn group=68.5m

with 25F:8 M; OPC

with 24F:7 M; pla‑

®Ginkgo synergy

=67.6 (± 6.3)m

with 21F:12 M

plus Choline

59–83 years,

60–93 years,

58–82 years,

years, range

[29]USA To extend the evalu‑

of nutritional thera‑

placebo‑controlled

pies through a ran‑

clinical trial assess‑

of dietary supple‑

ments’ efficacy

ing a regimen

double‑blind,

ative process

domised,

Lewis et al., 2014

Author and

nificant improvement

compared to placebo

in colour naming task

Colour and Word test

(missing > 20% treat‑

reasons, N.R = overall

over the trial period

reported by partici‑

females completed

to non‑compliance

3/4 due to medical

in the intervention

no adverse effects

not complete due

group across time

the study (40/44),

within the Stroop

ment), remaining

1 participant did

21 males and 19

Adverse events:

Cognition: sig‑

adherence

cognition Results

pants

and visual repro‑

memory 1 and 2

duction 1 and 2

revised, logical

and the WMS‑

control and dose DurationMeasures of

6 weeksSCWT (parts

A and B)

subtests

per day (methylcel‑

lulose), N.R = addi‑

EGBGinkgo biloba

capsules per day).

cebo × 3 capsules

day = 60 mg × 3

measure DesignIntervention/

tional placebo

761 (180 mg/

Matched pla‑

ingredients

trial, outcomes at 0

placebo control

double‑blind

Randomised,

and 6 weeks

of significant neuro‑

AimStudy populationDiagnosis criteria/

cognitive dysfunc‑

global cognition

cognitively intact

tion, considered

and no history

(self‑reported)

MMSE (≥ 24)

healthy older adults,

55–86 years of age:

Cognitively intact

group=68.65m

=67.5 (± 9.23)m

years, placebo

ginkgo group

(± 6.95) years,

24F:24 M

tively short‑term (i.e.

To examine the rela‑

functioning of cog‑

ropsychologic tests

nitively intact per‑

sons over the age

6 weeks) efficacy

on the cognitive

ofGinkgo biloba

extract EGB 761

battery of neu‑

and measures

via a diverse

of 55 years

Table 3(continued)

Mix et al., 2000USA

improved in SRT tasks

from the intervention

group were excluded

in the placebo group

tocol, 5 from the pla‑

ticipants in the inter‑

(missing > 20% treat‑

249/262 participants

testinal, nervous sys‑

tem and respiratory/

completed the pro‑

across both groups.

total of 32 reported

from the study due

ment), N.R = overall

limited to gastroin‑

free recall and rec‑

cebo) significantly

to non‑adherence

One serious event

(compared to pla‑

cebo group and 4

involving delayed

including but not

ognition of visual

allergic reactions,

of an intracranial

Adverse events:

Cognition: par‑

vention group

adherence

material

cognition Results

bleed

6 weeksSRT, WAIS‑3 block

subtests, WMS‑3

Symbol‑Coding

control and dose DurationMeasures of

faces 1 and 2

design, Digit

subtests

tablets × 3 per day,

EGBGinkgo biloba

Matched placebo

tablets per day).

day = 60 mg × 3

measure DesignIntervention/

N.R = placebo

761 (180 mg/

ingredients

trial, outcomes at 0

placebo control

double‑blind

Randomised,

and 6 weeks

nificant neurocogni‑

AimStudy populationDiagnosis criteria/

of dementia or sig‑

global cognition

tive impairment

and no history

(self‑reported)

MMSE (≥ 26)

after withdrawals/

non‑compliance,

adults, ≥ 60 years

=66.97(± 6.12)m

group=68.60m

ticipants in total

years, placebo

ginkgo group

(± 6.96) years,

with 262 par‑

(N.R = range),

in the study,

in the study

intact older

147F:102 M

Cognitively

remained

of age:

chological function‑

To conduct the first

intact older adults

ing of cognitively

on the neuropsy‑

scale clinical trial

ofGinkgo biloba

extract (EG 761)

of the efficacy

known, large‑

Table 3(continued)

Mix et al., 2002USA

total learning and ret‑

occurred significantly

completed the study.

roactive interference

group (side effects

and delayed recall,

Cognition:Bacopa

81/98 participants

frequency, nausea

learning, memory

more in the treat‑

Adverse events: 9

group, 2 placebo

improved verbal

in the treatment

N.R = adherence

and abdominal

increased stool

ment group:

significantly

acquisition

cramps)

cognition Results

(RAVLT)

measured by RAVLT,

ured by the MAC‑Q

and visual memory

CFT and the Reitan

the Rey‑Osterrieth

complaints meas‑

TMT, subjective

control and dose DurationMeasures of

performance

12 weeksAudio‑verbal

Matched placebo

tablet, N.R = dose,

300 mg/day (one

Bacopa monnieri

measure DesignIntervention/

™(BacoMind)

tablet daily).

ingredients

trial, outcomes at 0

placebo control

and 12 weeks

double‑blind

Randomised,

of depression (≤ 12)

study location AimStudy populationDiagnosis criteria/

global cognition

and absence

MMSE (≥ 24)

on HAMD

Healthy older adults

=65(± 7.53) years,m

range 55–86 years

group = 24F:25 M,

group = 28F:21 M

eral population

from the gen‑

placebo

Bacopa

ofBacopa monnieri

Linn. for improve‑

ment of memory

the effectiveness

in healthy older

[32]Australia To investigate

performance

persons

Table 3(continued)

Morgan et al., 2010

Author and

Table 3(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

to endpoint in imme‑

groups from baseline

N.R = specific adher‑

across both groups,

reported by partici‑

nificant differences

for the older adults

between the treat‑

ence: 1 participant

missed dose of 2.2

no adverse effects

recall for the older

Cognition: no sig‑

did not complete

Retention/adher‑

ment or placebo

the study (44/45

diate or delayed

Adverse events:

completed),

an average

group

pants

ence

tests of verbal epi‑

and delayed recall

2 weeksPen and paper

sodic memory

immediate

L.) ethanolofficinalis

5 ml of SRM (Salvia

(L.)), 1% Lyles Black

N.R = specific time

fresh sweet cicely

marinus officinalis

diluted in water)

L.,officinalisRos-

Treacle and 1 g/

(Myrrhis odorata

of day for dose,

extract or 5 ml

on smell, taste

twice per day,

ml 45% EtOH,

placebo (50%

L. andMelissa

or matched

trial, outcomes at 0

placebo control

double‑blind

Randomised,

and 2 weeks

of cognitive impair‑

N.R = global cogni‑

ment or dementia,

clinical diagnosis

No reported cur‑

rent or previous

tion measure

Healthy older adults

=61 (± 9.26) yearsm

38F:6 M total (older

tion group and 2

groups: younger

bers: 4 males = 2

in the interven‑

14 females = 10

and 4 placebo)

in intervention

(divided into 2

in the placebo

(43–62), older

group num‑

(63–80))

group

medicines on verbal

ditional European

and Melissa—tra‑

of sage, rosemary

of a combination

healthy subjects

time the effects

recall in normal

[34]UK To evaluate

for the first

Perry et al., 2018

Table 3(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

dosage, N.R = specific

not monitored in The

ticipants completing

and 9 in the placebo

ment groups on any

ply with medication

in the ginkgo group

group did not com‑

in non‑completion,

nificant differences

nificant differences

between the treat‑

outcome measure

withdrew consent

Cognition: no sig‑

Retention/adher‑

or between time

between groups

with 88% of par‑

Adverse events:

the trial, no sig‑

ence: 4 ginkgo

and 7 placebo

7 participants

adherence

points

study

test, Boston naming

of the WMS‑revised,

(WMS‑R) controlled

and mental control

tion, concentration

scale of the WAIS‑

Memory subscale

utilising the CVLT,

digit symbol sub‑

duction subscale,

revised), the digit

category fluency

the Visual Repro‑

language tested

memory, atten‑

and expressive

span (WMS‑R)

the Logical

6 weeksLearning,

test

times per day. States

is a tablet, placebo

matched placebo

Ginkgo (Ginkoba)

1 capsule 3 × per

day. Note: active

(lactose gelatin),

40 mg 1 tab‑

is a capsule

let, taken 3

trial, outcomes at 0

placebo control

double‑blind

good health Randomised,

and 6 weeks

and in generally

MMSE (> 26)

years, with 65F:46 M,

and ages calculated

years with 63F:45 M

dwelling volunteer

numbers, F:M ratio

after withdrawals)

aged between 60

older adults (total

of 132F:98 M, 115

in each group),

to intervention

=68.7 (± 4.7)m

=69.9 (± 5.4)m

placebo group

Ginkgo group

Community‑

and 82 years

(assignment

tests and subjective

neuropsychological

improves memory

whether ginkgo

in elderly adults

as measured

by objective

[36]USA To evaluate

ratings

Solomon et al., 2002

Table 3(continued)

cognition Results

control and dose DurationMeasures of

measure DesignIntervention/

study location AimStudy populationDiagnosis criteria/

global cognition

Author and

cance for ages 60–81)

Retention/adherence:

tion period (semantic

Adverse events: none

(Japanese version) Cognition: significant

drew from the study

fluency), total score

independent of sex

reported by partici‑

3 participants with‑

approached signifi‑

endpoint interven‑

sub‑group analysis

increase in RBANS

between baseline

but age‑depend‑

and the 12‑week

N.R = adherence

for 47–81 years,

ent (significant

(31 originally),

pants

RBANS, MMSE‑J

12 weeks intake,

washout period

with a 6‑week

the crossover

separating

period

was matched in col‑

are taken, if placebo

and white beeswax,

15 containing 8 mg

Diosgenin‑rich yam

vitamin E derivative

vitamin E derivative

and white beeswax

our, smell and taste

containing olive oil

diosgenin, 672 mg

are taken. Placebo

(672 mg), glycerol

N.R = when doses

N.R = when doses

extract diopower

olive oil, glycerol

(2 capsules/day)

fatty acid ester,

fatty acid ester,

day = 50 mg),

(2 capsules/

to active

trial, outcomes at 0,

Randomised, dou‑

ble‑blind placebo

control, crossover

12 and 30 weeks

physical and mental

health, no diagnosis

of AD or related dis‑

orders, N.R = global

cognition measure

Overall good

(subgroup for analy‑

numbers calculated

(16F:12 M)46.5m

60–81 years) (ages

range 20–81 years

after withdrawals)

sis of older adults

and participant

(± 18.67) years,

Healthy adults

yam extract on cog‑

of a diosgenin‑rich

ment in healthy

nitive enhance‑

[40]Japan Investigate

volunteers

the effects

Tohda et al., 2017

ADAEBOMCCFTCOWACVLTDATAlzheimer’s disease,Adverse event,Blessed Orientation Memory Concentration test,Complex Figure Test,Controlled Oral Word Association test,California Verbal Learning Test,Divided

HAMDHVLT-RMAC-QMMSEMoCAAttention Task,Hamilton Rating Scale for Depression,Hopkins Verbal Learning Test-Revised,Memory Complaint Questionnaire,Mini-Mental State Examination,Montreal Cognitive

N.RPOMSRAVLTRBANSSCWTAssessment,Not reported,Profile of Mood States,Rey Auditory Verbal Learning Test,Repeatable Battery for the Assessment of Neuropsychological Status,Stroop Colour and Word Test,

SPMSQSRTTMTVFTWAISWMSShort Portable Mental Status Questionnaire,Selective Reminding Test,Trail Making Test,Verbal Fluency Test,Wechsler Adult Intelligence Scale,Weschler Memory Scale

38], compared to 1136 from the twelve studies in older adults without SCI [23–25, 27, 29–32, 34, 36, 39, 40].

Eligibility criteria and global cognition measures

All twenty-one studies utilised cognitive scales or tests

1. [20–22, 25–33, 35, 36, 38, 39], medical questionnaires [23, 37], self-reports of cognitive function [22, 24, 26,

1. 27, 29–31, 34, 40] or clinical questionnaires [23, 24, 32, 38], to determine the eligibility for their respective study. Nineteen of these studies utilised a validated measure to test cognitive functioning [20–33, 35, 36, 38–40]. Fifteen out of twenty-one studies utilised the Mini-Mental State Exam (MMSE), as a measure of global cognition [20–22, 25–33, 35, 36, 38, 39]. The MMSE cut-off score for participant inclusion varied between studies and populations. For SCI studies, one utilised a cut-off of≥ 20 [22], another a range of 20–27 [26], one with≤ 24 [35], four studies with a cut-off of≥ 24 [21, 28, 33, 38] and one of≥ 25 [20]. For studies on older adults without SCI, one reported a cut-off of≥ 23 [29], one with a range of 24–29 [25], three with a cut-off of≥ 24 [27, 30, 32], one≥ 26 [31] and one each > 26 [36] and≥ 27 [39]. Overall, studies with an SCI population reported lower cut-off scores and ranges for participant inclusion.

Other scales included the Blessed Orientation Memory Scale (BOMC) [24], Weschler Memory Scale (WMS) [28, 29, 35], Clinical Dementia Rating (CDR) Scale [20], Memory Complaint Questionnaire (MAC-Q) [28] and Short Portable Mental Status Questionnaire (SPMSQ) [29]. Overall, four studies utilised a global cognition measure as their primary or secondary outcome measure, with three of these using the MMSE [26, 29, 39], and one the WMS (logical subset score of < 6) [35].

Two of the remaining four studies utilised a herbal combination via a liquid solution (Ginkgo biloba, alcohol/water solution [22] and SRM [Salvia officinalis L., Rosmarinus officinalis L. and Melissa officinalis L.]) [34], one study utilised a nutrient based juice (sweetened cranberry juice) [27], and one study used an oral capsule containing a type of fungus (Tremella fuciformis) [20]. Twenty out of twenty-one studies reported a method of administration [20–34, 36–40] with ten administering the intervention orally via capsule [20, 21, 25, 26, 28–30,

1. 33, 37, 40], seven utilised tablets [23, 24, 31, 32, 36, 38, 39] and three a liquid solution [22, 27, 34].

Intervention and control type

Seventeen out of twenty-one studies used a herbal supplement [21, 23–26, 28–33, 35–40] with most studies utilising a form of Ginkgo biloba [23, 25, 29–31, 36–38] or Bacopa monnieri as a primary ingredient in their intervention [21, 24, 26, 32, 35, 39]. Two of these seventeen studies used a combination formula (one containing Ginkgo biloba and 45 other herbs, minerals and vitamins specifically made for women [38]) (the other containing Bacopa monnieri, lycopene, astaxanthin and vitamin B12 [39]). In addition, one study each used a spearmint extract (Mentha spicata L.) [28], a standardised ginseng extract (G115) [33] and a diosgenin-rich yam extract (diopower 15) containing vitamins, oils and beeswax [40], and one used a nutritional supplement (OPC Synergy® plus Catalyn) containing buckwheat, teas, and fruit and vegetable extracts, as a secondary intervention [29].

Fig. 2 Risk of bias domains for older adults with SCI (parallel studies)

Retention and adherence

Nineteen of the twenty-one studies consistently reported retention, with an average retention rate of 92% across the studies [20–26, 28, 30–38, 38–40]. Comparatively, only 7/21 studies specifically reported treatment adherence, with an overall average of 93% across both intervention and placebo usage [20, 22, 24, 26, 28, 33, 38, 38].

Risk of bias within and across studies

Figures 2 and 3 (parallel studies) and Fig. 4 (cross-over study) provide a summary of each of the risk of bias domains, and an overall risk of bias assessment, for each of the twenty-one included studies. Green circles indicate that the domain or study has been evaluated as low risk, yellow as having some concerns and red as high risk.

Each article was assessed in terms of randomisation, intended interventions (effect of assignment and effect of adhering to the intervention), missing outcome data, measurement of outcomes and selection in reported results. In terms of the overall risk of bias assessment, only one study was deemed as low risk [26], some concerns were found for 6/21 studies [20, 24, 27, 28, 33, 39] and the remaining fourteen were deemed to be high risk

1. [21–23, 25, 29–32, 34–38, 40]. Between populations, three SCI studies were assessed as having some concerns

[20, 28, 33], five were deemed high risk [21, 22, 35, 37, 38] and one was deemed low risk [26]. For the non-SCI studies, three were assessed as having some methodological concerns [24, 27, 39], and the remaining nine were deemed as high risk [23, 25, 29–32, 34, 36, 40].

Despite all twenty-one studies stating the method of intervention assignment was randomised, only fourteen sufficiently detailed the randomisation process and were deemed as low risk [21–23, 25–27, 29–32, 36–38, 40]. Intended interventions (effect of assignment to interventions) were adequately reported in five studies (low risk) [20, 26, 28, 29, 36], nine were assessed as high risk [21– 23, 25, 30–32, 38, 40] and the remaining seven have some concerns [24, 27, 33–35, 37, 39]. Thirteen studies were assessed as low risk for reporting on intended interventions (effect of adhering to the intervention) [20, 22–24, 26–31, 33, 38, 39] and eight as high risk [24, 29, 32, 34– 37, 40].

In terms of missing outcome data (domain three), 17/21 studies were evaluated as low risk [20–22, 24, 26– 31, 33–37, 39, 40], and the remaining four were assessed as high risk [23, 25, 32, 38]. Within domain 4 (measurement of outcomes), 18/21 studies were deemed as low risk [20–33, 36–39], and the remaining three were as high risk [34, 35, 40]. Eighteen out of twenty-one studies

1. Fig. 3 Risk of bias domains for older adults without SCI (parallel studies)
2. Fig. 4 Risk of bias domains for older adults without SCI (cross‑over study)

were assessed as low risk for selection in reported results (domain 5) [20–22, 24–29, 31–39], with some concerns for only three studies [23, 30, 40]. In terms of bias arising from period or carryover effects (domain S) in the crossover study, this was deemed as low risk [40].

Study results

Results for all twenty-one studies are outlined below including intervention efficacy on cognitive function, adverse events and risk of bias.

Intervention efficacy in low risk of bias study

Only one study was deemed to be low risk for all domains, in terms of the overall methodological assessment. This 2017 randomised, double-blind placebocontrolled trial was conducted by Cicero and colleagues [26]. Participants were 30 older adults with self-perceived cognitive decline and ingested either a Bacopa monnieri formulation or a placebo capsule for 8 weeks; MMSE was measured at each time point. In terms of intervention efficacy, a significant increase in MMSE score was

found from baseline to endpoint in the treatment arm. Furthermore, a significant increase in score was also found in the treatment group at the endpoint, compared to placebo, demonstrating a significant improvement in cognitive function for the intervention group across time and between groups [26]. Only one adverse event was reported an aftertaste from active product intake.

Intervention efficacy in remaining SCI studies

Across time, a significant improvement in at least one cognitive outcome for participants in the intervention group (compared to placebo) was found in 6/8 of the remaining SCI studies [20, 21, 28, 33, 35, 38]. Improvements were mostly found in the areas of memory (working, spatial, short-term, retention and logical) [20, 28, 33, 35, 38] and executive functioning [20, 21, 35]. Three of the eight studies utilised a capsule containing a herbal extract: one contained Bacopa monnieri [21], one spearmint extract (Mentha spicata L.) [28] and one standardised ginseng extract [33]. One study used a combination supplement (tablet), containing 46 herbs, vitamins and minerals (mainly consisting of Ginkgo biloba, Silybum marianum dry fruit (St. Mary’s thistle) and Vitis vinifera dry seed (grape seed)) [38]. An additional study utilised a capsule containing Tremella fuciformis (a type of fungus) [20], and the last study did not specify an administration method but used a standardised extract of Bacopa monnieri [35].

Of these six studies, mild to moderate adverse events were reported in three of them [28, 35, 38]. Knee pain, myalgia, headaches and heartburn were reported in the study conducted by Herrlinger and colleagues utilising Mentha spicata L. as their intervention [28]. These adverse events were reported for both the treatment and placebo groups; however, heartburn experienced by a participant in the 600 mg/day Mentha spicata L. group was deemed as ‘probably related’, compared to all other events deemed as ‘not related’ [28]. One participant withdrew due to maculopapular rashes in the intervention group (Bacopa monnieri), in the study conducted by Raghav and colleagues [35]. Two participants withdrew from the study conducted by Macpherson and colleagues using a combination formula containing Ginkgo biloba (intervention) [38]. One participant withdrew due to nausea and vomiting in the intervention group and one in the placebo group due to a mild rash [38].

In relation to the risk of methodological bias for all six SCI studies with an improvement in cognitive functioning, two of the studies utilising Bacopa monnieri [21, 35] and one using Ginkgo biloba (combination supplement) [38] were deemed as being high-risk. The remaining three were assessed as having some concerns in terms of methodological reporting [20, 28, 33].

For the two studies that did not find an improvement in cognitive functioning between groups (intervention cf. placebo) or across time, both reported adverse events with the use of Ginkgo biloba alcohol/water extract (drops) [22] and a herbal/dietary supplement also containing Ginkgo biloba [37]. Gastrointestinal upset was reported as the main adverse reaction for both studies [22, 37] with dizziness, headaches and sleep disturbance also reported in the Ginkgo biloba alcohol/water extract study [22]. In total, Brautigam and colleagues reported adverse events for 25 participants across both the placebo and intervention groups [22]. In terms of the second study, it is not known whether the two participants who reported adverse events were receiving the intervention or placebo [37]. Overall, both studies were deemed as high risk in terms of the methodological risk of bias assessment.

Intervention efficacy in non‑SCI studies

Overall, 7/12 non-SCI studies reported a significant improvement in cognitive functioning in the intervention group (compared to placebo), across time [23, 24, 30–32, 39, 40]. The most common improvements were in memory (long-term storage, retrieval, delayed recall, recognition) [23, 24, 31, 32], executive functioning [24, 30, 39, 40] and language [30, 39, 40]. Two studies used a form of Ginkgo biloba capsule [23, 30]; one used a Ginkgo biloba tablet [31]; two used a form of Bacopa monnieri tablet [24, 32]; one used an antioxidant combination formula (tablet) containing Bacopa monnieri, lycopene, astaxanthin and vitamin B12 [39]; and one a diosgenin-rich yam extract capsule [40]. An additional study reported a significant improvement in executive functioning across time, using a combined herbal and nutritional supplement containing Ginkgo (Ginkgo Synergy® plus Choline) [29]. A significant improvement in verbal fluency was also found in the secondary intervention group (across time, compared to the Ginkgo and placebo groups) using OPC Synergy®, a dietary supplement (plus Catalyn) [29]. A further study using a Ginkgo biloba-based supplement found a significant improvement in a list learning strict task in the placebo group only, across time [25].

Seven of the nine total studies were deemed as having a high methodological risk of bias [23, 25, 29–32, 40], with the remaining two (using a form of Bacopa monnieri) having some concerns [24, 39]. Five of the nine studies reported adverse events, in both the placebo and intervention groups (Ginkgo or Bacopa monnieri interventions) [24, 25, 29, 31, 32]. An additional two studies reported adverse events only occurring in the intervention group using a Ginkgo biloba capsule [23] or an antioxidant combination formula containing Bacopa monnieri [39]. The most common events reported across

6/7 studies were gastrointestinal issues (including nausea, abdominal cramps, digestive problems) [24, 25, 31, 32] and sleep disturbance, with the use of Ginkgo biloba [23] or placebo [29]. Exacerbation of sinusitis (n= 1) and a serious but short-term event of hepatitis E (n= 1) were reported as non-treatment-related adverse events in the remaining study [39].

For the three remaining non-SCI studies, all reported no significant improvements across time in cognitive functioning (for both intervention and placebo groups), nor between groups [27, 34, 36]. One study used a Ginkgo tablet [36], one used a sweetened cranberry juice [27] and the other used a liquid solution of SRM Salvia officinalis L., Rosmarinus officinalis L. and Melissa officinalis L. [34].

Adverse events were monitored in two of the three studies; however, no events were reported in one (SRM solution) [34], and the other study did not report serious events or document mild/minor events (sweetened cranberry juice intervention) [27]. Two of the three studies were deemed as having a high methodological risk of bias [34, 36], and the remaining one had some concerns [27].

Overall, twenty-one studies were identified for inclusion in this review, nine with an SCI population [20–22, 26,

1. 28, 33, 35, 37, 38] and twelve studies utilising older adults without SCI [23–25, 27, 29–32, 34, 36, 39]. Outcomes were mainly positive, with 14/21 studies overall reporting improvements in at least one area of cognitive functioning across time, in the intervention group (compared to placebo) [20, 21, 23, 24, 26, 28, 30–33, 35, 38–40]. Overall, only one study (using an SCI population) was assessed as having a low methodological risk of reporting, conduct and quality of trial design bias [26]. Due to the heterogeneous nature of eligible studies (including cognitive measures and interventions used and the type of data analysis and reporting conducted) and the large number of studies (14/21) with a high methodological risk of bias [21–23, 25, 29–32, 34–38, 40], a certainty of evidence analysis (GRADE) was not conducted.

Extent of literature using herbal and nutritional medicines for older adults with and without SCI

Despite the growing interest in the prevention and treatment of cognitive decline in older adults [8, 9], review search outcomes were not reflective of this interest, given that most of the articles eligible for this review were conducted prior to 2018. Editorials, book chapters, reviews and opinion articles seem to be more common formats of evidence, compared to research using the ‘gold standard’ method, randomised control trials (RCTs) [41, 42] (Fig. 1).

Measurement of cognitive change was not common in the literature; rather, relevant population studies focussed on biochemistry or progression to MCI or dementia. This was an unexpected outcome during the records search. Cognitive testing and assessment are generally affordable and accessible methods of providing insights into an individual’s current cognitive functioning and any decline over time [43]. However, there are currently no recommendations for specific primary or secondary outcome measures of cognition to determine a clinically significant improvement in cognitive function [44]. It has recently been recommended that composite outcomes including the monitoring of dementia risk factors alongside changes in cognition may be advantageous in preclinical dementia [44].

For cognitive outcome measures, an effect size of 0.40 has been reported as a clinically meaningful improvement for cognitive training interventions in healthy older adults and those with MCI or dementia [45]. This could be applied in studies utilising cognitive outcomes in people with SCI to determine whether a change in cognitive function is clinically meaningful, particularly in light of potential ceiling effects in this relatively unimpaired group. Future research should strive to investigate appropriate cognitive measures to detect a clinically significant change in SCI and implement gold standard, high-quality research methods to produce informative and translational outcomes.

Study characteristics

In terms of participant characteristics, across the twentyone studies, there were more females (61%) compared to male participants. It is difficult to ascertain the true difference in the prevalence of SCI between the sexes, as a larger number of females (rather than males) are participating in these studies. Furthermore, inconsistencies in reporting prevalence between the sexes are typical in this field, again making it hard to determine whether SCI affects more females or males [2]. However, research within the area of cognitive decline suggests that females have a greater cognitive reserve but have a faster rate of cognitive decline (particularly, in the areas of global cognition and executive function) compared to males [46]. This outcome has been confirmed in dementia research. Dementia is reported to be the leading cause of death in women, with twice as many females compared to males being affected by the disease [47]. Further SCI prevalence research needs to be conducted to determine the true prevalence of SCI, between the sexes.

A high number of older adults reporting SCI are within the 60–64 year age range [2], compared to studies included in this review that saw an overall average age of

65 years for participants. Sex and age outcomes derived from this review highlight the importance of finding a way to address low research participation in males and monitoring the faster rate of female decline.

In terms of participant retention and adherence to treatment, these were both surprisingly high across the studies at an average of 92% and 93%, respectively, despite the literature suggesting these figures are quite difficult to achieve [48]. These outcomes should be considered with caution due to the subpar methodologies used to treat missing values.

Study methodologies

Reflective on previous research, the eligibility criteria for participation across the SCI and non-SCI studies were inconsistent [8, 9], with varying scales, tests and questionnaires used, particularly for the MMSE [20–22, 25– 33, 35, 36, 38, 39]. Research investigating the diagnostic accuracy (sensitivity, specificity, positive and negative predictive power) of MMSE cut-off scores in detecting cognitive dysfunction found that scores of≤ 26 showed optimal sensitivity and specificity balance, with a correct classification of MCI and dementia in older adults to be 90% [49]. The varying MMSE cut-offs used here (≥ 20, > 25 and≤ 24) may have incorrectly classified participants (with and without SCI), potentially impacting the study outcomes. This interpretation is further supported by the identification of all eligible studies in this review not using a combination of self-report cognitive concerns (in line with the definition of SCI), cognitive scales (such as the MMSE), a general health questionnaire (including non-diagnosis of MCI or dementia) and screening of mental health conditions. Reliability on only one or two measures for classification of an impairment (or no impairment) is problematic and certainly requires future attention within this area of clinical practice and research.

An additional concern regarding the methodologies of accepted studies in this review is the large number of those deemed as having a high risk of bias, particularly within the bias due to assignment and adherence domains [21–23, 25, 29–32, 34–38, 40]. Either intention-to-treat (ITT) or modified intention-to-treat (mITT) approaches were not employed for participants with missing outcomes or outlier data, with participants being excluded completely from the analysis despite being randomised. Future studies in this field should consider using appropriate analysis to treat missing or outlier data, for postrandomisation outcomes as detailed above. The blinding of participants and other individuals involved in the trial was also identified as a concern. However, it is difficult to

ascertain whether it was in fact the blinding process itself that was not conducted appropriately in these studies or if it was simply not reported sufficiently according to the ROB assessment standards. Future studies should look to adopting greater transparency and accuracy in the process (specifically stating who was blinded and how), as this would go a long way in demonstrating non-biassed outcomes.

Intervention efficacy on cognitive function and safety

Despite the majority of studies reporting positive results [20, 21, 23, 24, 26, 28, 30–33, 35, 38–40], a large number of these were deemed as having an overall high methodological risk of bias [21, 23, 30–32, 35, 38, 40]. These methodological concerns unfortunately do not assist in determining the true efficacy of herbal and nutritional medicines on cognitive functioning for older adults with and without SCI. This is particularly the case for Ginkgo biloba [23, 25, 29–31, 36–38] and Bacopa monnieri [21, 24, 26, 32, 35, 39], given how common they were as interventions across the accepted studies of this review.

The efficacy of Ginkgo biloba has been consistently unclear across the spectrum of cognitive decline. An earlier review investigating RCTs using Ginkgo biloba for the treatment of dementia [50] highlighted the concerns around the low quality of studies available, namely to do with utilisation of unsatisfactory methods. However, on a positive note, adverse effects found with the use of Ginkgo biloba (across the accepted studies in this review) appeared to be consistent with those reported with the use of a placebo [23, 29, 31, 38], indicating that Ginkgo biloba may be comparable in terms of safety with placebo intake. These results are in line with what has been found previously in a dementia population [50].

Strengths and limitations of the review

This review had several strengths. A broad and extensive literature search was conducted (in accordance with the aims and PICOS criteria of the review), comprehensively summarising the overall current state of the field. The lack of high-quality research has been addressed, highlighting the specific aspects which require improvement in future studies. The concerns surrounding the classification of SCI and the disparities between current research outcomes and clinical statistics have been presented.

There were a number of limitations to this review. First, the establishment of article alerts from 2018 until the completion of the review meant that despite the authors’ best efforts to monitor the addition of newly published research in each database, it is acknowledged that alerts

may not have been the most appropriate way to capture all potential studies for inclusion. Furthermore, a metaanalysis was not feasible due to the inconsistent classification of SCI and non-SCI samples and the varying cognitive testing measures. The infancy of this area of research (despite broad interest from the general public) makes it difficult to conduct such an analysis at this time. The population was difficult to define due to the inherent heterogeneity of definitions and lack of consensus within the field, particularly with reference to the age range selected (despite being guided by the US CDC’s definition), and the terminology and language used (e.g. person-centred terminology). It is also acknowledged that the current review did not take into consideration the varying terminology utilised to classify ‘older adults’. The exclusion of non-English language studies, the initial article screening conducted by one reviewer and the search strategy developed in consultation with only one librarian were further limitations.

Recommendations for future research

First and foremost, an increased understanding and awareness of the features and characteristics of SCI needs to occur [8, 9]. This should be considered in collaboration with the difference between the presentation of older adults without SCI and those with MCI, in line with the cognitive decline continuum [2]. Future research should aim at clarifying the characteristics, classification measures and features of SCI to allow for more homogeneous sample classification. Overall, by better understanding of SCI, this may provide greater support for outcomes in high-quality efficacy studies utilising herbal and nutritional medicines as a means of managing selfperceived (or subtle) cognitive decline and, ideally, lowering dementia risk or facilitating the secondary prevention of dementia.

The development of a standardised outcome measure package (including cognitive testing, medical questionnaires, self-reports and mental health questionnaires) for use in SCI clinical trials would be the next step in moving the field forward. Increased accuracy in the differentiation between healthy older adults (without SCI) and those with SCI would assist in determining whether herbal and nutritional medicines have a positive effect on cognitive outcomes for this population.

Conclusions

Whilst most studies deemed eligible for inclusion in the review found positive results (particularly, those that used Ginkgo biloba or Bacopa monnieri), these outcomes need to be considered with caution, due to the high risk of methodological bias found. The literature in

this area is in its infancy, with concerns around population and intervention heterogeneity evident. The use of supplements for cognition by older people is an area that attracts much interest from the community, yet our review shows that high-quality research on efficacy and safety is somewhat lagging.

This review has provided an insight into the current state and quality of the literature on the safety and efficacy of cognitive function of herbal and nutritional medicines in older adults with and without SCI.

Acknowledgements Not applicable.

Authors’ contributions AEC and GZS contributed to the conceptualisation and design of the review. AEC took the lead in drafting the review paper. GZS provided guidance throughout. All authors provided critical feedback and reviewed the final manuscript.

Funding AEC’s contribution was supported by PhD scholarship from FIT‑BioCeuticals Pty Ltd. and NICM Health Research Institute, Western Sydney University. GZS’s contribution was supported by funding from a National Health and Medical Research Council (NHMRC)‑Australian Research Council (ARC) Dementia Research Development Fellowship (APP1102532) and an NHMRC Investigator Grant (APP1195709). The funders played no role in this study.

Availability of data and materials Not applicable.

NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. 2School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia. 3Translational Health Research Institute (THRI), Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.