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

Burns et al., 2006 Australia [23]

To extend on previous research in order to determine the efficacy of 120 mg ginkgo, to benefit performance of healthy older and young adults on cognitive outcomes

Healthy older adults m = 61.7 (± 5.5) range 55–79 years:

50 males (26 males in placebo, 24 in ginkgo) and 43 females (21 females in placebo, 22 in ginkgo)

Younger adults also included in this study however analysed separately

Medical questionnaire—medical history and current medications, POMS, N.R = global cognition measure and names of medical questionnaires

Randomised, double-blind placebo control trial, outcomes at 0 and 12 weeks

Ginkgoforte™ (Ginkgo biloba) 120 mg per day (3 tablets daily of 40 mg each—1 per meal)

Matched placebo (3 tablets per day—1 per meal), N.R = placebo ingredients

12 weeks

Woodcock-Johnson Psycho-educational battery-revised (fluid ability, crystallised ability, short-term memory, cognitive processing speed, long-term storage and retrieval, delayed recall, spot-the word (vocabulary), self-ordered pointing (executive function), odd-man-out (both movement and decision time), inspection time

Cognition: significant improvement in long-term storage and retrieval only in the ginkgo group

Retention/adherence: 13 participants withdrew between pre- and post-treatment, adherence measured as ≥ 75% intake, all participants were compliant

Adverse events: reported by 2 participants who withdrew in the ginkgo condition due to headaches and sleep disturbance

Calabrese et al., 2008 U.S.A [24]

To evaluate the effects of Bacopa monnieri (whole plant standardised dry extract) on cognitive function and its affect, safety and tolerability in healthy elderly participants

54 healthy older adults (60% women) living independently aged 65 years or older m = 73.5 years, N.R = range, S.D (27 participants in each group)

BOMC and no complaints of memory impairment, POMS, N.R = BOMC cut-off

Randomised, double-blind placebo control trial, outcomes at 0, 6 and 12 weeks

Standardised Bacopa monnieri extract, 300 mg/day (1 tablet daily)

Matched placebo (1 tablet daily), N.R = placebo ingredients

6 weeks of placebo for control group and 12 weeks of Bacopa monnieri for the treatment group

Delayed recall score from RAVLT. Additionally, Stroop task assessing ability to ignore irrelevant information, the DAT and the WAIS letter digit test of immediate working memory

Cognition: significant improvement in RAVLT delayed recall and Stroop tasks for the Bacopa monnieri group

Retention/adherence: 6 participants withdrew from study in total, average of 3.9 (out of 84) tablets missed with no difference between groups

Adverse events: 10 in placebo group, 9 in the intervention group reporting flu like symptoms and digestive problems

Carlson et al., 2007 USA [25]

To determine if a Ginkgo biloba—containing supplement improves cognitive function and quality of life, alters primary haemostasis, and is safe in healthy, cognitively intact older adults

Healthy, cognitively intact older adults: ginkgo group (21F:21 M 73.1 (± 4.8) years range 65–84 years), placebo group (15F:21 M, 72.1 (± 6.0) years, range 65–83 years)

MMSE (24–29)

Randomised, double-blind placebo control trial, outcomes at 0 and 4 months

Ginkgo biloba-based supplement containing 160 mg of Ginkgo biloba, 68 mg of Gotu kola, 180 mg of DHA, a bioflavonoid concentrate (100 mg) and vitamin A (300 IU) as beta carotene, three capsules/day with meals. All participants were also given a once-daily multivitamin/multimineral supplement (Nutrilite Daily)

Matched placebo three capsules/day with meals, N.R = placebo ingredients

4 months

Benton visual retention, controlled oral word association, judgement of line orientation, modified mini mental screening, list learning easy, list learning strict and symbol digit modalities

Cognition: significant improvement only in list learning strict task for the placebo group

Retention/adherence: 3 participants from the Ginkgo group and 8 from the placebo group dropped out, > 95% adherence for all participants

Adverse events: 17% of each group reported they had one AE attributed to the product they ingested, with the most common AEs being nausea/stomach upset and flatulence, two reports of headaches, rash and dizziness

Crews et al., 2005 USA [27]

To conduct the first known clinical trial of the short-term efficacy of cranberry juice on the neuropsychologic functioning of cognitively intact older adults

Cognitively intact older adults (> 60 years of age): cranberry group (25 adults) m = 69.17 (± 7.11) years placebo group (25 adults) m = 69.39 (± 5.80) (N.R = range, sex)

MMSE (≥ 24) and reporting no history dementia or significant neurocognitive impairment

Randomised, double-blind placebo control trial, outcomes at 0 and 6 weeks

32 oz/day (2 × 16 oz) of a beverage containing 27% cranberry juice sweetened with sucralose

Matched placebo beverage 32 oz/day (2 × 16 oz), N.R = specific placebo ingredients

6 weeks

Selective Reminding Test, WMS-3 (face 1 and face 2 subtests), Trail Making Test (parts A and B), SCWT the WAIS-3 Digit Symbol-Coding subtest

Cognition: no significant improvements in neuropsychologic test data

Retention/adherence: 3 participants excluded from analysis due to non-compliance, N.R = adherence

Adverse events: no serious adverse effects were reported by participants, N.R = minor AEs

Crosta et al., 2020 Italy [39]

To evaluate the changes in the trail making test scores from baseline to 8 weeks of treatment with an antioxidant mix compared to placebo in healthy older adults

Healthy older adults (> 60 years of age): antioxidants mix group (28F:12 M, m = 61.88 (± 1.36) years), placebo group (27F:13 M, m = 62.05 (± 1.55) years) N.R = range

MMSE (≥ 27) and no neurological disorders

Randomised, double-blind placebo controlled trial, outcomes at 0 and 8 weeks

Antioxidant mix 1 tablet daily containing Bacopa monnieri, lycopene, astaxanthin and vitamin B12. Matched placebo tablet taken once daily containing magnesium vegetable stearate (5 mg) and non-active substances

1-week run-in period (unclear of what occurred during this time) followed by 8 weeks intake or intervention or placebo

TMT, VFT, MMSE, MoCA and RAVLT

Cognition: significant improvements in TMT A and TMT B, and VFT across time, and in the antioxidant group compared to placebo

Retention/adherence: 2 participants excluded from the final analysis due to withdrawal (1 adverse event, 1 could not attend study sessions), compliance reported as 100% for nearly all participants

Adverse events: 1 participant reported non-serious event of exacerbation of sinusitis in active group and 1 participant experienced an acute serious event of hepatitis E

Lewis et al., 2014 USA [29]

To extend the evaluative process of nutritional therapies through a randomised, double-blind, placebo-controlled clinical trial assessing a regimen of dietary supplements’ efficacy

Healthy older adults

Ginkgo synergy® plus Choline m = 67.6 (± 6.3) years, range 58–82 years, with 25F:8 M; OPC Synergy® plus Catalyn group m = 68.5 (± 6.7) years, range 59–83 years, with 24F:7 M; placebo group m = 70.3 (± 8.3) years, range 60–93 years, with 21F:12 M

MMSE (≥ 23), SPMSQ, WMS-Story A, no AD or related disorders, not living in a nursing facility

Randomised, double-blind placebo control trial, outcomes at 0, 3 and 6 months

1) Ginkgo Synergy® (2 capsules/day—120 mg/day total) and choline (4 tablets/day to 700 mg/day total)

2) OPC Synergy® (2 capsules/day) and Catalyn (4 tablets/day)

3) Placebo containing cellulose, lactose and beet powder, N.R = placebo administration method/type, dose

6 months

MMSE, SCWT, the TMT Parts A and B, COWA, the Digit Symbol subtest of the WAIS and the HVLT-R

Cognition: according to time in the TMT-B the Ginkgo group showed improvement from baseline to 3 months, on the controlled oral word association trial-S scores significantly increased for the Ginkgo group from baseline to endpoint and in the OPC group from baseline to 3 months

Retention/adherence: retention numbers inconsistently reported, N.R = adherence

Adverse events: one participant in the OPC synergy group diagnosed with ulcerative colitis shortly after enrolling, one participant in the ginkgo synergy group reported joint aches and one placebo participant reported insomnia and heightened energy at night

Mix et al., 2000 USA [30]

To examine the relatively short-term (i.e. 6 weeks) efficacy of Ginkgo biloba extract EGB 761 on the cognitive functioning of cognitively intact persons over the age of 55 years via a diverse battery of neuropsychologic tests and measures

Cognitively intact healthy older adults, 55–86 years of age: ginkgo group m = 67.5 (± 9.23) years, placebo group m = 68.65 (± 6.95) years, 24F:24 M

MMSE (≥ 24) and no history of significant neurocognitive dysfunction, considered cognitively intact (self-reported)

Randomised, double-blind placebo control trial, outcomes at 0 and 6 weeks

Ginkgo biloba EGB 761 (180 mg/day = 60 mg × 3 capsules per day). Matched placebo × 3 capsules per day (methylcellulose), N.R = additional placebo ingredients

6 weeks

SCWT (parts A and B) and the WMS-revised, logical memory 1 and 2 and visual reproduction 1 and 2 subtests

Cognition: significant improvement in the intervention group across time in colour naming task within the Stroop Colour and Word test compared to placebo over the trial period

Retention/adherence: 21 males and 19 females completed the study (40/44), 1 participant did not complete due to non-compliance (missing > 20% treatment), remaining 3/4 due to medical reasons, N.R = overall adherence

Adverse events: no adverse effects reported by participants

Mix et al., 2002 USA [31]

To conduct the first known, large-scale clinical trial of the efficacy of Ginkgo biloba extract (EG 761) on the neuropsychological functioning of cognitively intact older adults

Cognitively intact older adults, ≥ 60 years of age: ginkgo group m = 66.97(± 6.12) years, placebo group m = 68.60 (± 6.96) years, (N.R = range), with 262 participants in total in the study, after withdrawals/non-compliance, 147F:102 M remained in the study

MMSE (≥ 26) and no history of dementia or significant neurocognitive impairment (self-reported)

Randomised, double-blind placebo control trial, outcomes at 0 and 6 weeks

Ginkgo biloba EGB 761 (180 mg/day = 60 mg × 3 tablets per day). Matched placebo tablets × 3 per day, N.R = placebo ingredients

6 weeks

SRT, WAIS-3 block design, Digit Symbol-Coding subtests, WMS-3 faces 1 and 2 subtests

Cognition: participants in the intervention group (compared to placebo) significantly improved in SRT tasks involving delayed free recall and recognition of visual material

Retention/adherence: 249/262 participants completed the protocol, 5 from the placebo group and 4 from the intervention group were excluded from the study due to non-adherence (missing > 20% treatment), N.R = overall adherence

Adverse events: total of 32 reported including but not limited to gastrointestinal, nervous system and respiratory/allergic reactions, across both groups. One serious event in the placebo group of an intracranial bleed

Morgan et al., 2010 Australia [32]

To investigate the effectiveness of Bacopa monnieri Linn. for improvement of memory performance in healthy older persons

Healthy older adults from the general population m = 65(± 7.53) years, range 55–86 years

Bacopa group = 24F:25 M, placebo group = 28F:21 M

MMSE (≥ 24) and absence of depression (≤ 12) on HAMD

Randomised, double-blind placebo control trial, outcomes at 0 and 12 weeks

Bacopa monnieri (BacoMind™) 300 mg/day (one tablet daily). Matched placebo tablet, N.R = dose, ingredients

12 weeks

Audio-verbal and visual memory performance measured by RAVLT, the Rey-Osterrieth CFT and the Reitan TMT, subjective complaints measured by the MAC-Q

Cognition: Bacopa significantly improved verbal learning, memory acquisition and delayed recall, total learning and retroactive interference (RAVLT)

Retention/adherence: 81/98 participants completed the study. N.R = adherence

Adverse events: 9 in the treatment group, 2 placebo group (side effects occurred significantly more in the treatment group: increased stool frequency, nausea and abdominal cramps)

Perry et al., 2018 UK [34]

To evaluate for the first time the effects of a combination of sage, rosemary and Melissa—traditional European medicines on verbal recall in normal healthy subjects

Healthy older adults m = 61 (± 9.26) years (divided into 2 groups: younger (43–62), older (63–80))

38F:6 M total (older group numbers: 4 males = 2 in the intervention group and 2 in the placebo group

14 females = 10 in intervention and 4 placebo)

No reported current or previous clinical diagnosis of cognitive impairment or dementia, N.R = global cognition measure

Randomised, double-blind placebo control trial, outcomes at 0 and 2 weeks

5 ml of SRM (Salvia officinalis L., Rosmarinus officinalis L. and Melissa officinalis L.) ethanol extract or 5 ml placebo (50% fresh sweet cicely (Myrrhis odorata (L.)), 1% Lyles Black Treacle and 1 g/ml 45% EtOH, diluted in water) twice per day, N.R = specific time of day for dose, or matched on smell, taste

2 weeks

Pen and paper immediate and delayed recall tests of verbal episodic memory

Cognition: no significant differences between the treatment or placebo groups from baseline to endpoint in immediate or delayed recall for the older group

Retention/adherence: 1 participant did not complete the study (44/45 completed), an average missed dose of 2.2 for the older adults across both groups, N.R = specific adherence

Adverse events: no adverse effects reported by participants

Solomon et al., 2002 USA [36]

To evaluate whether ginkgo improves memory in elderly adults as measured by objective neuropsychological tests and subjective ratings

Community-dwelling volunteer older adults (total of 132F:98 M, 115 in each group), aged between 60 and 82 years

Ginkgo group m = 68.7 (± 4.7) years, with 65F:46 M, placebo group m = 69.9 (± 5.4) years with 63F:45 M (assignment to intervention numbers, F:M ratio and ages calculated after withdrawals)

MMSE (> 26) and in generally good health

Randomised, double-blind placebo control trial, outcomes at 0 and 6 weeks

Ginkgo (Ginkoba) 40 mg 1 tablet, taken 3 times per day. States matched placebo (lactose gelatin), 1 capsule 3 × per day. Note: active is a tablet, placebo is a capsule

6 weeks

Learning, memory, attention, concentration and expressive language tested utilising the CVLT, the Logical Memory subscale of the WMS-revised, the Visual Reproduction subscale, digit symbol subscale of the WAIS-revised), the digit span (WMS-R) and mental control (WMS-R) controlled category fluency test, Boston naming test

Cognition: no significant differences between the treatment groups on any outcome measure or between time points

Retention/adherence: 4 ginkgo and 7 placebo withdrew consent with 88% of participants completing the trial, no significant differences between groups in non-completion, 7 participants in the ginkgo group and 9 in the placebo group did not comply with medication dosage, N.R = specific adherence

Adverse events: not monitored in The study

Tohda et al., 2017 Japan [40]

Investigate the effects of a diosgenin-rich yam extract on cognitive enhancement in healthy volunteers

Healthy adults (16F:12 M) m = 46.5 (± 18.67) years, range 20–81 years (subgroup for analysis of older adults 60–81 years) (ages and participant numbers calculated after withdrawals)

Overall good physical and mental health, no diagnosis of AD or related disorders, N.R = global cognition measure

Randomised, double-blind placebo control, crossover trial, outcomes at 0, 12 and 30 weeks

Diosgenin-rich yam extract diopower 15 containing 8 mg diosgenin, 672 mg olive oil, glycerol fatty acid ester, vitamin E derivative and white beeswax (2 capsules/day = 50 mg), N.R = when doses are taken. Placebo (2 capsules/day) containing olive oil (672 mg), glycerol fatty acid ester, vitamin E derivative and white beeswax, N.R = when doses are taken, if placebo was matched in colour, smell and taste to active

12 weeks intake, with a 6-week washout period separating the crossover period

RBANS, MMSE-J (Japanese version)

Cognition: significant increase in RBANS between baseline and the 12-week endpoint intervention period (semantic fluency), total score independent of sex but age-dependent (significant for 47–81 years, sub-group analysis approached significance for ages 60–81)

Retention/adherence: 3 participants withdrew from the study (31 originally), N.R = adherence

Adverse events: none reported by participants