Table 3b.
(continued)
| References | Test methods (PASSCLAIM criteria 3 + 4) | Effect size (per dosing or time) (PASSCLAIM criteria 2H + 5) | Remarks | |||
|---|---|---|---|---|---|---|
| Blood circulation: studies in healthy volunteers: insufficient evidence | ||||||
| Boelsma et al. (27) | Skin blood flow: assessed on forefoot with laser Doppler flow meter after 3 weeks. Metabolic fingerprinting: changes in urinary metabolites measured. | Blood flow after 3 weeks: placebo EGb761 baseline 10.4±6.7; 7.1±4.4 p<0.01 peak 29.1±18.9; 20.9±16.8 p<0.01 subjects with highest resting blood flow demonstrated a decrease after treatment, subjects with average blood flow no change, subjects with lowest resting blood flow slight increase after treatment. | Conclusion authors: mean decrease of skin blood flow with ginkgo use. The data suggest that EGb761 exerts dilatory or constrictive effects on blood vessels probably according to the physiological/pathological condition. | |||
| Effects of GB on skin blood flow in healthy humans may be either inhibitory or enhancing which may be related to individual metabolism; healthy subjects under normal conditions are functioning close to optimum conditions, so less or not influenced by improvement. | ||||||
| Santos et al. (25) | SPECT | SPECT: significant differences between the groups in medial-temporal area, area one basal ganglia, area two basal ganglia; sign increase of cerebral perfusion in left hemisphere areas. | Conclusion authors: significant reduction in blood viscosity and increased cerebral perfusion in several areas. Appears to be effective in the treatment of cognitive deficits in older people. | |||
| Blood viscosity determined with a rotational viscosimeter neuropsychological assessment (before and at 8 months) | Blood viscosity baseline 8 months placebo 4.1±0.8; 4.8±0.7 p<0.0001 ginkgo 4.6±0.6 3.6±0.6 p<0.0001 sign difference between the groups, p<0.0001 | |||||
| Mehlsen et al. (81) | Measurements of systemic blood pressure and forearm hemodynamics: at time of inclusion, 3, 6, 9, 12 weeks. Forearm blood flow measured by venous occlusion technique; forearm venous capacity: single measurement after venous occlusion | Forearm blood flow: GB treatment vs. placebo 3 weeks: 3.2 ml vs. 2.2 ml p<0.05 6 weeks: 3.3 ml vs. 2.8 ml p<0.05 forearm venous capacity: GB treatment vs. placebo 3 weeks: 1.2 ml vs. 0.8 ml p<0.05 6 weeks: 1 ml vs. 0.8 ml n.s. | Conclusion authors: GB extract is able to dilate forearm blood vessels causing increments in regional blood flow without changing blood pressure levels in healthy subjects. Our study has confirmed the claimed vasodilating effect of GB extract on peripheral vessels preferentially on the arterial/arteriolar level. | |||
| Comment: No difference made between subjects with high, average, low resting blood flow, Boelsma et al. (27) have shown that this could influence the effect. | ||||||
| Memory improvement: studies in healthy volunteers: insufficient evidence | ||||||
| Burns et al. (41) [Included in review Canter] | Study 2: test performed pre- and post-intervention (12 weeks) cognitive abilities testing
|
Study 2: withdrawal of 21 participants. | Conclusion authors: positive results limited to a single cognitive measure, for the older participants only. | |||
| Digit symbol, small effect size d=0.17, p<0.10, enhanced performance in ginkgo group. | Study 2 only males, because ethics committee didn't approve inclusion of females at child-bearing age in absence of any evidence of effects during pregnancy. | |||||
| No stat sign effects of ginkgo enhancement. | No studies that are directly comparable in healthy young adults, others focused on acute effects of higher doses, or short term interventions. | |||||
| Sample sizes were adequate for detecting medium-sized differential improvement of about half a standard deviation. | ||||||
| Elsabagh et al. (83) [Included in review Canter] | Exp 1: subjects tested after 4 h | Exp 1: significantly improved performance on tests of sustained attention (PASAT) and PRM, no effects on SRM, SWM, IDED, SoC. | Conclusion authors: in line with literature, acute administration improved performance in tests of attention and memory; however, after 6 weeks no effects in young, healthy participants, suggesting that tolerance develops. | |||
| Exp 2: subjects tested at baseline and 6 weeks | Exp 2: no sign effects on mood or any of the cognitive test | |||||
| National Adult Reading Test-Revised (NART-R), Hospital Anxiety and Depression Scale (HAD), Intra Dimensional/Extra Dimensional set shifting task (IDED), Stockings of Cambridge (SoC), Spatial working memory (SWM), pattern recognition memory (PRM), spatial recognition memory (SRM), word recall, picture recall, paced auditory serial addition task (PASAT) | Comment: PASATdifference at baseline between groups in Exp 2 is similar to the effect found in exp 1!! | |||||
| Persson et al. (84) | Eight memory tasks: SPTB free recall of sentences encoded by enactment; VTB free recall of sentences encoded by verbal rehearsal; FLUA verbal fluency, FLUPB verbal fluency; SRB word comprehension; FACRN recognition of faces, CRSPT cued recall of sentences encoded by enactment; CRVT cued recall of words encoded by verbal rehearsal | No significant differences between ginkgo group and control group 1 or control group 2. | Conclusion authors: regular use of Ginkgo biloba during a long period of time does not enhance memory performance in healthy participants with intact cognitive functions. | |||
| Significant effect in the cued recall test of sentences for control group 2 compared to ginkgo group, in favor of control group! | No well-controlled studies found supporting the claims for long-term effects on memory. | |||||
| No explanation for this result. | Comment: unknown dose and frequency of use ginkgo. Authors assume that recommendations are followed. | |||||
| Kennedy et al. (85) | Participants assessed 4 h after consuming treatment: EEG recording | Significant decreases in theta and beta wavebands, predominantly in frontal scalp areas; ginkgo not associated with modulation of evoked potentials. | Conclusion authors: study confirms that single dose of Ginkgo biloba exert effects on cerebral bioelectrical activity in healthy, young volunteers. | |||
| Hartley et al. (86) | Cognitive testing at baseline and day 7.
|
Episodic memory: ginkgo group sign better in some, but not all parameters | Conclusion authors: 1 week of ginkgo treatment improved performance in three of the cognitive tasks. The benefits of ginkgo on memory and frontal lobe function are modest. | |||
| Frontal lobe function: ginkgo group sign better, but not in test of planning. | Few ginkgo effect, at marginal levels of significance. | |||||
| PASAT: ginkgo group sign better | ||||||
| No differences in mood ratings | ||||||
| Stough et al. (88) [Included in review Canter] | Well-validated neuropsychological tests at baseline and 30 days:
|
Significant changes of EGb761 compared to placebo for:
|
Conclusion authors: EGb761 treatment improves memory processes, particularly working memory and memory consolidation. This improvement was clearly evident to participants throughout the trial, they subjectively noticed it. | |||
| Further research is urgently required to substantiate these finding in healthy participants. | ||||||
| Moulton et al. (89) |
|
No significant differences on any tests between ginkgo en placebo, except for Sternberg Memory Scanning Test. | Conclusion authors: largely ineffective in enhancing memory | |||
| Comment: no baseline measurements, in order to avoid practice effects; comparability of the two groups assumed | ||||||
| Kennedy et al. (39) [Included in review Canter] | CDR computerised assessment battery prior to dosing and at 1, 2.5, 4 and 6 h after: word presentation, immediate word recall, picture presentation, simple reaction time, digit vigilance task, choice reaction time, spatial working memory, numeric working memory, word recall, delayed word recognition, delayed picture recognition, speed of attention, accuracy of attention, quality of memory, speed of memory. | Dose-dependent improvement of the speed of attention-factor at 2.5 and 6 h: sign improvement for 240 and 360 mg. | Conclusion authors: acute administration of Ginkgo biloba (240 and 360 mg) is capable of producing a sustained improvement in attention in healthy young volunteers. | |||
| Quality of memory: convincing pattern, performance sign enhanced for dose 120 mg at 1 and 4 h; 240 mg: same trend toward sign. | Comment: improvement was not replicated in similar study in the same population Kennedy (40) | |||||
| Also, a number of time- and dose-specific changes (both positive and negative) in performance of the other factors. | ||||||
| Rigney et al. (90) [Included in review Canter] | Test battery conducted pre-dose and hourly. | Sternberg: reaction times GBE 120 mg and 300 mg sign. faster than placebo on both days; most evident for 120 mg: mean decrease in reaction time of 69 ms on day 1, 73.8 ms on day 2; more pronounced in older age group 50–59 years: day 1 decrease of 165.6 ms, day 2 decrease of 172.2 ms. | Conclusion authors: effects on aspects of cognition in normal healthy volunteers are more pronounced for memory, particularly working memory, than for arousal or selective attention; 120 mg produces the most evidence effect. | |||
| Range of cognitive outcome measures: immediate word recall (central loop component of working memory); Sternberg's Short Term Memory Scanning Task (articulary loop component of working memory); stroop color task; word recall test (immediate and delayed); critical flicker fusion (CFF); choice reaction time (CRT); digit symbol substitution taks (DSST); line analog rating scales for subjective sedation (LARS); leeds sleep evaluation questionnaire (LSEQ); wrist actigraphy subjective measures of sedation and sleep | 120 mg produces most evident effects | Comment by Solomon et al. (35): only improvement found with 1 dose of ginkgo (120) in oldest group 50–59, and only in one of the multiple tests of memory administered | ||||
| Comment: subjects were trained on the experimental measures to a performance plateau to mitigate against learning effects before proceeding to the study. | ||||||
| Total of 31 volunteers, unknown number in age group 50–59 years. | ||||||
| Comment by ESCOP: the results suggested that cognition-enhanced effects of the extract are more likely to be apparent in individuals aged 50–59 years, compared to 30–50 years | ||||||
| Snitz et al. (38) | Assessments repeated every 6 months | Median follow-up 6.1 years. | Conclusion authors: GB did not result in less cognitive decline in older adults compared to placebo. | |||
| Primary outcome: incidence of all-cause dementia. | No differences between GB and placebo group in domain memory, attention, visuospatial abilities, language, executive functions, 3MSE, ADAS-Cog. | |||||
| Secondary outcomes: rate of cognitive and functional decline, incidence of cardiovascular and cerebrovascular events, mortality | ||||||
| Dodge et al. (37) | Outcome measures: mild cognitive decline (CDR = 0 to CDR = 0.5), rated by a neurologists, decline in memory function (10-word Word List Delayed Recall test); adverse events. | No differences between GB and placebo group in cognitive decline or memory function decline. After controlling for medication adherence level, lower risk of cognitive decline and lower decline in memory function. | Comment: Ginkgo did not effect cognitive function, because the study was under powered. Information as to the vehicle and content of the placebo is not provided. The participants were provided vitamin E tablets; this may have confounded any potential effect of Ginkgo biloba. There was an apparently high rate of (non-hemorrhagic) stroke among the treatment group. | |||
| Carlson et al. (36) | Six standardized cognitive function tests: SF-36 quality of life questionnaire, platelet function analyzer, monitoring of adverse events. | 87% completed study. | Conclusion authors: the data do not support the use of Ginkgo biloba supplements to improve cognitive function or quality of life in healthy adults. | |||
| Cognitive function above average at baseline. 1 of 6 cognitive tests significant better after 4 months (p=0.03) in placebo group. No significant differences in quality of life, platelet function or adverse events | ||||||
| DeKosky et al. (91) | Assessments repeated every 6 months | Ongoing trial | ||||
| Primary outcome: incidence of all-cause dementia. | ||||||
| Secondary outcomes: rate of cognitive and functional decline, incidence of cardiovascular and cerebrovascular events, mortality | ||||||
| Burns et al. (41) [Included in review Canter] | Study 1: tests performed pre- and post-intervention (12 weeks)
|
Study 1: withdrawal of 13 participants. | Conclusion authors: our result suggests that intermediate-term storage and retrieval among elderly persons can be differentially improved by taking ginkgo. | |||
| Longer-term memory, assessed by associational learning tasks showed improvement with ginkgo: | Positive results limited to a single cognitive measure, for the older participants only. | |||||
| Long-term storage and retrieval (Glr), part of Woodcock, d=0.52, p=0.04 | Sample sizes were adequate for detecting medium-sized differential improvement of about half a standard deviation. | |||||
| No stat sign difference on any other measure. | ||||||
| Cieza et al. (92) | Primary and secondary outcome measures at baseline and day 28. | Primary outcomes: self-estimated mental health and quality of life significant better in ginkgo group | Conclusion authors: no effect on memory, perception, activation/attention and temporal organization, possibly due to short time period, low reliability of performed tests and the study group (enhancement in some mental functions can be clearly shown in cognitively impaired patients, but less in healthy volunteers). | |||
| Primary outcomes: subject's judgment of own mental health, general health, Quality of Life on VAS scales | Secondary outcomes: stimulus representation: no differences information processing: no differences emotional evaluation: no differences action/reaction: in favor of ginkgo in some aspects of ART, MT activation/attention: no differences temporal mechanism: in favor of ginkgo in some TR test | Positive effect on general mental health and quality of life of elderly people after a treatment of 4 weeks. | ||||
| Secondary outcomes: stimulus representation (perception) Increment Threshold for Visual Stimuli (ITVS) information processing Digit connection test-G (DCT-G) Worl list test (WL) emotional evaluation profile of mood states (POMS) subjective intensity scale-mood (SIS-M) self-rating depression scale (SDS) action, reaction, volition and decision Finger tapping test-personal tempo (PT) Finger tapping test-speed (MT) Auditory choice reaction time (ART) activation/attention color word test (CWT) incidental learning test (ILT) subjective intensity scale-tiredness (SIS-T) temporal mechanism auditory order threshold test (AOT) temporal reproduction test (TR) sensorimotor synchronization test (SMS) | ||||||
| Mix and Crews (34) | objective, standardized neuropsychological measures at start and end: Selective Reminding Test (SRT) Wechsler Adult Intelligence Scale-III Block Design and Digit Symbol Coding Wechsler Memory Scales (WMS) subjective Follow-up Self-Report Questionnaire | More improvement on SRT tasks (2 out of 9) compared to placebo sign. greater improvement on WMS compared to placebo (but also sign. difference on baseline!!) sign. more subjects rated themselves as improved. | Conclusion authors: objective and subjective results provide evidence of the potential efficacy of EGb761 in enhancing certain neuropsychological/memory processes of cognitively intact older adults, 180 mg daily for 6 weeks. | |||
| Large-scaled clinical trials are needed to examine the efficacy of EGb761 on the neuropsychological processes of younger, cognitively intact groups. | ||||||
| Comment: No predefined primary and secondary endpoints, because of relative absence of previous clinical trials. | ||||||
| Nathan et al. (93) | Testing pre- and 90 min post-drug administration (peak plasma levels): CDR computer test numeric working memory spatial working memory picture recognition simple reaction time choice reaction time AVLT (Rey auditory verbal learning task) | No acute effects of Ginkgo biloba on cognitive functioning. | Conclusion authors: no acute nootropic effects of Ginkgo biloba in healthy older humans. | |||
| Comment by authors: no significant effects of 120 mg G. biloba in healthy older subjects, but other studies find memory enhancing effects at higher doses (600 mg) or with more chronic administration. | ||||||
| Solomon et al. (35) | Test of learning and memory: California Verbal Learning Test (CVLT), Logical Memory subscale of the Wechsler Memory Scale-Revised (WMS-R); Visual Reproduction subscale. | Analysis of the modified intent-to treat population: 88% completed study. No significant differences between treatment groups on any outcome measure. Also no difference in the evaluation. In total, 14 different measures of cognition were evaluated in the study. | Conclusion authors: ginkgo did not enhance performance on standard neuropsychological tests of learning, memory, naming and verbal fluency, or attention and concentration. | |||
| Test of attention and concentration: Digit Symbol subscale of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Stroop test, the Digit Span (WMS-R); Mental Control (WMS-R). | Seven of the measures were better in the placebo group, seven in the ginkgo group. None of the differences were statistically significant. | No measurable benefit in cognitive function in elderly adults with intact cognitive function, when taken following the manufacturer's instructions. | ||||
| Test of expressive language: Controlled Category Fluency test; Boston Naming Test + Memory Questionnaire for participant + global evaluation for spouse (Caregiver Global Impression of Change rating scale). | Comments by letters (JAMA, 2003): product is not tested, exact quantity of the active ingredients remains unknown; randomization performed by lead investigator, tests conducted by pill providers, baseline differences for several of the tests are not discussed. | |||||
| All tests (with exception of global evaluation) administered at beginning and end. | Comment in ESCOP: use of non-matching placebos (different dosage forms) criticized. | |||||
| Cockle et al. (94) | B-ADL Scale (at baseline + 4 months); self-rating ADL scale; Line Analog Ratings Scales of mood and sleep (months 1–4) | Sign differences between ginkgo and control group on all scales at each time point (1–4 months) | Conclusion authors: GBE has beneficial effects on areas of functioning that have implications for quality of life in an older population. | |||
| Comment: subjects not randomized, no placebo, subjective questionnaires, compliance not measured. | ||||||
| Trick et al. (95) | At the end of the 6 months follow-up period: Line Analog rating scale (LARS), self rating ADL scale | Sign. differences in mean overall LARS and SR-ADL score between the three treatment groups. Magnitude of improvement on all scales was related to overall duration of GBE supplementation. | Conclusion authors: Sign. differences between the groups suggests that the extract had a demonstrable effect in improving mood and the self-assessed performance of the tasks of everyday living. | |||
| Comment: no placebo used; no baseline measurements; sequel to study mentioned above; subjects selected their own treatment option. | ||||||
| Memory improvement: patient studies | ||||||
| DeKosky et al. (31) | Assessments repeated every 6 months Primary outcome: incidence of all-cause dementia. | Hazard ratio (GB compared to placebo group): all-cause dementia: 1.12 (0.94–1.33, p=0.21) | Conclusion authors: No effect of GB in reducing incidence of dementia or Alzheimer disease in elderly individuals | |||
| Secondary outcomes: rate of cognitive and functional decline, incidence of cardiovascular and cerebrovascular events, mortality | Alzheimer disease: 1.16 (0.97–1.39, p=0.11) | |||||
| van Dongen et al. (96) | Outcomes measured after 4, 8, 12, 18, 24 weeks. | Intervention period: 24 weeks, n=123; 79 ginkgo, 44 placebo Ginkgo (both doses) vs placebo, mean change of scores: SKT: + 0.4 (−0.9 − 1.7) CGI-2: +0.1 (−0.3–0.4) NAI-NAA: −0.4 (−1.9–1.2) positive small difference in favor of Ginkgo, but not statistically significant nor clinically meaningful for dementia subgroup nor AAMI subgroup. | Conclusion authors: the trial results do not support the view that ginkgo is beneficial for patients with dementia or age-associated memory impairment. | |||
| Memory and attention | Comment by authors: AAMI and beginning dementia patients used, because it is assumed that relative mild stages of cognitive decline provide for the clearest manifestations of any effect. The negative results of this trial cannot fully neutralize the positive results of previous studies. | |||||
| Syndrome Kurz Test (SKT, psychometric functioning); Clinical Global Impression of change (CGI-2, by nurse), activities of daily life Nuremberg Gerontopsychological Rating Scale for Activities of Daily Living (NAI-NAA, behavioral functioning) | ||||||
| van Dongen et al. (97) [Included in review Birks] | Assessment of objective measures of cognitive performance, after 12 and 24 weeks: neuropsychological testing trail-making speed digit memory span verbal learning clinical assessment presence and severity of geriatric symptoms (SCAG), depressive mood (GDS), self-perceived health and memory status behavioral assessment self-reported level of instrumental daily life activities | Intention-to-treat analysis: no beneficial effects on neuropsychological, psychopathological, or behavioral outcomes for ginkgo group compared to placebo at t=24 weeks. | Conclusion authors: ginkgo is not effective as a treatment for older people with mild to moderate dementia or age associated memory impairment. | |||
| At t=12 weeks: 2 ginkgo groups (high-and low-dose) combined performed better at self-reported activities of daily life, but worse at self-perceived health status, compared to placebo. | Comment: External validity of the study questioned, all kinds of memory loss were included, heterogeneous population. | |||||
| Le Bars et al. (29) [Included in meta-analysis Birks and in meta-analysis Oken] | Primary outcome measures at baseline, 12, 26, and 52 weeks. Cognitive impairment by Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS–Cog) daily living and social behavior by Geriatric Evaluation by Relative's Rating Instrument (GERRI) general psychopathology by Clinical Global Impression of Change (CGIC) | Intent to treat analysis, EGb761 compared to placebo: ADAS-Cog 1.4 points better, p=0.04 improvement of at least 4-point: 27% EGb group compared to 14% placebo-group, p=0.005 GERRI score 0.14 points better, p=0.004 improvement 37% EGb group compared to 23% placebo-group, p=0.003 CGIC no significant difference | Conclusion authors: EGb761 is capable of stabilizing and improving the cognitive performance and the social functioning of demented patients for 6 months to 1-year. | |||
| Comment: only 137 patients completed the trial: 78 EGb group, 59 placebo-group. comment by van Dongen et al. (96): Modest improvement of the cognitive performance and the social functioning of the demented patients involved. No objective measures of cognitive performance, cognitive impairment measured. | ||||||