R. W. McCarney, J. P. W. Warner
INTRODUCTION
Ginkgo is a herbal (or complementary or alternative) medicine classified as a dietary supple- ment in the UK and thus available for purchase without prescription. Its use amongst people with dementia is considerable, with surveys suggesting as many as 11% of individuals using Ginkgo. The therapeutic target for Ginkgo is the symptomatic improvement of cognitive functioning in dementia and a systematic review and meta-analysis of published trials has shown a modest but positive effect in achieving this. However, the more recent, better qual- ity trials have been inconsistent in their conclusions and there is a need for more research.
WHAT IS COMPLEMENTARY AND ALTERNATIVE MEDICINE?
Complementary and alternative medicine (CAM) is an umbrella term covering a large num- ber of therapies from diverse origins, often with radically different theories and modes of delivery. It is dependent on the prevailing knowledge system within a culture and the avail- ability of therapies within that culture: CAM use is essentially everything lying outside of the dominant health system within a given society and within the current epoch. As a result, definitions are relative. Ginkgo biloba is a ‘biologically based practice’, based on the defin- ition of the National Centre for Complementary and Alternative Medicine (NCCAM).
The sheer number of available therapies means guidance as to what they are and what is effective is essential. The ‘safe’ image of CAM is often not justified as side-effects and inter- actions are widely reported [1–3] – so patients should be encouraged to keep their doctors informed of CAM use. One recent survey has reported just over half actively doing this.
Furthermore, although a considerable number of healthcare professionals now offer many CAM treatments within the bounds of the National Health Service (NHS) [4, 5], a significant proportion are unregulated and sought privately; consequently advice on identifying reli- able practitioners is important.
It is important that healthcare professionals are open to the notion of and actively enquire about CAM use. As Ginkgo is available over the counter it is imperative that this attitude is adopted, as concurrent use is possible.
A HISTORY OF GINKGO BILOBA
The herbal medicine Ginkgo bilobais derived from the leaves of the tree Ginkgo bilobaL. It is scientifically classified in its own division, the Ginkgophyta, within the genus Ginkgo. The
Robert W. McCarney, MPhil, Research Associate, Department of Psychological Medicine, Imperial College, London, UK James P. W. Warner, MD, MRCPsych, Senior Lecturer/Honorary Consultant in Old Age Psychiatry, Department of Psychological Medicine, Imperial College, London, UK
©Atlas Medical Publishing Ltd 2007
German physician and botanist Englebert Kaempfer (1651–1716) gave the tree its common name after the Japanese word for it at the time, pronounced ‘Ginkyo’(meaning silver apri- cot: ‘apricot’ for the appearance of its seeds and ‘silver’ the bloom on the fruit). The Ginkgo is perhaps more commonly known in the UK as the maidenhair tree (its leaves similar in shape to Adiantum monochlamys Eat., the maidenhair fern). Other popular names include the Kew tree (after the impressive example in Kew Gardens, London); the Fossil tree; and the Temple tree.
Fossilized remains of trees from the genus Ginkgohave been dated to the Jurassic period (206–144 million years ago) [6] and possibly earlier, and Ginkgo is probably what Charles Darwin (1809–1882) had in mind when he coined the phrase ‘living fossil’! The tree was once present globally, as indicated by fossil finds up to the end of the Pilocene period (5.4–2.4 million years ago), subsequently surviving in China and Japan where its spiritual significance, as well as its ornamental, medicinal and culinary properties, ensured its cultivation. The current existence of wild specimens of Ginkgo is debated. Kaempfer re-introduced the tree to the West in the early 1700s.
The average, fully-grown Ginkgo is between 20 m and 35 m tall often with an angular crown and erratic branches. It is a deciduous tree and dioecious, with separate male and female trees. It is a gymnosperm, with seeds unprotected by fruit and with motive sperm.
Its leaf has a very distinct fan shape (cf. ‘maidenhair’) and often has one single, deep groove in the middle that produces two distinct lobes (giving rise to the name ‘biloba’). The leaf veins do not deliquesce; they are open-dichotomous, running in pairs from the base of the leaf to its edges.
Its good leaf cover, long life span and its high resistance to insects, infection and air pol- lution make it a common sight in cities. A good example can be seen on the Queen’s Lawn of Imperial College London’s South Kensington Campus. The male tree is most commonly used ornamentally as the female tree produces foul-smelling seeds. The tree has inspired artists over the centuries but of most interest to us here is its inspiration to scientists.
Exactly how long Ginkgo has been used in Traditional Chinese Medicine (TCM) is not known; some suggest more than 5000 years [7]. It is mentioned in the Chinese Materia Medica Shen Nung Pen Tsao Ching, although there does not seem to be a consensus on pre- cisely when this book was written and considering the importance of the oral tradition in TCM [8], it is likely that Ginkgo use probably existed long before written records began.
Ginkgo has many varied indications in TCM and Japanese Traditional Medicine (Kanpo), in which the seeds are more commonly but not exclusively used. In the West, its leaves are processed to produce the herbal supplement.
Christen sums up the scientific interest in Ginkgo with his term ‘ginkgology’ [9]. It has featured in publications on botany, evolution, ethnography, anthropology, mythology, chemistry, pharmacology and medicine; to name but a few. There has been an exponential rise in dedicated scientific publications from less than 50 a year up to and including 1984 to over 600 in 2001 [9]. This fascination with Ginkgo is fascinating in itself and shared by the general public (see Epidemiology): Ginkgo is one of the best selling herbal supplements in Europe and in the US [10]. But is the interest warranted?
MECHANISM OF ACTION
It has not been firmly established how the purported cognitive enhancing effect of Ginkgo may work. It is thought to be a platelet-aggregation factor antagonist and a vasodilator, and so may improve the blood flow to the brain. It is also a powerful anti-oxidant which may counteract the effect of free radicals in the brain.
A more recent hypothesis [11] is that it is a combination of this purported effect on blood flow, as a vasodilator and through its influence on platelet activating factor; its anti-oxidant properties [12]; and also through a direct effect on the cholinergic system. This effect on the
cholinergic system, neurotransmitters implicated in the dementias, is inferred from animal studies.
EPIDEMIOLOGY OF GINKGO
Kelly’s recent general population survey [13] of 8740 American adults found Ginkgo is one of the most widely used herbal medicines in the United States. In those aged 65 years or older, 4.0% of women and 2.2% of men reported weekly use, which made Ginkgo the 4th and 6th most commonly reported herbal medicine used by women and men respectively.
Over a third of responders reported using Ginkgo specifically for ‘memory’, ‘mental alert- ness’ or ‘their brain’.
Looking more specifically at use amongst people with dementia, Hogan [14] undertook a survey of CAM use in an outpatients clinic and found 10% were using CAM specifically for their cognitive problems: the most common form of CAM used was Ginkgo, although it does not state the exact number of users. This was a relatively small survey (115 individuals participated) and Ginkgo awareness, and so quite possibly use, has risen in the decade since it was conducted.
Dergal’s survey [15] investigated the potential for interactions between herbal and con- ventional medication in memory clinic attendees. Although the interesting finding of this survey is how common reported concomitant use is: 22 of 195 patients sampled (11.3%) were using Gingko, of which over a third (eight of the 22) were also using aspirin. Their sur- vey of 63 caregivers of attendees at an outpatient dementia clinic found six (9.5%) reported the use of Ginkgo for their care-recipient’s dementia.
A much larger survey of 1222 participants of an Alzheimer’s caregiver’s health project [16] found 3.4% of the care-recipients used Ginkgo alone and a further 2.7% were using donepezil and Ginkgo concomitantly.
In conclusion amongst individuals with dementia, the evidence suggests the prevalence of Ginkgo use alone or in combination with other cognitive enhancement medication is cur- rently somewhere between 6.1% and 11.3%.
EVIDENCE FOR THE USE OF GINKGO IN TREATING DEMENTIA
A recent Cochrane review [17] reported ‘promising’ evidence for Ginkgo in treating ‘cogni- tive impairment’ (one criticism of the earlier studies is that they are imprecise in their use of diagnostic criteria) and dementia. The meta-analysis suggested a modest but positive effect of Ginkgo in improving cognition and general functioning. No data relating to other out- comes, e.g. quality of life or behavioural functioning were sufficiently and consistently used to be meta-analysed. It found that Ginkgo had a good safety profile with reporting of adverse events no greater in the Ginkgo than in the placebo groups. However, the review concludes that more research of this herbal treatment needs to be done and in particular there is a need for good quality, large-scale and valid trials undertaken with a sound methodological approach, that are representative of the populations most likely to use Ginkgo. For example, the data available (and which they report) are based on completer as opposed to intention-to-treat (ITT) analyses only. Other earlier systematic reviews exist [18, 19] and support the conclusions made by the Cochrane team.
Thirty-three trials were included in the Cochrane review [17], however there was signifi- cant heterogeneity with the majority of trials being either small or of short duration. The Cochrane reviewers stated they could not rule out publication bias. The three most recent, good quality, large-scale trials, published in English language journals and included in the review, are summarized and critically appraised below.
Le Bars et al. [20] designed a trial to assess the efficacy and safety of Ginkgo extract in Alzheimer’s disease and multi-infarct dementia. It was a randomized, double-blind,
placebo-controlled, parallel-group, multicentre trial with a long follow-up of 52 weeks.
Participants received either 120 mg of the Ginkgo extract EGb761®per day or a similar placebo tablet. Of the 327 participants randomized to the trial, aged between 45 and 90 years, 251 had a diagnosis of Alzheimer’s disease. The ITT analysis included 236 of the Alzheimer’s participants. One hundred and thirty-seven (42% of those randomized) partici- pants completed the 12-month follow-up. Reported outcome measures included an assess- ment of cognitive functioning, the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) [21] their carer’s evaluation of daily living and social functioning, using the Geriatric Evaluation by Relative’s Rating Instrument (GERRI) [22] and general clinical state using the Clinical Global Impression of Change (CGIC) [23]. A treatment response was described using two cut-offs previously employed in dementia trials; two- point and a four-point difference in means between the active treatment and placebo on the ADAS-Cog. The paper reports a statistically significant between-groups difference in favour of EGb761®at 52 weeks in the ITT analysis (P!0.04), using the two-point mean difference cut-off on the ADAS-Cog. The safety of Ginkgo was reported as good, with a similar num- ber of adverse events reported in both the Ginkgo and the placebo groups.
There are a number of potential shortcomings with this study. The ITT analysis was selected as the primary analysis a posterioribecause of the large number of dropouts and their unequal distribution between the two arms. Perhaps the high rate of attrition led to the decision to use ITT and it is unusual that this was the initial choice. Although a large num- ber dropped out, it is reasonable to assume that this would have been considered previously in a 52-week dementia trial; and the numbers finishing in each group were not considerably different (78 and 59 respectively in the Ginkgo and placebo groups). Also the ITT analysis was calculated using last observation carried forward (LOCF). This is a method of imputing missing data by using the last available value for that individual so the assumption is that the condition does not worsen after this point. The treatment effect could therefore be over- estimated by using this method; however as more dropped out of the placebo group, this may still be conservative. The authors do comment that with a degenerative condition such as dementia this is not an ideal choice, however they still use this method.
Furthermore, the study employed a ‘humanitarian’ protocol. If there was a one-point change (worsening) as measured by the CGIC, the clinician could withdraw that individual from the study and treat them with Ginkgo. Although the ethics of this can be appreciated it could effectively remove progressive cases from the study and replace their missing data with their LOCF, which could further overestimate the treatment effect.
Statistical significance is defined as a two-point or four-point difference in mean ADAS- Cog score at 52 weeks. Whilst this is based on previous studies which use the ADAS-Cog, it could be argued that this does not indicate a clinicallysignificant difference: this is less than a 6% change on a 70-point scale over a year.
No attempt was made to stratify the analyses by centre: this is important as there may be centre effects which were not controlled for. Finally, the manufacturers of the extract used in the trial (Schwabe) funded the study. There is evidence to suggest that the published results of commercially and non-commercially funded research differ [24], with com- mercially funded trials more likely to report positive findings. Research sponsored by non- independent bodies should therefore be viewed with some caution.
The Cochrane review [17] states that outpatients took part in this study, however this is not clear in the original article. Assuming that they are outpatients, this limits the applic- ability of the results as this is a select group of patients, whereas the potential for Ginkgo may be as an early, primary care intervention. It also highlights the difficulty of conducting trials in dementia with a follow-up period greater than 6 months: the high and unantici- pated rate of attrition thus resulted in an analysis that was not ideal.
Van Dongen et al. [25] conducted a randomized, placebo-controlled, parallel-group, multicentre trial of EGb761®for treating dementia and age associated memory impairment
(AAMI). This was a 24-week study conducted in care homes for the elderly in The Netherlands and its three aims were: to determine the effectiveness of Ginkgo in treating cognitive decline by using randomized controlled trial (RCT) methodology; to address questions of dosage with Ginkgo by using 240 mg and 160 mg interventions; and to investi- gate whether there are persisting effects from Ginkgo by having a second randomization in the Ginkgo groups to either Ginkgo or placebo. The design was quite complex and featured two randomizations: one at baseline after a 3-week run-in period and another at 12 weeks.
The first randomization was to 160 mg Ginkgo, 240 mg Ginkgo or placebo. The second (in the Ginkgo groups) was to either continue with that dosage of Ginkgo or to switch to a placebo for the remaining 12 weeks. Outcome assessment described in this paper included measures of: cognitive functioning (the ZN-G, testing short-term memory; the WL, a verbal learning test; and the ZVT-G, a trail-making test measuring cognitive speed); psychopathol- ogy (the Sandoz Clinical Assessment–Geriatric [SCAG], a geriatric symptom rating scale; the Global Deterioration Scale (GDS), measuring depressive mood; a measure of self-perceived health status and a measure of self-perceived memory status); and activities of daily living (the self-assessment version of the NAA). Most of the tests are German in origin. Pre-defined analysis were ITT conducted by replacing missing values with a pre-defined algorithm, based mainly on the LOCF principle: however, per-protocol analyses were also conducted.
The paper reported no significant effects for any of the outcomes and no subgroup that ben- efited from Ginkgo. After 12 weeks of treatment, those taking Ginkgo seemed to perform slightly better with regard to self-reported activities of daily living (ADL) but slightly worse with regard to self-perceived health status compared with the placebo group. Gingko use was not associated with the occurrence of serious adverse events (SAEs).
This study, funded by a commercial company (Schwabe), appears on the whole well conducted and comprehensively reported. Of the 214 participants enrolled into the study, 63 (29%) were diagnosed as having dementia according to DSM-III-R criteria [26] and 151 (71%) were diagnosed with AAMI. This limits the applicability of the trial to dementia research. The number of Alzheimer’s patients (n"63) may mean analyses in this group are under-powered.
As with the Le Bars study [20] the LOCF principle of the ITT analysis is not ideal for degenerative conditions and the same criticism applies here as to that for Le Bar’s trial [22].
Finally, there is a question with regard to blinding in the trial. It is not clear in the report but it is likely that the 160 mg and 240 mg tablets are different in size and, if so, which the placebo size matches. Although medication was administered by a member of the nursing staff and outcome assessment by another individual, it was possible that the assessor could have been aware of the medication and therefore treatment allocation could have been revealed to the assessor in one of the Ginkgo groups.
The study of Kanowski et al. [27] is a randomized, double-blind, placebo-controlled, multicentre trial of the Ginkgo extract EGb761®for Alzheimer’s disease or multi-infarct dementia. After a 4-week run-in period, 216 participants were randomized to receive either 240 mg of Ginkgo daily or a placebo for 24 weeks. Outcomes were: Clinical Global Impressions (CGI) for psychopathology; Syndrom-Kurztest (SKT) (or Short Syndrome Test) for attention and memory; and the Nürnberger Alters-Beobachtungskala (NAB) for activi- ties of daily living. Using a responder analysis (response in at least two of the three primary outcomes) to determine clinical efficacy, 156 participants were included in the per-protocol analysis and showed a statistically significant difference in favour of the Ginkgo extract.
The ITT analysis also showed a statistically significant difference in favour of Ginkgo.
This study was conducted at 41 centres around three geographical locations in Germany, from a number of healthcare settings (primary and secondary care). The paper states that participants were only included if they could provide informed consent either written or orally in the presence of a witness. As the participants had mild to moderate dementia, it seems unlikely that they all would be able to provide informed consent so this could
indicate a sampling bias against individuals without the capacity to provide informed con- sent. This may be a considerable number: a recent analysis of baseline data found that 75%
of participants in a Ginkgo trial of mild to moderate dementia were unable to give informed consent. However, this study predates current guidelines [28] stating that in cases where potential participants in dementia research do not have the capacity to provide informed consent, their assent and the agreement of their legal representatives should be obtained.
Again the ITT analysis used the LOCF principle.
The other 30 studies included in the Cochrane review [19] have in general small numbers of participants, short follow-up periods, and idiosyncratic outcomes or admissions criteria.
Since the publication of the Cochrane review, one further large-scale study has been pub- lished. Schneider et al. [29] compared two doses of Ginkgo (120 mg and 240 mg daily) against placebo in Alzheimer’s patients. This study was conducted with 513 outpatients aged 60 and over with a 6-month follow-up. Recruitment was from 44 centres in the United States and the study was again funded by Schwabe. Diagnosis was made using DSM-IV [30] and NINCDS-ADRDA [31] criteria, with a scan from the year prior to enrolment consistent with the diagnosis. An MMSE [32] score between 10 and 24 inclusive and chronicity of at least 6 months formed part of the eligibility criteria, with a stipulation that each centre could not recruit more than a third of participants with an MMSE of 20 or above. Evidence of vascu- lar comorbidity excluded potential participants. The use of anti-dementia drugs (cholinesterase inhibitors or ‘cognitive-enhancing substances’) 6 weeks prior or during the study period was not allowed. Evidence of behavioural or psychological symptoms or treat- ment were also grounds for exclusion (i.e. major or clinically significant depression as meas- ured by the Hamilton rating scale for Depression (HAMD) [33] or any other current psychiatric disorder; psychotropic medication was ‘prohibited’ or allowed in the 3 months preceding randomization, apart from short-acting benzodiazepines).
The primary outcomes were change in ADAS-Cog score and Clinical Global Impression of Change with caregiver’s input (CIBIC#) [34] from baseline to 6 months. The power calculation used a 2.5 point difference in ADAS-Cog score. Safety was assessed by an assess- ment of bleeding time in a subgroup of 280 of the participants (although it is not clear whether these were randomly selected from the three groups); and an analysis of adverse events and relevant laboratory tests on the whole sample.
No significant difference was found between the groups in the planned primary ITT analysis, which used LOCF to impute the missing data (although they do state other meth- ods of imputation were be used in the sensitivity analysis, they were not reported).
However, a subgroup analysis was conducted ad hocusing participants with behavioural and psychological symptoms of dementia (BPSD) and a significant difference between Ginkgo and placebo was reported. The conclusion made in this study is that the primary analysis is inconclusive as the participants are atypical, as evidenced by the lack of decline in ADAS-Cog score amongst the placebo group.
Four SAEs were reported, one in the 120 mg Ginkgo group and three in the 240 mg Ginkgo group. The SAE in the 120 mg group was retinal haemorrhage: although they report that this is probably due to vessel malformation, hypertension and aspirin intake, this is a safety concern of Ginkgo.
There appear to be a number of inconsistencies in the reporting of the study. Although a criterion for inclusion is age 60 years and over, the demographics report an age range of 56–98 years; but more significantly, psychotropics are prohibited but their use is reported during the trial (with 3.5% taking concomitant psychotropic medication at baseline and 13.6% using any during the study).
Of note is the robustness of the diagnostic process, as a counter to the heterogeneous samples (and ‘looser’ diagnoses) common in previous Ginkgo trials. Further, the elimin- ation of the potential confounding effects from other psychoactive medication that may influ- ence cognition is also of value. However, the ad hocanalysis uses a subgroup of participants