Ginkgo biloba and Alzheimer's dementia

Alzheimer's disease is the most common cause of dementia at any age level. Its cause is unknown and is assumed to be heterogenous. Treatment is largely confined to treatment of concurrent illnesses and ailments that contribute to the patient's confusion. In the overwhelming majority of patients, the dementia continues and becomes progressively worse.

Results from randomized, placebo-controlled, double-blind clinical trials are beginning to demonstrate that supplementation with ginkgo biloba extracts can have an ameliorative effect in patients suffering from mild to moderate dementia of the Alzheimer type. The effects seem to be noticeable in both the cognitive and the affective domain.

Three double-blind clinical trials of ginkgo biloba supplementation merit special attention.

PL LeBars et al conducted a 52-week, randomized double-blind, placebo-controlled, parallel-group, multi-center study. The patients were mildly to severely demented outpatients with Alzheimer's disease or multi-infarct dementia, without other significant medical conditions. They were assigned randomly to treatment with a ginkgo biloba extract (3 x 40 mg/daily) or placebo. Safety, compliance, and drug dispensation were monitored every 3 months with complete outcome evaluation at 12, 26, and 52 weeks.

LeBars and his team of researchers concluded that the supplementation with ginkgo biloba "was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year." The changes induced by the ginkgo biloba extract were, admittedly, modest but could be objectively measured and, moreover, "were of sufficient magnitude to be recognized by the caregivers." [4]

B. Hofferberth has also reported on the efficacy of ginkgo biloba extract in patients with senile dementia of the Alzheimer type, again as demonstrated in a double-blind, placebo-controlled study of forty patients who had been received either 80 mg ginkgo biloba extract or matching placebo three times a day for three months and assessed using a test battery at baseline and at 1, 2 and 3 months.

Memory and attention in the active treatment group improved significantly after one month. Similar improvement was recorded in tests of the actively treated patients' psychopathology, psychomotor performance and neurophysiology. Moreover, the ginkgo biloba extract in this dosage was seen to be well tolerated; no adverse drug reactions were recorded during the trial [2].

S Kanowski et al tested the efficacy of ginkgo biloba extract in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia in a randomized, double-blind, placebo-controlled, multi-center study. The patients in the study received either a daily oral dose of 240 mg ginkgo biloba extract or placebo for a period of four weeks.

Data from the 156 patients who completed the study in accordance with the study protocol showed statistically significant differences between the treatment and placebo groups well tolerated. The ginkgo biloba extract was also well tolerated [3].

A fourth placebo-controlled, double-blind study of the efficacy of ginkgo biloba extract in Alzheimer's patients differed from the above studies in that the active treatment and the placebo were administered intravenously via a drip four days a week for four weeks rather than in tablet form.

In this fourth study, the ginkgo biloba therapy was seen to be significantly better (at the p < 0.05 level) than placebo. Researchers were able to document clinical improvement in both the cognitive and the behavioural domains of the moderately afflicted patients who also demonstrated an "increased ability to cope with the demands of daily living." [1]

These four methodologically sound studies show a potential for Ginkgo biloba in the prevention and treatment of mild to moderate Alzheimer's. None of the studies found serious side effects in connection with Ginkgo biloba treatment. There is no indication, however, that Ginkgo biloba will be a "cure-all" for Alzheimer patients, and further studies are needed to corroborate the effects seen and to establish optimal long-term dosages.

References:

Haase J; Halama P; Horr R:
Wirksamkeit kurzdauernder Infusionsbehandlungen mit Ginkgo- biloba-Spezialextrakt EGb 761 bei Demenz vom vaskularen und Alzheimer-Typ.
Z Gerontol Geriatr: 29:4:302-9 (1996)
In a placebo-controlled, randomized, double-blind clinical trial, 40 patients with a mean age of 68 (+/- 12.5) years suffering from moderate dementia (Alzheimer, vascular, or mixed type) according to DSM-III-R criteria were included. Severity of the disease had to correspond to stages 4 or 5 of Reisberg's Global Deterioration Scale. Infusions of either EGb 761 or placebo were administered 4 days per week for 4 weeks. Primary outcome measure was the activities of daily living as assessed by the Nurnberger-Alters- Beobachtungsskala (NAB). The Clinical Global Impressions of change (CGI, item 2) and the actual intelligence as assessed by
the Kurztest fur Allgemeine Intelligenz (KAI) were further target variables. No relevant group differences could be detected at baseline. After therapy, patients of the active substance group scored significantly better (p < 0.05) on each outcome measure than those who received placebo. Using a sequential testing procedure, a global significance level of p < 0.05 could be assured. Superiority of EGb 761 therapy was also found with respect to a self- rating scale for instrumental activities of daily living (Nurnberger-Alters-Alltagsaktivitatenskala), the improvement of the most prominent symptom of illness, and the decrease of depression. Thus clinical efficacy of EGb 761 could be shown on three planes of assessment: the behavioral, the psychopathologic and the psychometric plane. It could be confirmed that, in patients with moderate dementia, short- term intravenous infusion therapy with EGb 761 results in an improvement of psychopathology and cognitive performance, which is reflected in an increased ability to cope with the demands of daily living.

Hofferberth B:
The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type: a double-blind, placebo-controlled study:
Human Psychopharmacology: 9:215-22 (1994)
Forty patients diagnosed as suffering from senile dementia of the Alzheimer type received either 80 mg Ginkgo biloba special extract (GBE) or matching placebo t.i.d. for three months in a randomized, double blind study of the efficacy and tolerance of GBE. The patients were assessed using a test battery at baseline and at 1, 2 and 3 months. The test battery included the SKT (a brief test of cognitive function, memory and attention), the Sandoz Clinical Assessment Geriatric Scale, choice reaction time, saccadic eye movements and EEG. Memory and attention, as measured by the SKT, improved significantly in the active treatment group after one month, as did psychopathology, psychomotor performance, functional dynamics and neurophysiology as measured by the above tests. The drug was well tolerated and no adverse drug reactions were recorded during the trial.

Kanowski S; Herrmann WM; Stephan K; Wierich W; Horr R:
Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia.
Pharmacopsychiatry: 29:2:47-56 (1996)
The efficacy of the ginkgo biloba special extract EGb 761 in outpatients with presenile and senile primary degenerative dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) according to DSM-III-R was investigated in a prospective, randomized, double-blind, placebo-controlled, multi-center study. After a 4-week run-in period, 216 patients were included in the randomized 24-week treatment period. These received either a daily oral dose of 240 mg EGb 761 or placebo. In accordance with the recommended multi-dimensional evaluation approach, three primary variables were chosen: the Clinical Global Impressions (CGI Item 2) for psychopathological assessment, the Syndrom- Kurztest (SKT) for the assessment of the patient's attention and memory, and the Nurnberger Alters-Beobachtungsskala (NAB) for behavioral assessment of activities of daily life. Clinical efficacy was assessed by means of a responder analysis, with therapy response being defined as response in at least two of the three primary variables. The data from the 156 patients who completed the study in accordance with the study protocol were taken into account in the confirmatory analysis of valid cases. The frequency of therapy responders in the two treatment groups differed significantly in favor of EGb 761, with p < 0.005 in Fisher's Exact Test. The intent-to-treat analysis of 205 patients led to similar efficacy results. Thus, the clinical efficacy of the ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type and multi-infarct dementia was confirmed. The investigational drug was
found to be well tolerated.

LeBars PL; Katz MM; Berman N; Schatzberg AF; Itil TM; Freedman AM:
A placebo-controlled, double-blind, randomized trial of an extract of ginkgo biloba for dementia:
JAMA: 278:1327-32 (1997)
Context: EGb 761 is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior. Objective: To assess the efficacy and safety of EGb in Alzheimer disease and multi-infarct dementia. Design: A 52-week, randomized double-blind, placebo controlled, parallel-group, multicenter study. Patients: Mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions. Intervention: Patients assigned randomly to treatment with EGb (3 x 40 mg/d) or placebo. Safety, compliance, and drug dispensation were monitored every 3 months with complete outcome evaluation at 12, 26, and 52 weeks. Primary Outcome Measures: Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC).
Results:
From 309 patients included in an intent-to-treat analysis, 202 provided evaluable data for the 52-week end point analysis. In the intent-to-treat analysis, the EGb group had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with EGb achieved at least a 4-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with EGb, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. Regarding the safety profile of EGb, no significant differences compared with placebo were observed in the number of patients reporting adverse events or in the incidence and severity of these events. Conclusions: EGb was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. Although modest, the changes induced by EGb were objectively measured by the ADAS-Cog and were of sufficient magnitude to be recognized by the caregivers in the GERRI.

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