Nervous System Effects

The pharmacological basis of the effects of GBE on brain function has been addressed in a number of studies. One study (6) showed that dietary GBE 761 (prepared by the Henri Baeufour Institute) protected striatal dopaminergic neurons of male Sprague-Dawley rats from damage caused by N-me-thyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP, which has caused Parkinsonism in young drug abusers, is thought to damage these neurons through formation of free radicals. The mechanism of GBE's protective effect was attributed to an antioxidant action, rather than to prevention of neuronal uptake of MPTP. Whether chronic GBE ingestion could prevent development of idiopathic Parkinson's disease in humans remains to be seen.

The effectiveness of GB in improving memory and cognition remains controversial, with most studies demonstrating no effect or only very modest improvement. Readers of the original papers listed below are encouraged to closely examine the reported results and conclusions in addition to the abstract, as the claims are not always justified by the results. In one study (8), 40-mg EGb 761 (Murdock, Springville, UT) tablets taken three times daily before meals was compared to placebo in a double-blind, randomized trial in patients with mild to severe Alzheimer type or multiinfarct dementia, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised and International Statistical Classification of Diseases, Tenth Revision criteria. The study lasted 52 weeks, and patients were assessed at weeks 3, 26, and 52 using the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Geriatric Evaluation by Relative's Rating Instrument (GERRI), and the Clinical Global Impression of Change (CGIC), three validated rating instruments. Thus, participants' cognitive impairment, daily living and social behavior, and general psychopathology were objectively evaluated. Modest improvement was appreciated using ADAS-Cog and GERRI, but the CGIC score did not reveal improvement compared to placebo. Adverse effects did not differ from those of placebo. The relatively large number of dropouts (only 202 of 309 patients were assessed at week 52) raises questions about the validity of the results. In addition, a metaanalysis of four double-blind, placebo-controlled studies including a total of 424 patients with Alzheimer's found a small (3%) but clinically significant improvement on the ADAS-Cog with 120-240 mg of GB administered for 3-6 months (9). A number of double-blind, placebo-controlled studies have been conducted recently to assess the effect of GB on cognition and memory, particularly in elderly subjects or those with dementia. Four of these studies have reported no beneficial effect of GB administration on tests of memory and cognitive function (10-13). Other studies have reported only modest beneficial effect of GB on some measures of memory and cognition, mostly related to measures of attention (14-18). Thus, it appears that GB administration has little benefit on improvement of cognition and memory.

Anxiolytic effects have been demonstrated in animal models. The effect of Zingicomb® (Mattern et Partner, Starnberg, Germany), a combination product containing 24% ginkgo flavonoids and 23.5% gingerols, administered orally to rats at a dose of 0.5-100 mg/kg was compared with the effects of placebo and diazepam administered intraperitoneally at a dose of 1 mg/kg on anxiety-associated behaviors (4). The rats were subjected to an elevated plus-maze consisting of enclosed and open arms. The 0.5 mg/kg dose of Zingicomb was associated with rats spending more time in the open arms and with more excursions toward the ends of the open arms as compared to placebo. At a dose of 100 mg/kg, excursions to the ends of the open arms and scanning (protruding the head over the edge of an open arm and looking around) were fewer. These results were interpreted to mean that the preparation exhibited anxiolytic effects at a dose of 0.5 mg/kg, but anxiogenic effects at 100 mg/kg. Both the herbal product at a 0.5 mg/kg dose and diazepam increased the number of entries into the open arms, but unlike diazepam, Zingicomb did not increase open-arm scanning, nor did it attenuate risk assessment (protruding the forepaws and head from an enclosed arm). These effects of the herbal preparation were attributed to blockade of 5-hydroxytryptamine3 (5-HT3; serotonin) receptors, which has been shown in previous studies to produce similar results in the elevated plus-maze. In addition, components of both ginger and GB have been shown in several animal studies to exert 5-HT3 receptor-blocking effects.

Though early reports had suggested that vertigo and tinnitus could be successfully relieved with GB treatment at doses of 16-160 mg/day for 3 months (19), this effect has not been borne out in double-blind, placebo-controlled trials. Rejali and colleagues studied the effectiveness of GB administration in 66 adult subjects with tinnitus (20). Using the Tinnitus Handicap Inventory as the primary outcome measure, these investigators found that administration of GB was of no benefit to patients with tinnitus. They also conducted a metaanalysis of five additional studies (plus theirs) and confirmed the lack of effect of GB in treating tinnitus. In a similar study of ginkgo treatment (Vertigoheel®), Issing and colleagues found that both placebo and the ginkgo preparation improved vertigo equally, suggesting no additional benefit of ginkgo treatment (21). It should be noted that this study was conducted in a randomized, placebo-controlled, double-blind fashion.

Acute mountain sickness can occur when unacclimatized individuals ascend to altitudes above 2000 meters. Chow and colleagues compared the efficacy of either acetazolamide or GB prophylaxis for preventing acute mountain sickness (22). The trial was completed by 57 subjects, with 20 receiving acetazolamide, 17 receiving GB, and 20 receiving placebo. GB had no effect on either the symptoms or incidence of acute mountain sickness. Acetazola-mide reduced the symptoms of acute mountain sickness but did not reduce the incidence. A similar lack of effect on acute mountain sickness among Himalayan trekkers taking GB was noted by Gertsch et al. (23).

Interestingly, GB treatment has been demonstrated to be effective in reversing the symptoms of sudden hearing loss. In one study of 106 patients receiving either GBE (EGb 761) or placebo and suffering from idiopathic sudden sensorineural hearing loss, the GBE treatment appeared to speed up recovery and improve the chances of complete recovery as compared to placebo (24). Similarly, Reisser and Weidauer (25) observed that GBE (EGb 761) and pentoxifylline were equally effective in reversing hearing loss and reducing tinnitus. Though the study was randomized and double blinded, no placebo control was utilized.

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