Ginkgo and Memory To the Editor: Dr Solomon and colleagues1 reported that 6 weeks of treatment with Ginkgo biloba failed to improve performance on standardized neuropsychological tests of learning, memory, attention, and verbal ability in healthy elderly adults without cognitive impairment. The authors argue that clinical findings to date have not supported claims that ginkgo improves cognitive efficiency. Their study, however, is not directly comparable with prior studies, which have varied significantly in terms of trial durations, predictor and outcome measures used, and the type of cohort tested. Moreover, the authors do not mention several methodologically comparable studies,2, 3 including our 1-month trial,4 which have reported selective improvements in neuropsychological status in young adults and healthy older subjects treated with ginkgo. In addition, we believe that outcome trials should use cognitive tests that are sensitive to ginkgo's pharmacologic mode of action in the brain. It has been suggested that ginkgo's effects may be explained by its modulatory influence on the human cholinergic system.5 Furthermore, ginkgo may have remediating effects in patients with mild to moderate Alzheimer disease, a disorder putatively associated with cholinergic dysfunction.5 The selection of tests by Solomon et al and others, while validated as clinical measures of brain and behavioral function, may not be suitable to outcome studies of complementary therapies such as ginkgo, which generally produce only a mild to moderate benefit with continued use. Finally, as is often the case with pharmacologic studies in healthy participants, cognitive change may in part relate to individual differences in baseline cognitive and intellectual ability. Our study of ginkgo found that young adults categorized into a "low cognitive ability" group improved on certain tests when compared with those with a "high cognitive ability."4 We believe that further large-scale trials are needed to establish ginkgo's efficacy as a cognitive enhancer. Pradeep J. Nathan, PhD, MRACI, CChem, FCP Ben J. Harrison, BApSci (Hons) Cali Bartholomeusz, BA, BApSci (Hons) Brain Sciences Institute Swinburne University of Technology Victoria, Australia 1. Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial. JAMA. 2002;288:835-840. 2. Mix JA, Crews WD Jr. An examination of the efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults. J Altern Complement Med. 2000;6:219-229. 3. Mix JA, Crews WD Jr. A double-blind, placebo controlled, randomized trial of Ginkgo biloba extract EGb761 in a sample of cognitively intact older adults: neuropsychological findings. Hum Psychopharmacol Clin Exp. 2002;17:267-277. 4. Stough C, Clarke J, Lloyd J, Nathan PJ. Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol. 2001;4:131-134. 5. Nathan PJ. Can the cognitive enhancing effects of Ginkgo biloba be explained by its pharmacology? Med Hypotheses. 2000;55:491-493. To the Editor: I have several concerns about the study by Dr Solomon and colleagues.1 First, it may be inappropriate for the randomization to be performed by the lead investigator and not by an independent person. Second, the authors state that their placebo was "lactose gelatin capsules of similar appearance." The active pill, however, is a film-coated tablet; it is virtually inconceivable that a gelatin capsule could be sufficiently similar in shape and surface to effectively maintain double-blind conditions. Furthermore, the same persons who provided the pills to the study participants also conducted the neuropsychological evaluations, which may have further compromised the blinding. Third, the authors reported data for only 1 of the 3 trials of the Stroop test. It is noteworthy that another recent study found ginkgo to be superior to placebo in this task.2 Fourth, there were significant baseline differences for several of the tests. The authors do not discuss how they accounted for these baseline differences in their analyses. Fifth, the authors consider it unlikely that test results were limited by ceiling effects, yet this does not preclude each subject's performance being at an individual limit not allowing further improvement. Finally, the authors do not discuss recent studies in healthy subjects with outcomes favorable to ginkgo.3-5 Klaus R. Arnold, PhD Erlangen, Germany 1. Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial. JAMA. 2002;288:835-840. 2. Mix JA, Crews WD Jr. An examination of the efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults. J Altern Complement Med. 2000;6:219-229. 3. Kennedy DO, Scholey AB, Wesnes KA. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology. 2000;151:416-423. 4. Stough C, Clarke J, Lloyd J, Nathan PJ. Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol. 2001;4:131-134. 5. Mix JA, Crews WD Jr. A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb761 in a sample of cognitively intact older adults: neuropsychological findings. Hum Psychopharmacol Clin Exp. 2002;17:267-277. To the Editor: Dr Solomon and colleagues1 studied the effect of ginkgo in enhancing cognitive abilities among individuals with normal baseline function. It is unclear, however, whether these negative results apply to a population with impaired cognitive function. By contrast, Le Bars et al2 reported significant improvement among patients with either multi-infarct dementia or Alzheimer disease. For such individuals, clinicians in Europe generally use the higher dose of 240 mg/d for at least 3 months. The results of Solomon et al do not rule out a beneficial effect of this higher dosage in the subjects they tested. David Wheatley, MD, FRCPsych Richmond, England 1. Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial. JAMA. 2002;288:835-840. 2. Le Bars PL, Katz MM, Berman N, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA. 1997;278:1237-1332. Financial Disclosure: Dr Wheatley is an independent medical consultant to Lichtwer-Pharma UK Ltd. To the Editor: Dr Solomon and colleagues1 found that an over-the-counter ginkgo supplement did not enhance memory in elderly individuals after 6 weeks of supplementation at the manufacturer's recommended dose and duration. The authors acknowledged that they did not conduct an independent laboratory analysis of the product. Unfortunately, quantitative analysis of the product is proprietary company information (Anne LaRusso, product manager, and David R. Morrison, director of scientific affairs, Boehringer Ingelheim; written communication, 2002). As a result, the exact quantity of the active ingredients remains unknown. More importantly, even if the standardized quantities of active ingredients in the product were confirmed, the bioavailability and bioactivity of each ingredient are not equal.2 For example, a 6% terpene lactone concentration may contain a reproducible composition of ginkgolide A, B, C, or J, but these and other potentially active compounds (secondary metabolites3) may act synergistically or antagonistically in vivo.2 Therefore, product testing even standardized supplements might not substantially advance understanding of the bioactivity of the active ingredients from the ginkgo tree. Testing the safety and efficacy of isolated extract compounds with known or suspected biological activity would provide a more rigorous scientific inquiry and eventually provide more definitive conclusions. Samuel N. Cheuvront, PhD, RD Robert Carter III, PhD, MPH US Army Research Institute of Environmental Medicine Natick, Mass 1. Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial. JAMA. 2002;288:835-840. 2. Field BH, Vadnal R. Ginkgo biloba and memory: an overview. Nutr Neurosci. 1998;1:255-267. 3. Bedir E, Tatli II, Khan RA, et al. Biologically active secondary metabolites of Ginkgo biloba. J Agric Food Chem. 2002;50:3150-3155. To the Editor: Dr Solomon and colleagues1 state that the cognitive effect size for ginkgo in dementia is significantly smaller than that of cholinesterase inhibitors. Effect sizes for cholinesterase inhibitors in mild to moderate Alzheimer disease have tended to be larger than those seen with other classes of agents.2, 3 However, to our knowledge, there are no adequately powered published trials that have directly compared a cholinesterase inhibitor with ginkgo for dementia. Indirect comparisons of effect sizes across dementia trials must be interpreted with caution because the rate of cognitive decline varies significantly by type of dementia, baseline dementia severity, trial duration, and dose of agents being studied.2, 3 It is possible that cholinesterase inhibitors may benefit individuals with normal cognitive abilities,4, 5 and both ginkgo and cholinesterase inhibitors are being studied for their effects on dementia prevention. However, as with dementia, we know of no published direct comparison trials of a cholinesterase inhibitor with ginkgo in unimpaired elderly subjects. Finally, a lack of demonstrable effects on cognition does not necessarily mean that ginkgo has no beneficial effects on brain function. For instance, -tocopherol, a putative antioxidant like ginkgo,6 significantly slowed primary dementia-related outcomes in a 2-year trial even though it had no measurable benefit on cognition.7 P. Murali Doraiswamy, MD Departments of Psychiatry and Medicine (Geriatrics) Duke University Medical Center Durham, NC Nunzio Pomara, MD Nathan S. Kline Institute for Psychiatric Research New York University School of Medicine New York, NY 1. Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial. JAMA. 2002;288:835-840. 2. Doraiswamy PM, Doraiswamy PM, Kaiser L, Bieber F, Garmen R. The Alzheimer's Disease Assessment Scale: evaluation of psychometric properties and patterns of cognitive decline in multicenter trials of Alzheimer's disease. Alzheimer Dis Assoc Disord. 2001;15:174-183. 3. McLendon B, Chen GG, Doraiswamy PM. Current and future treatments for cognitive deficits in dementia. Curr Psychiatry Rep. 2000;2:20-23. 4. Yesavage JA, Mumenthaler MS, Taylor JL, et al. Donepezil and flight stimulator performance: effects on retention of cognitive skills. Neurology. 2002;59:123-125. 5. Davis KL, Mohs RC, Tinkleburg JR, et al. Physostigmine: improvement of long-term memory processes in normal humans. Science. 1978;201:272-274. 6. Pitchumoni S, Doraiswamy PM. Current status of anti-oxidant therapy for Alzheimer's disease. J Am Geriatr Soc. 1998;46:1566-1572. MEDLINE 7. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of seligiline, alpha-tocopherol or both as treatment for Alzheimer's disease. N Engl J Med. 1997;336:1216-1222. MEDLINE Financial Disclosure: Dr Doraiswamy has received research grants and/or honoraria from Eisai, Pfizer, Forest, Novartis, Janssen, Merck, GlaxoSmithKline, Lilly, Organon, and Wyeth-Ayerst. Dr Pomara has received research grants and/or honoraria from Eisai, Pfizer, Novartis, Janssen, Merck, and Forest. In Reply: Several of these letters suggest that we did not cite studies that provided positive findings for ginkgo. We believe that these studies do not meet the rigor of the US Food and Drug Administration (FDA) guidelines.1 These standards include randomized, double-blind, placebo-controlled studies with outcome measures that demonstrate both statistical differences on objective cognitive tests and global measures to ensure that the statistical differences have tangible effects in day-to-day activities. Both Dr Nathan et al and Dr Arnold cite the study by Mix and Crews.2 Although this study did use a randomized, double-blind, placebo-controlled design, it reported the results of 13 neuropsychological tests (or subtests) of which only 3 were statistically significant. We question whether these inconsistent results constitute a truly positive study. This study also did not include a global measure, as required for FDA studies. Arnold and Nathan et al cite other articles that they claim support the efficacy of ginkgo.3, 4 As in the case of the work by Mix and Crews,2 these articles report benefit in only a small fraction of cognitive tests and none include a global measure of clinical importance. A recent review of these and other articles concluded that there were no rigorously conducted studies that provide any evidence that ginkgo improves memory.5 Both Nathan et al and Dr Wheatley raise the issue of whether ginkgo is helpful in treating populations with impaired memory. Wheatley also suggests that higher doses may be more beneficial. Drs Cheuvront and Carter raise the issue of purity of the compound. As we stated in our article, our study was a test of the manufacturer's claim that ginkgo in the recommended dosage (120 mg/d) improved memory and related aspects of cognition in healthy adults. We made no claims regarding individuals with memory disorders or the potential effects of higher doses over longer periods of time. Well-controlled studies are currently ongoing that address each of these issues. Based on the work of Le Bars et al,6 Nathan et al and Wheatley also suggest that ginkgo may be effective in treating patients with Alzheimer disease and/or multi-infarct dementia. Although the study by Le Bars et al was a randomized, double-blind, placebo-controlled trial, the results indicated a very modest (but statistically significant) effect on objective cognitive tests that was not detectable by clinicians who were blinded to treatment condition. This trial also had an unusually large number of dropouts, making the validity questionable. Moreover, a recent large and well-controlled study in patients with mild to moderate dementia reported no "systematic or clinically significant effect of ginkgo" on any cognitive measures used.7 Arnold suggests the subjects in our study were not blinded. We recognized this possibility and indicated that this was unlikely because similar proportions of participants taking ginkgo and placebo reported that they believed they were taking ginkgo. Finally, we agree with the point raised by Drs Doraiswamy and Pomara that in the absence of head-to-head trials, it is inappropriate to make comparative statements regarding compounds. Paul R. Solomon, PhD Department of Psychology Program in Neuroscience Richard DeVeaux, PhD Department of Mathematics and Statistics Williams College Williamstown, Mass 1. Leber P. Guidelines for the Evaluation of Antidementia Drugs [first draft]. Rockville, Md: US Food and Drug Administration; 1990. 2. Mix JA, Crews WD Jr. A double-blind, placebo controlled, randomized trial of Ginkgo biloba extract EGb761 in a sample of cognitively intact older adults: neuropsychological findings. Hum Psychopharmacol Clin Exp. 2002;17:267-277. 3. Kennedy DO, Scholey AB, Wesnes KA. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology. 2000;151:416-423. 4. Stough C, Clarke J, Lloyd J, Nathan PJ. Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol. 2001;4:131-134. 5. Gold PE, Cahill L, Wenk GL. Ginkgo biloba: a cognitive enhancer? Psychol Sci Public Interest. 2002;3:2-11. 6. Le Bars PL, Katz MM, Berman N, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA. 1997;278:1327-1332. 7. van Donegan MJ, van Rossum E, Kessels A, Sielhorst H, Knipschild P. The efficacy of Ginkgo for people with dementia and age associated memory impairment. J Am Geriatr Soc. 2000;48:1183-1194. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.