Ginkgo · 2019-04-16 · Cognition), Ginkgo biloba and Memory, Ginkgo biloba and Healthy, Ginkgo bilobaand Cognitively Intact, the authors of this paper conducted comprehensive literature

www.herbalgram.org 2005 HerbalGram 67 | 43

Introduction

In recent years, there has been increased interest in theutilization of ginkgo (Ginkgo biloba L., Ginkgoaceae)leaf standardized extract (GBE) for the treatment of

dementia and cognitive impairment. Much of this interesthas undoubtedly been related to the growing number ofresearch studies and clinical trials that have demonstratedthe potential efficacy of GBE in the treatment of suchdisorders. While a detailed, systemic review of these stud-ies is beyond the scope of this paper, a recent CochranReview1 of 33 randomized, double-blind, controlled trialsthat examined the effects of GBE on individuals withacquired cognitive impairment (including dementias)concluded that GBE was associated with “promisingevidence of improvement in cognition and function.”

Similarly, there is also a growing body of publishedresearch that has focused on the potential efficacy of GBEin enhancing the neuropsychological processes of “healthy”adults and those who are not experiencing (or withoutevidence of ) notable cognitive difficulties (i.e., cognitivelyintact individuals). Canter and Ernst2 authored a review ofthe controlled trials involving GBE’s potential effects oncognitive functioning in healthy persons in 2002; however,there appears to be an absence of more recent reviews thathave focused solely on such published studies of GBE.Thus, the purpose of this paper is to provide a comprehen-sive review of the published scientific literature (throughSeptember 2004) that has examined the efficacy of GBE(and unspecified preparations of ginkgo in one study) inhealthy and cognitively intact persons.

The studies reviewed in this paper are divided into 2categories: acute studies and short- to long-term studies.Acute studies were defined as the administration of GBE tohealthy/cognitively intact adults for 2 days or less. Short- tolong-term studies were defined as the administration ofGBE to healthy/cognitively intact adults for a minimum of5 days and up to 2 or more years. This review contains thefollowing sections: Methods, Acute Studies, Summary ofAcute Studies, Short- to Long-Term Studies, Summary ofShort- to Long-Term Studies, and Conclusions and Direc-tions for Future Research.

MethodUsing the key words Ginkgo biloba and Cognitive (or

Cognition), Ginkgo biloba and Memory, Ginkgo biloba andHealthy, Ginkgo biloba and Cognitively Intact, the authorsof this paper conducted comprehensive literature searchesin September 2004 of the following databases: PubMed(entire database through September 2004) and PsycINFO(entire database through September 2004). All articlesobtained via these searches were also reviewed for addi-tional, related articles that addressed the efficacy of ginkgoin healthy and cognitively intact persons. Published studieswere selected for inclusion in this review if they utilizedonly “healthy” and/or “cognitively intact” adult partici-pants, and if they employed one or more outcome meas-ures that assessed the efficacy of ginkgo on some aspect(s)of neuropsychological functioning. It should be noted,however, that trials which involved the administration ofGBE in combination with other agents, such as Asianginseng (Panax ginseng C. A. Meyer, Araliaceae) root

GinkgoThe Neuropsychological Efficacy of

Preparations in Healthy and Cognitively Intact Adults

by W. David Crews, Jr., PhD, David W. Harrison, PhD, Melanie L. Griffin, Katherine D. Falwell, Tara Crist, Lesley Longest, Laura Hehemann, and Stephenie T. Rey

Illustration by Christy Krames, MA, CMI

Christy Krames is a Certified Medical Illustrator living and working in Austin, Texas. She received her Master's degree in Medical Illustration in 1981 fromUT Southwestern Medical Center in Dallas. Examples of her medical and biological artwork may be seen at www.kramestudios.com.

A C O M P R E H E N S I V E R E V I E W

44 | HerbalGram 67 2005 www.herbalgram.org

extract, 3-5 or bacopa (Bacopa monnieri[L.] Pennell, Scrophulariaceae)6 were notincluded in this review due to the inabil-ity to separate the specific effects of GBEfrom the other phytomedicinal prepara-tions.

Acute StudiesA total of 7 published studies were

found which have examined the acuteneuropsychological effects of GBE inhealthy individuals. (Acute studies weredefined as the administration of GBE tohealthy/cognitively intact adults for 2days or less.) Table 1 on page 54 provides an overview of thesestudies, which are listed in chronological order. Table 2 providessummaries of the proprietary GBE preparations and Table 3provides outcome measures utilized in the investigations (see pages56 and 57, respectively).

Subhan and Hindmarch7 were among the first to investigate theacute effects of GBE in healthy volunteers. In particular, 8 healthyfemale participants received 3 different doses (i.e., 120, 240, and600 mg) of GBE [Tanakan®/Tebonin®, Dr. Willmar SchwabePharmaceuticals GmbH & Co., Karlsruhe, Germany] or a match-ing placebo via a randomized, double-blind, crossover design. Abattery of psychological tests was administered one hour after each

treatment (see Table 1 for a listing of the specific tests utilized).Among the extract doses and 4 outcome measures utilized in thestudy, participants exhibited significant improvement in theirmemory scanning abilities (a decrease in response latency on theSternberg technique) following ingestion of 600 mg of GBE, ascompared to placebo. The authors indicated that these results weresuggestive of an effect of GBE on the serial comparison stage of thereaction process on the Sternberg task.

Similarly, Hindmarch8 reported in a French journal the results ofan investigation involving 8 healthy female volunteers that appears

strikingly similar, if not identical, to theone previously co-authored by Subhanand Hindmarch.7 As noted in Table 1,the sample characteristics (i.e., size,gender-makeup, mean age and agerange), study design, duration of treat-ments/assessments, GBE compositionand doses, and outcome measuresutilized appeared identical in bothstudies. Furthermore, the results acrossthe 2 studies appeared identical, as theHindmarch8 study also indicatedsignificant improvements in aspects ofparticipants’ short-term memory

processes, as assessed via the Sternberg technique, 1 hour afteringestion of 600 mg of the GBE (Tanakan®), versus placebo. Simi-lar to the Subhan and Hindmarch7 study, no significant effects werefound for any of the other extract doses or assessment measures.

In another investigation published in a French journal, Warotand colleagues9 evaluated the acute efficacy of 600 mg of 2 GBEpreparations (Ginkgo® and Tanakan®), versus a placebo, on thepsychomotor and memory performances of 12 healthy femaleparticipants via a double-blind, placebo-controlled design (seeTable 1 for a listing of the specific tests utilized). Psychological test-ing was completed before and 1 hour after the ingestion of eachdose. Although no significant improvements were noted for theGBE treatments on any of the tests and measures utilized, ascompared to baseline, participants’ scores for image recall (picturerecall) remained relatively unchanged during the Tanakan® trial,but decreased under the placebo and Ginkgo® conditions.

Rigney, Kimber, and Hindmarch10 appeared to be among thefirst to include healthy males in an examination of the efficacy ofacute doses of a GBE [Ginkgo Special Extract LI 1370; LichtwerPharma, Berlin, Germany] on memory and psychomotor perform-ances. Specifically, their study compared 4 doses of GBE (i.e., totaldoses of 120, 150, 240, and 300 mg/day), versus placebo, for 2days via a randomized, double-blind, placebo-controlled, 5-waycross-over design in a sample of 36 asymptomatic/healthy volun-teers (i.e., 22 males, 14 females). Psychometric test batteries wereadministered across the 2 days of each treatment prior to GBEingestion and then hourly until 11 hours post-dosing (see Table 1for a listing of the specific tests utilized). Findings indicated thaton the Sternberg short-term memory scanning task, participantsexhibited significantly faster reaction times for both 120 mg and300 mg of GBE, as compared to placebo, on each of the 2 days ofthe study. Participants receiving 240 mg of GBE, versus placebo,displayed significantly faster performances on the second day ofthe trial. It was noted that this enhancing effect was most evidentfor those taking the 120 mg dose of GBE and most pronouncedfor the oldest age group (i.e., 50 to 59 years). Although no signif-icant treatment effects were observed on immediate and delayedword recall tasks, both 120 mg and 240 mg increased the overallnumber of words recalled during the immediate recall task, with amore pronounced increase noted for the 120 mg dose. On theCritical Flicker Fusion (CFF) task, although an overall treatmenteffect was significant, none of the GBE doses produced effects thatdiffered significantly from placebo. Participants who received 120mg of GBE, however, exhibited higher CFF thresholds, as

Ginkgo Ginkgo biloba. Photo © 2005 stevenfoster.com

The purpose of this paper is to provide a comprehensive

review of the publishedscientific literature that

has examined theneuropsychological efficacy

of GBE in healthy andcognitively intact persons.


compared to all other treatments and placebo, and their perform-ances were significantly higher than those who ingested 240 mg ofthe extract. No other significant treatment effects were observedfor any of the remaining outcome measures. Overall, Rigney andassociates10 indicated that their results were very similar to those ofSubhan and Hindmarch7 which also found improved perform-ances on the Sternberg memory scanning task, but no significantresults on the CFF, choice reaction time, or subject ratings ofarousal measures. It was noted, however, that as compared to theSubhan and Hindmarch7 study, the Rigney and associates10 find-ings suggested that (1) a much lower dose of GBE (i.e., 120 mgversus 600 mg) resulted in the most cognitive enhancement (e.g.,working memory), (2) the effects of GBE may be dose dependent,but not necessarily in a linear dose-related fashion, and (3) suchenhancing effects were more likely to be displayed by individuals50 to 59 years old.

The dose-dependent cognitive effects of acute GBE administra-tion in 20 healthy young adults were also examined by Kennedyand colleagues11 via a double-blind, placebo-controlled, multi-dose, balanced, crossover design. Participants were administered 3different doses (i.e., 120, 240, and 360 mg) of a standardizedGBE [GK501; Pharmaton, SA, Lugano, Switzerland] or a match-ing placebo. The cognitive performances of the participants wereevaluated via a tailored version of the Cognitive Drug Research(CDR) computerized assessment battery immediately prior to,and again at 1, 2.5, 4, and 6 hours after, each dose. Four cogni-tive performance factors, derived via factor analysis of the CDR

battery’s subtests (i.e., speed of attention, accuracy of attention,quality of memory, and speed of memory factors), were utilized asthe primary outcome measures. The findings indicated significantimprovements on the speed of attention factor for the 2 highestGBE doses (i.e., 240 and 360 mg) at time points 2.5, 4, and 6hours post-dose. For the quality of memory factor, significantlyenhanced performances were exhibited by participants after inges-tion of 120 mg of GBE at both 1 and 4 hours post-dosing, ascompared to placebo. A similar positive trend was also noted forthe 240 mg dose of GBE for the same post-dosing time points.For the speed of memory factor, significantly enhanced speed wasdemonstrated on memory tasks after the administration of 360mg of GBE at 2.5 hours post-dose, with positive trends also notedfor the 120 mg and 360 mg at 6 hours post-dosing. Alternatively,a significant reduction in speed of memory was noted for the 240mg dose of GBE, versus placebo, at 4 hours post-dosing and thisdose was noted to “under-perform” the other doses on the speedof memory factor at all post-dose time points. Similarly, on theaccuracy of attention factor, a significant decrease in accuracy wasnoted for the 240 mg dose of GBE at 1 hour post-dose. No signif-icant treatment effects were found on 3 mood factors (i.e., alert-ness, contentedness, or calmness) derived from the Bond-Ladervisual analogue scales. Taken together, the authors noted that (1)cognitive enhancement following administration of GBE wasmost evident in participants’ increased speed of performance ontasks assessing attention and (2) such effects appeared both doseand time dependent (i.e., significant improvement seen only at



the 2 highest doses and at the 3later time points). A differentpattern of effects was also notedon the quality of memory factorwith significant enhancementobserved for the lowest dose(i.e., 120 mg) at 1 and 4 hourspost-dose, with similar trendsapparent for 240 mg at the sametime points.

Similarly, Scholey andKennedy12 documented thefindings of 3 studies that exam-ined the acute, dose-dependentcognitive effects of GBE[GK501; Pharmaton, SA,Lugano, Switzerland], Ginsengextract [G115; aka Ginsana®,Pharmaton, SA, Lugano,Switzerland], and a combinationof the 2 extracts via double-blind, placebo-controlled, balanced,crossover designs. For the purposes of this paper, only the studyinvolving doses of GBE will be reviewed. The GBE study involveda total of 20 healthy young volunteers who were each administered3 different doses (120, 240, and 360 mg) of GBE or a placebo onseparate days. The participants completed 2 computerized serialsubtraction tasks (i.e., Serial Threes and Serial Sevens) at eachpretreatment baseline and again after 1, 2.5, 4, and 6 hours post-dose. Findings indicated that all 3 doses of the GBE, as comparedto placebo, resulted in significant increases in the number of SerialThrees subtractions at the 4-hour post-dosing testing session. Asignificant increase in Serial Threes subtractions was also observed6 hours after ingestion of the 240 mg dose of GBE. In contrast, 4hours after the administration of 120 mg of the GBE, significantlymore subtraction errors were noted on the Serial Threes task. Forthe Serial Sevens task, while no significant differences were notedin the total number of subtractions for any of the doses of GBE,all doses resulted in significantly fewer errors at 2.5 hours post-dose, as compared to placebo.

When literature searches were conducted for the present paper,the most recent study of the acute cognitive effects of GBE wasconducted by Nathan and associates,13 which involved an exami-nation of the phytomedicinal product on the memory function-ing of 11 healthy “older” adults. In particular, participants wereadministered 120 mg of GBE [Ginkgoforte™; Blackmore’s Ltd.,Balgowlah, NSW, Australia] or a placebo during separate sessionsvia a repeated measures, double-blind, placebo-controlled design.During each treatment condition, participants were administereda series of memory tests from the Cognitive Drug Researchcomputerized assessment system and the Rey Auditory VerbalLearning test at pretreatment baseline and again at 90 minutespost-dose. No significant acute effects of 120 mg of GBE werefound for any of the memory tests utilized in the study. Theauthors indicated that these findings were consistent with those ofSubhan and Hindmarch7 and Kennedy and colleagues,11 whichalso demonstrated no acute effects of GBE on memory at a doseof 120 mg.

Summary of Acute StudiesAs of September 2004, there

have been a total of 7 publishedstudies that have examined theacute neuropsychological effectsof GBE in healthy adults. (Acutestudies were defined as theadministration of GBE tohealthy/cognitively intact adultsfor 2 days or less.) Two of thesestudies (one published in English7

and one in French8), however,appeared very similar, if not iden-tical, particularly in terms of suchfeatures as their sample character-istics, methodology/design, treat-ments/doses, and results.

The sample sizes used in theacute studies were relatively smalland ranged from a low of 87,8 to a

high of 3610 participants. All but one10 of these reports examinedmore females than males, including 3 studies7,8,10 that involvedonly females. With the exception of 2 studies where the mean ageof participants was 43.610 and 58.4613 years, the remaining acutestudies of GBE utilized participants whose mean ages fell between19.9 and 32 years. While the majority of the acute studies involvedyounger, versus older, participants who reportedly were “healthy,”only one of these investigations appeared to include any objectivemeasures to access levels of cognitive intactness.

All of the acute studies indicated that they employed double-blind, placebo-controlled, crossover/repeated measures designswith the duration of their GBE treatments/assessments rangingfrom 1 hour per dose7,8,9 to 2 days.10 In addition to a placebo, treat-ments involved the administration of various GBE preparationsthat were identified as follows:

• Tanakan®/Tebonin®, • EGb 761, • Ginkgo®, • Ginkgo Special Extract LI 1370, • Ginkgo biloba extract GK501, and • GinkgoforteTM.

Five of the acute studies7,8,10,11,12 evaluated multiple doses ofGBE formulas, while 2 investigations9,13 utilized only a single dose.The doses of GBE used in these studies ranged from a low of 120mg to a high of 600 mg.

A diversity of outcome measures, assessing a wide range ofneuropsychological processes, were administered across the acutestudies ranging from measures of reaction time and line analoguerating scales, to computerized assessment batteries from whichfactor-derived scores were obtained. Among the most commonmeasures that were administered in these studies were the CriticalFlicker Fusion, Choice Reaction Time, Line/Visual AnalogueRating Scales, and Sternberg Memory tasks, as well as tests fromthe Cognitive Drug Research computerized assessment battery.

Significant, positive neuropsychological effects of a GBE werefound in 5 out of 7 acute studies (4 of 6 if the Subhan and Hind-march7 and Hindmarch8 studies represent the same investigation).In particular, higher doses (i.e., 240 and 360 mg) of an extract

The majority of studies that haveexamined the acute effects of GBE

administration in healthy adultshave found the herbal compound tobe efficacious in enhancing certain

aspects of participants’neuropsychological functioning,

particularly performances on tasksassessing attention, memory, and

speed of processing.


were shown to result in improvements on a factor-derived, speedof attention factor at 2.5, 4, and 6 hours post-dose and to signifi-cantly enhance a quality of memory factor after the ingestion of120 mg of the product at 1 and 4 hours post-dose.11 Furthermore,while significant enhancement was found for 360 mg of the GBEat 2.5 hours post-dose for a speed of memory factor, a significantreduction in this factor was observed for the 240 mg dose 4 hoursafter ingestion.11 A significant decrease in an accuracy of attentionfactor was also noted for a 240 mg dose of GBE 1 hour afteradministration.11 The authors acknowledged that these contrastingfindings were not readily interpretable.

Additional dose and time-dependent effects were found for aGBE in a study that utilized 2 computerized serial subtractiontasks.12 Specifically, single doses of 120, 240, and 360 mg of GBEwere noted to significantly increase the number of Serial Threessubtractions (described as an attentional/concentration task with aprocedural learning element) 4 hours post dose, while a 240 mgdose increased subtractions 6 hours after ingestion. In contrast,significantly more errors were made on the Serial Threes taskfollowing 120 mg of the extract at 4 hours post dose. While nosignificant differences were observed in the number of subtractionsfor any dose on a Serial Sevens task (reportedly involved in centralexecutive resources), significantly fewer errors were noted after 2.5hours for all doses. Although the precise interpretation of theseobserved effects remain somewhat difficult, the authors12 notedthat the results appeared broadly consistent with an improved“speed of attention” factor following GBE administration that wasfound in their previous study.11

The acute, positive effects of a GBE were also demonstrated inaspects of participants’ high speed scanning and retrieval fromshort-term memory processes (as assessed via the SternbergMemory Scanning task) after a single dose of 600 mg.7,8 Similar,positive Sternberg results were exhibited across a 2-day period for120 and 300 mg/day doses of a GBE and for a 240 mg/day doseof the extract on day 2.10 In contrast, no significant effects werefound on the Sternberg task 1 hour after the ingestion of single120 and 240 mg doses of GBE.7,8

Two other acute studies, which administered either a 120 mg13

or 600 mg9 dose of a GBE, failed to find significant positive effectson the neuropsychological processes of healthy adults. In one ofthese studies,9 however, while no significant improvements werefound for the GBE treatment on any of the tests and measuresutilized, as compared to baseline, participants’ image free recallscores remain relatively unchanged during a trial of Tanakan®, butdecreased under the placebo and Ginkgo® conditions.

A diversity of factors may have contributed to the generalabsence of positive results in these 2 investigations. Specifically,upon comparison of the Warot et al9 study to the one conductedby Subhan and Hindmarch7 (and Hindmarch8), which also admin-istered a 600 mg dose of a GBE, the mean age of participants inthe Warot trial9 was almost a decade younger than the mean age ofparticipants in the Subhan and Hindmarch study.7 This factor,combined with the limited sample size and assessment duration(i.e., 1 hour, which is shorter than the extract’s reported peak activ-ity level(s) of 1.5 to 4 hours; see American Herbal Pharmacopoeia,200314) may have negatively impacted the results of Warot’s9 study.Furthermore, Nathan and colleagues13 utilized a small sample ofparticipants whose mean age (x = 58.46 years) was the highest of

all the acute studies. They also limited their assessment duration to90 minutes and administered a lower (i.e., 120 mg), versus higher,dose of a GBE which, when these factors were combined, mayhave interacted synergistically to contribute to the study’s nullfindings.

Taken together, the majority of studies that have examined theacute effects of GBE administration in healthy adults have foundthe herbal compound to be efficacious in enhancing certain aspectsof participants’ neuropsychological functioning, particularlyperformances on tasks assessing attention, memory, and speed ofprocessing. While some of these studies have found the effects tobe dose and time-dependent, though not necessarily in a linearfashion, inconsistencies remain among the acute studies that havebeen conducted to date. There appears to be a trend, however,among the limited number of acute studies that have includeddifferent doses of GBE for positive neuropsychological effects to bemore closely associated with higher doses of GBE (i.e., > 240 mg)and/or longer treatment/assessment durations (i.e., > 2.5 hours).(The limited number of acute studies that included different dosesof GBE is n = 4; i.e., if the Subhan & Hindmarch7 and Hind-march8 studies represent the same data set.)

Short- to Long-Term StudiesA total of 9 published studies were found which have examined

the short- to long-term neuropsychological effects of GBE/ginkgoin healthy/cognitively intact individuals. (Short- to long-termstudies were defined as the administration of GBE tohealthy/cognitively intact adults for a minimum of 5 days and upto 2 or more years.) Table 4 on page 59 provides an overview ofthese studies, which are listed in chronological order. Table 2provides summaries of the proprietary GBE preparations and Table3 provides outcome measures utilized in the investigations (seepages 56 and 57, respectively).

Mix & Crews15 conducted the first known double-blind, fixed-dose, placebo-controlled, parallel-group design study that exam-ined the short-term (6 weeks) efficacy of GBE (EGb 761®) on theneuropsychological functioning of 48 generally healthy, cogni-tively intact, older adults (i.e., 55 to 86 years of age). Participantsin this study were randomly assigned to receive 180 mg/day of

Chemical structure of bilobalide. Image ©2005 ChromaDex


GBE or a matching placebo, and they completed a series ofneuropsychological tests and measures both at pretreatment base-line and again after 6 weeks of treatment (i.e., just prior to thetermination of the regimen. (See Table 4 for a listing of the specifictests utilized.) The findings from this trial revealed that partici-pants who received 180 mg/day of GBE (EGb 761®) for 6 weeksexhibited significantly more improvement on a task assessing speedof processing abilities (i.e., Stroop Color and Word Test Color-naming task) by the end of treatment, as compared to placebocontrols. Nonsignificant trends favoring improved performancesin the GBE group were also demonstrated on 3 of the 4 remainingtasks that involved a timed, speed of processing component.Furthermore, no significant differences were found between theGBE and placebo groups’ change in performance scores on any of

the verbal or nonverbal/visual memory measures included in thestudy. However, a nonsignificant trend, favoring the GBE group,was evident by treatment end on the Wechsler Memory Scale-Revised Visual Reproduction I subtest. Additionally, significantlymore participants in the GBE group rated (via a self-report ques-tionnaire) their overall abilities to remember by treatment end as“improved,” as compared to placebo controls.

Similarly, Stough and associates16 investigated the neuropsycho-logical changes in 50 healthy participants over a 30-day trial of 120mg/day of GBE [Blackmore’s Ginkgo Biloba Forte, Blackmore’sLtd., Balgowlah, NSW, Australia] via a randomized, double-blind,placebo-controlled design. Participants were administered batteriesof neuropsychological tests designed to assess a diversity of cogni-tive variables both at pretreatment baseline and again following the30-day treatment phase (see Table 4 on page 59 for a listing of thespecific tests utilized). The results indicated that the group receiv-ing the GBE exhibited significant improvements in speed of infor-mation processing (i.e., Working Memory Speed), workingmemory (i.e., Digit Span Backwards), and memory consolidation(i.e., over the 30-minute delay between presentations of the ReyAuditory Verbal Learning Test word list trials). Furthermore,participants who were classified in a “low,” versus “high,” cognitiveability group (via the Wechsler Adult Intelligence Scale-III Vocab-ulary subtest scores) exhibited significantly improved scores on theTrail Making Test (Part A), which the authors attributed to theGBE. A significant number of positive subjective effects were alsoreported by the GBE, versus the placebo, group; namely, subjectivefeelings of cognitive clarity and self-reported improvements inmemory and attention. Conversely, no significant differences werefound for negative side effects such as headaches and nausea.

In another study, Moulton and her colleagues17 examined theeffects of 120 mg/day of Ginkgo biloba [BioGinkgo 27/7, donatedby Pharmanex, Inc., a division of NuSkin International, Provo,Utah] on the memory processes of 60 healthy, young male volun-teers over 5 consecutive days via a double-blind, placebo-controlled, between-subjects design. On the fifth day of the study,after obtaining the GBE or placebo treatment, a series of cognitivetests were administered to participants (see Table 4 for a listing ofthe specific tests utilized). Results indicated that the group receiv-ing the GBE, as compared to placebo controls, failed to demon-strate significantly improved performances on any of the memorymeasures. However, the Wechsler Adult Intelligence Scale-RevisedDigit Span subtest results approached significance, with a highermean score observed in the GBE, versus placebo, group. Theauthors acknowledged that factors such as the following may havecontributed to the absence of significant findings: utilization ofyoung healthy participants, limited dosage (120 mg/day) andtreatment regimen (5 days), and the fact that baseline assessmentswere not administered to participants to which their performancesat the end of treatment could have been compared.

In an effort to expand upon their previous study15 of GBE (EGb761®), Mix and Crews18 published the first known, large-scale clin-ical trial of the short-term efficacy of GBE on the neuropsycho-logical functioning of cognitively intact older adults (as assessed bythe Mini Mental State Examination; MMSE). Two-hundred andsixty-two community dwelling adults, 60 years of age and older,who reported no history of dementia or significant neurocognitiveimpairments and obtained MMSE scores of at least 26, were exam-ined via a 6-week, randomized, double-blind, fixed-dose, placebo-controlled, parallel-group design. Participants were randomlyassigned to receive either 180 mg/day of EGb 761® or a matchingplacebo for 6 weeks and were administered a series of neuropsy-chological tests and measures at pretreatment baseline and againafter 6 weeks of treatment (i.e., just prior to the cessation of theregimen). (See Table 4 for a listing of the specific tests utilized.)



The primary findings of the trial indicated that, compared toplacebo controls, participants who received 180 mg/day of EGb761® for 6 weeks exhibited significantly more improvement on (1)tasks (i.e., Selective Reminding Test) involving delayed (30minutes) free recall and recognition of noncontextual, auditory-verbal material, and (2) a task (i.e., Wechsler Memory Scale-III,Faces II subtest) assessing delayed (30 minutes) recognition ofvisual material/human faces. It should be noted, however, thatbased on the significant difference found between the 2 groupspretreatment baseline scores on this particular visual/facialmemory task, this result should be interpreted with caution. Addi-tionally, of the 13 total neuropsychological outcome/efficacy vari-ables included in this study, the GBE group exhibited moreimprovement by treatment end on 11 of these measures (includesboth significant and nonsignificant results), as compared to theplacebo group. Supporting data for these objective, standardized,neuropsychological findings were found via a subjective, Follow-up Self-report Questionnaire, in which participants rated changesin their overall abilities to remember from pretreatment baseline to6 weeks after treatment. Specifically, significantly more olderadults in the GBE group rated their overall abilities to rememberby treatment end as “improved,” as compared to placebo controls,which was a consistent finding with the investigators’ previoussmaller-scaled GBE study.15 Taken together, the results from boththe objective, standardized neuropsychological tests and thesubjective, Follow-up Self-report Questionnaire utilized in thislarge-scale trial18 provided complementary evidence of the poten-tial efficacy of relatively short-term (6 weeks) utilization of GBE(EGb 761®) in enhancing certain neuropsychological/memoryfunctions of cognitively intact older adults, 60 years of age andover.

Approximately 6 weeks after the online publication of the Mixand Crews large-scale clinical trial,18 the results of a clinical trialconducted by Solomon and his colleagues19 were published. Thistrial reportedly involved a 6-week, randomized, double-blind,placebo-controlled, parallel-group design using 120 mg/day ofGinkgo biloba extract [Ginkoba®, Pharmaton, Division ofBoehringer Ingelheim, Ridgefield, CT.]. In this trial, 230 generallyhealthy and cognitively intact (as assessed by the MMSE) commu-nity-dwelling adults between 60 and 82 years of age were random-ized in the study. Participants were administered a series ofneuropsychological tests and measures one day prior to beginningthe GBE or placebo treatment, and again, within 3 days of the endof the trial (see Table 4 on page 59 for a listing of the specific testsutilized). Analysis of both the modified intent-to-treat sample (n =219) and the fully evaluable sample, which complied with thetreatment regimen and returned for testing (n = 203), indicated nosignificant differences between treatment groups for any of theoutcome measures. Furthermore, no significant differences werefound between participants in the GBE and placebo groups on asubjective, self-report measure of memory functioning or on aglobal rating scale by spouses, relatives, and friends. It should benoted, however, that this study has not been free from controversy.In particular, a diversity of questions/concerns and potentiallyproblematic issues have been raised about the study. These issuesinclude the following: the reported utilization of both placebocapsules and GBE tablets (that were likely not similar in appear-ance and which may have compromised/not maintained blinding),

questions concerning the appropriateness of the lead investigator(versus an independent party) performing the randomization ofparticipants, and the apparent baseline differences among severaloutcome measures that were not accounted for in their analyses(see Arnold20 and Cott21 for detailed reviews). Such concerns raisequestions about the validity of the study’s overall findings andconclusions. [Despite these potentially confounding methodologi-cal questions, the reported negative outcomes of this trial receivedmore media attention in the United States than probably anyprevious clinical trial on ginkgo. The general message was that“ginkgo does not work.” The media apparently failed to provideany qualification that this trial was performed on healthy adults,which distinguished it from most of the trials previouslyconducted on cognitively impaired subjects, most of whichreported positive findings. —Editor’s note]

In another study, Hartley and his colleagues22 examined theeffects of GBE [Ginkyo One-A-Day tablets, (LI 1370), LichtwerPharma UK, Mere Park, Marlow, Bucks, UK] on cognition andmood in 34 healthy, post-menopausal women via a randomized,double-blind, placebo-controlled design. The women were admin-istered a battery of cognitive tests and measures of mood andmenopausal symptoms at baseline and again following 7 days oftreatment (see Table 4 for a listing of the specific tests utilized).The results of the investigation revealed that the group treated withthe GBE, as compared to placebo controls, performed significantlybetter on a matching-to-sample test of short-term nonverbalmemory, as well as on a frontal lobe task involving mental flexibil-ity/rule shifting (i.e., IDED test), and on a test requiring sustainedattention and frontal lobe functioning (i.e., PASAT). Alternatively,no group effects were found for the women’s ratings of theirmenopausal and bodily symptoms, sleepiness, aggression, ormood. The authors noted that these results suggested that theobserved cognitive benefits demonstrated by the women in theGBE group were unlikely due to any of the assessedmenopausal/bodily symptoms, major mood changes, or sleepiness.

Ginkgo Ginkgo biloba grows in the gardens of the headquarters of the Ameri-

can Botanical Council in Austin, Texas. Photo © 2005 ABC.


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Cieza and associates23 also investigated the short-term (i.e., 28days) efficacy of 240 mg/day GBE (EGb 761®) on the “mentalfunctioning” of 66 healthy volunteers, without age-associatedcognitive impairment, via a randomized, double-blind, fixed-dose,placebo-controlled, parallel-group, monocentric design. Partici-pants completed a series of subjective measures concerning theirmental and general health and quality of life, as well as a diversityof tasks that were based on a neurobiologically based classificationof functioning (see Table 4 on page 59 for a listing of the specifictests utilized), both at baseline and at the end of treatment (i.e., 28days later). The results of the study indicated that GBE had signif-icant, positive effects on participants’ self-estimated mental healthand quality of life. The GBE, versus placebo, group also demon-strated significantly better action and reaction motor performances(i.e., Finger Tapping Test) and judged their subjective mood statesmore positively during the entire treatment phase, especially (andsignificantly more) after 2 weeks of therapy.

Santos and colleagues24 appeared to have reported the results ofthe first long-term (i.e., 8 months) study of the efficacy of GBE in48 non-demented, elderly men. Specifically, the investigationutilized a double-blind, placebo-controlled, independent groupdesign where participants consumed either 80 mg/day of a GBE[produced by Maze Produtos Quimicos e Farmaceuticos Ltda.] ormatching placebo for 8 months. The men were evaluated at base-line and post-treatment via Single Photon Emission Computed

Tomography (SPECT) scans, measures of blood viscosity, and adiversity of neuropsychological tests (see Table 4 for a listing of thespecific tests utilized). By the end of treatment, the GBE groupexhibited increased cerebral perfusion in several areas correspon-ding to bilateral frontal, bilateral parietal, right frontal-parietal, lefttemporal, and right occipital brain regions, as well as reducedblood viscosity. In contrast, the placebo group displayed areas ofreduced cerebral perfusion and higher blood viscosity. Further-more, the GBE, versus placebo, group exhibited improvements onthe following: tests of general intelligence (e.g., WAIS-R Vocabu-lary, Comprehension, and Similarities subtests), visuospatial abili-ties (e.g., WAIS-R Block Design and Object Assembly subtests,Corsi Blocks), attentional processes (e.g., WAIS-R Digit Symbol,Toulouse-Pieron Concentrated Attention), information processingspeed (assessed via timed tasks), enhanced verbal memory (e.g.,WMS-R unrelated Verbal Paired Associates), delayed retrieval ofvisual material (e.g., Rey-Osterrieth Complex Figure Test), fewernon-perseveration errors per category on the Wisconsin Card Sort-ing Test, and fewer word intrusion, perseveration, and repetitionerrors on a verbal free recall task.

Persson and associates25 also examined the utilization of unspec-ified formulas of ginkgo and ginseng in healthy volunteers, ascompared to age and education-matched control groups that usedeither no nutritional supplements or nutritional supplements otherthan ginkgo or ginseng. For the purposes of this paper, the data


involving participants who utilized only ginkgo, as compared tocontrols, will be reviewed. Participants, who were free fromorganic disease (such as dementia) and scored 24 or greater onthe MMSE, were selected from the Betula Prospective CohortStudy: Memory, Health, and Aging database (n = 3500) inSweden. Among the 40 individuals who indicated current usageof ginkgo at the time of the study, 19 had been utilizing thephytomedicinal compound for 2 or more years, while the meanginkgo intake time for the remaining 21 individuals was 5.3months. Participants were evaluated at only one time point on adiversity of episodic and semantic memory tests and via ques-tionnaires concerning individuals’ life style factors and subjectivememory ratings (see Table 4 on page 59 for a listing of thespecific tests utilized). The performances of the individuals utiliz-

ing ginkgo were then compared to those obtained by the 2control groups. With the exception of significantly betterperformances by Control Group 2 (see Table 2 on page 56 forinclusion criteria), versus the ginkgo group, on a cued recall taskinvolving nouns from sentences encoded by verbal rehearsal, nosignificant group differences were found for any of the memorymeasures. As noted by the authors, however, this study lackeddirect control of the dosage and specificity of ginkgo formulasutilized and, thus, did not report on the dosages or types ofginkgo that were used by participants, nor their overall levels ofcompliance over time. Furthermore, participants were evaluatedat only one time point. Such concerns raise questions about thevalidity of the study’s overall findings and conclusions.

Summary of Short- to Long-Term StudiesA total of 9 published studies were found in the literature that

have evaluated the short- to long-term neuropsychological effectsof GBE (and unspecified preparations of ginkgo in one study25)in healthy/cognitively intact adults. (Short- to long-term studieswere defined as the administration of GBE to healthy/cognitivelyintact adults for a minimum of 5 days and up to 2 or more years.)

The number of participants enrolled in these studies rangedfrom a low of 3422 to a high of 262.18 Three investigations15,16,23

utilized relatively similar numbers of male and female partici-

pants, while 3 other studies18,19,25 included notably more (i.e., n> 20) females than males. Two additional trials17, 24 included onlymales, while 1 study22 assessed only females. With the exceptionof 2 investigations16,17 where the mean age of participants fellbelow 31 years, the remaining short- to long-term studies ofginkgo involved participants whose mean ages were greater than55 years. In contrast to the acute studies, 5 of the short- to long-term trials15,18,19,24,25 included an objective measure to assessparticipants’ levels of cognitive intactness (and specified inclusion


A wide array of outcome measureswere administered in the short- tolong-term studies. These rangedfrom standardized and objectiveneuropsychological tests that are

frequently utilized in clinicalpractice, to author-generated,

subjective, self-report questionnairesand surveys of caregiver’s

impressions of global change.


criteria scores), while 1 study denoted that participants were with-out “age-associated cognitive impairment” (as judged by CognitiveMinimal Screening).23 The remaining 3 studies16,17,22 indicatedonly that they included “healthy” participants.

All but one investigation25 utilized double-blind, placebo-controlled designs. The duration of the short- to long-term stud-ies’ GBE/ginkgo treatments ranged from 5 days17 to 2-plus years.25

In addition to a placebo, treatments involved the administration ofvarious GBEs/ginkgo treatments that were identified as follows:

• Ginkgo biloba extract EGb 761®, • Blackmore’s Ginkgo Biloba Forte, • BioGinkgo 27/7, • Ginkoba®, Ginkyo One-A-Day (LI 1370), • A GBE that was only cited as having been produced by Maze

Produtos Quimicos e Farmaceuticos Ltda. and prepared byMagister Medicamentos, Ltda., and

• Unspecified preparations of ginkgo in one study.25

The daily doses of GBE in these trials ranged from a low of 80mg24 to a high of 240 mg.23 It should be noted that in one addi-tional study,25 the formula(s) and dose(s) of ginkgo were unspeci-fied and participants’ levels of compliance with the treatment regi-men(s) were not monitored.

A wide array of outcome measures, assessing a diversity ofneuropsychological processes, were administered in the short- tolong-term studies. These ranged from standardized and objectiveneuropsychological tests that are frequently utilized in clinical

practice, to author-generated, subjective, self-report questionnairesand surveys of caregiver’s impressions of global change.

Significant, positive effects of GBE/ginkgo were found in 6 outof 9 short- to long-term studies. Specifically, a dose of 80 mg/day ofa GBE administered for 8 months was shown to increase cerebralperfusion in various brain regions and result in a significant reduc-tion in blood viscosity, as compared to placebo.24 Participants whoreceived this GBE treatment also performed significantly better thancontrols on several verbal and performance subtests of the WAIS-R,on 2 subtests from the WMS-R, and on 3 additional retrieval tasks.In addition, the GBE group exhibited fewer non-perseverative errorsper category on the WCST and significantly more cancellations andfewer errors on a test assessing concentrated attention, as well asfewer word intrusion, perseveration, and repetition errors on a verbalfree recall task, as compared to placebo controls.

Doses of 120 mg/day of GBE were utilized in 4 of the short- tolong-term studies.16, 17, 19, 22 In one trial,22 after 7 days of 120mg/day of a GBE, the treatment group, versus placebo controls,displayed significantly better short-term verbal memory on theDigit Matching-to-Sample Test and enhanced performances ontasks involving rule shifting (i.e., IDED task) and sustained atten-tion (i.e., PASAT). Stough and associates16 also found significantneurocognitive improvements in participants who received 120mg/day of a GBE for 30 days, as compared to placebo controls, ona backwards digit span task, in working memory speed, and on anauditory verbal learning delayed recall task. Improved perform-

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ances on a task involving sequencing and psychomotor speed (i.e.,TMT, Part A) were also noted in a low, versus high, cognitive abil-ity group that received the extract. Furthermore, the GBE, versusplacebo, group self-reported significantly more feelings of clarityand improvements in memory and attention.

The Mix and Crews research group has conducted 2 clinicaltrials15,18 that examined the neuropsychological efficacy of 180mg/day of a GBE for 6 weeks. Results of these studies revealed thatolder, cognitively intact participants who received the phytomedi-cinal extract for 6 weeks exhibited significantly more improvementon standardized neuropsychological tests assessing speed ofprocessing abilities,15 delayed free recall and recognition of audi-tory-verbal material,18 and delayed recognition of visual material,18

as compared to placebo controls. Furthermore, in both studiessignificantly more older adults who received the GBE, versus aplacebo, rated their overall abilities to remember by treatment endas “improved.”

Another short- to long-term study examined the effectivenessof 240 mg/day of a GBE administered for 28 days.23 Participantsin the GBE group exhibited superior performances on a motortask (i.e., Finger Tapping Test) measuring both action and reac-tion functions, and they self-rated their levels of mental healthand quality of life higher and judged their mood states morepositively during the treatment phase, as compared to thecontrols.

In contrast, 3 short- to long-term studies17,19,25 failed to findsignificant positive results for formulas of GBE or unspecifiedginkgo preparations. As noted earlier, in at least 2 of these investi-gations, which utilized either 120 mg/day dose of a GBE for 6weeks19 or unspecified formulas and doses of ginkgo products forup to 2-plus years,25 questions/concerns have been raised about thesoundness of their methodologies and validity of their findings.Furthermore, the third investigation17 with null results utilized theyoungest sample of participants (i.e., x < 21.0 years), the shortesttreatment/assessment duration (i.e., 5 days) of any of the short- tolong-term studies, and did not conduct baseline cognitive/memoryassessments, which may have contributed to the reported negativefindings in this study.

Overall, the majority of investigations that have examined theshort- to long-term effects of GBE/ginkgo in healthy/cognitivelyintact persons have found the herbal product to improve certainneuropsychological processes, especially performances on tasksassessing aspects of memory, attention, and speed of processingabilities. Four of the short-term studies also bolstered their objec-tive neurocognitive test findings with self-report data, as comparedto placebo controls. In 2 of these studies,15,18 significantly moreparticipants who received GBE rated their overall abilities toremember by treatment end as improved. In the third study,16

participants reported significantly more feelings of clarity andimprovements in memory and attention. In the forth study, 23

participants rated their levels of mental health and quality of lifesignificantly higher, and they judged their mood states more posi-tively during treatment.

Conclusions and Directions for Future ResearchTaken together, a total of 16 published studies were found in the

scientific literature (through September 2004) which have exam-ined the acute or short- to long-term neuropsychological efficacy

of GBE (and unspecified preparations of ginkgo in one study25) inhealthy and cognitively intact adults. Significant positive results forformulas of GBE were found in 11 out of 16 studies (10 of 15studies if the Subhan & Hindmarch7 and Hindmarch8 studiesrepresent the same investigation). Although inconsistencies exist in




this limited body of research, some of the most common positiveneuropsychological effects found for GBE across the acute and short-to long-term studies involving healthy/cognitively intact participantshave been enhanced performances on tasks assessing aspects ofmemory, attention, and speed of processing abilities. Furthermore, ascited earlier, complementary subjective/self-report evidence tosupport the findings from the objective neurocognitive tests has beenprovided in four of the short- to long-term studies that included suchmeasures.

However, this review of the scientific literature on acute and short-to long-term studies has also revealed a diversity of findings. Thesefindings include an array of ginkgo product formulations, doses, treat-ments/assessment durations, and outcome measures utilized, as well asthe methodological limitations of some of the investigations (e.g.,limited sample sizes, young ages of participants). Because of thesediverse findings, future well-designed trials are required to preciselyidentify the optimum dose(s), type(s)/formula(s) of ginkgoproduct(s), and treatment regimen(s). These kinds of trials will maxi-mize the likelihood of obtaining certain neurocognitive/neuropsycho-logical benefits in particular groups of healthy/cognitively intactadults (e.g., of varying ages and genders). Specifically, large-scaleinvestigations (both acute and short-term) are needed, especially withhealthy/cognitively intact middle-aged and older adults who oftencomplain of (age-related) memory/cognitive difficulties, that compareand contrast different formulas, dosage regimens, andtreatment/assessment durations of GBE in healthy/cognitively intactmales and females from various age groups. These clinical trials shouldutilize rigorous methodology/designs, and precisely define and assesstheir medical and neuropsychological inclusionary/exclusionary crite-ria (e.g., via objective measures of cognitive intactness). Outcomemeasures should be carefully selected to ensure that they have beendocumented to be reliable, valid, and sensitive measures of particularneuropsychological processes, and that they decrease the possibility offamiliarity/practice effects over successive administrations (e.g., alter-nate forms). Furthermore, methodologically sound, longitudinal,clinical trials are also needed that examine the neuropsychological effi-cacy of GBE(s) over periods of several months to years to ascertain ifadditional neuropsychological benefits/effects become evident and/orif the phytomedicinal compound demonstrates long-term neuropro-tective properties.

Authors’ Biographical SketchesW. David Crews, Jr., PhD: Dr. Crews is a licensed clinical

neuropsychologist, President of Virginia Neuropsychology Associates,Inc. and CogniCheck, Inc. (www.CogniCheck.com) and an AdjunctAssistant Professor in the Department of Psychology at Virginia Poly-technic Institute and State University. He has authored/co-authoredover 50 peer-reviewed publications in clinical neuropsychology,behavioral medicine, and the neuropsychological effects of herbalcompounds. He has been awarded Diplomate status through theAmerican Board of Psychological Specialties (Neuropsychology) andthe American Board of Disability Analysts and was elected as a Fellowby the National Academy of Neuropsychology.

David W. Harrison, PhD: Dr. Harrison is a licensed clinicalneuropsychologist and an Associate Professor and Director of theNeuropsychology Laboratory in the Department of Psychology atVirginia Polytechnic Institute and State University. He hasauthored/co-authored over 150 peer-reviewed publications in clinicalneuropsychology and behavioral/cognitive neuroscience. He has beenawarded Diplomate status through the American Board of Psycholog-ical Specialties (Neuropsychology), American Board of DisabilityAnalysts, Neurotherapy Certification Board, American Board ofForensic Examiners, and the American Board of Vocational


Neuropsychology and was elected as a Fellow by the NationalAcademy of Neuropsychology.

Melanie L. Griffin: Ms. Griffin obtained her Bachelor ofScience degree in Psychology from Virginia Polytechnic Instituteand State University and is currently a graduate student at South-eastern Louisiana University. Upon her graduation at VirginiaTech, she received the Department of Psychology’s OutstandingUndergraduate of the Year and Undergraduate Researcher of theYear awards for 2004. She has also served as the clinical researchcoordinator on a grant-funded trial that examined the neuropsy-chological efficacy of cranberry juice.

Katherine D. Falwell: Ms. Falwell obtained her Master of Artsdegree in Clinical and Community Psychology from the Univer-sity of North Carolina-Charlotte and a Post-Graduate Certificatein Applied Behavior Analysis from George Mason University. Sheis currently completing her PhD in Clinical Psychology at theFielding Graduate Institute and is employed as a psychologist atthe Central Virginia Training Center.

Tara Crist: Ms. Crist is currently pursuing her Bachelor ofScience degree in Psychology at Virginia Polytechnic Institute andState University, where she also serves as a research associate in theNeuropsychology Laboratory.

Lesley Longest: Ms. Longest is currently pursuing her Bachelorof Science degree in Psychology at Virginia Polytechnic Instituteand State University, where she also serves as a research associate inthe Neuropsychology Laboratory.

Laura Hehemann: Ms. Hehmann obtained her Bachelor ofScience degree in Psychology at Virginia Polytechnic Institute and

State University and is currently a graduate student at RadfordUniversity.

Stephenie T. Rey, OTR/L: Ms. Rey obtained her Master ofScience degree in Occupational Therapy from Rush Presbyterian-St. Lukes Medical Center/School and is currently a registered andlicensed Occupational Therapist. She also currently serves as aresearch associate with Virginia Neuropsychology Associates, Inc.

Address correspondence to W. David Crews, Jr., PhD, Virginia Neuropsychology Associates, Inc., P.O. Box 11754,Lynchburg, Virginia 24506; telephone: 434-942-9325; e-mail:[email protected].






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Ginkgo · 2019-04-16 · Cognition), Ginkgo biloba and Memory, Ginkgo biloba and Healthy, Ginkgo bilobaand Cognitively Intact, the authors of this paper conducted comprehensive literature