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human psychopharmacology. Hum Psychopharmacol Clin Exp 2002; 17: 45±49. DOI: 10.1002/hup.353. The acute nootropic effects of Ginkgo biloba in healthy.
human psychopharmacology

Hum Psychopharmacol Clin Exp 2002; 17: 45±49. DOI: 10.1002/hup.353

The acute nootropic effects of Ginkgo biloba in healthy older human subjects: a preliminary investigation Pradeep J. Nathan1*, Emily Ricketts1,2, Keith Wesnes3, Ludek Mrazek4, Warick Greville5 and Con Stough2 1

Neuropharmacology Laboratory, Brain Sciences Institute, Swinburne University of Technology, Australia Neuropsychology Laboratory, School of Biophysical Science and Electrical Engineering, Swinburne University of Technology, Australia 3 Cognitive Drug Research Ltd, Reading, UK 4 Graduate School of Integrative Medicine, Swinburne University of Technology, Australia 5 Redwood Anti-Aging Clinic, Melbourne, Australia 2

Ginkgo biloba has been shown to have chronic memory enhancing effects in healthy subjects and patients with dementia. There is limited research on the acute nootropic effects of Ginkgo biloba in humans. The current study aimed to examine the acute effects of Ginkgo biloba (120 mg) on memory functioning in healthy older volunteers using the cognitive drug research (CDR) battery of memory tests and the Rey auditory verbal learning task (AVLT). The study was a double-blind placebo-controlled design, with each participant tested under both placebo and Ginkgo biloba treatment conditions. Testing was conducted pre- and 90 min post-drug administration for each treatment condition. Treatment conditions were separated by a 7 day wash out period. No acute effects of Ginkgo biloba were found for any of the memory tests examined. The ®ndings suggest that 120 mg of Ginkgo biloba has no acute nootropic effects in healthy older humans. Copyright # 2002 John Wiley & Sons, Ltd. key words Ð Ginkgo biloba; nootropic; memory; cognition; acute; older human subjects

INTRODUCTION Ginkgo biloba is an extract derived from the dried leaves of the Maidenhair tree and has been used in therapeutic application for centuries (Pang et al., 1996). It remains one of the most popular plant extracts used in Europe to alleviate symptoms associated with a range of cognitive disorders such as Alzheimer's disease, vascular dementia and agerelated amnesic conditions (Warburton et al., 1986). The exact mechanism of action of Ginkgo biloba is still uncertain, as the pharmacology of Ginkgo biloba is extremely complex due to its multiple active

* Correspondence to: Dr P. J. Nathan, Neuropharmacology Laboratory, Brain Sciences Institute, Swinburne University of Technology, 400 Burwood Road, Hawthorne, Victoria 3122, Australia. Tel: ‡ 61 3 9214 5216. Fax: ‡ 61 3 9214 5525. E-mail: [email protected] Copyright # 2002 John Wiley & Sons, Ltd.

constituents. The active compounds of the extract are mainly ¯avonal glycosides (24%) and the terpene substances such as ginkgolides and bilobalide (6%) with smaller amounts of proathocyanidines and some organic acids (Pang et al., 1996). It is possible that the effects of Ginkgo biloba on cognition may be caused by a single constituent or by some combination of any active constituents found in the extract. However, it is most likely that the differing pharmacology of each of the constituents together contribute towards the overall pharmacodynamic effect on cognition (Nathan, 2000). Ginkgo biloba's neuroprotective and cognitive enhancing effects have been attributed to (1) its platelet-activating factor (PAF) antagonistic effects and (2) its free-radical scavenger activity (Del Cerro, et al., 1990; Wieraszko et al., 1993; Oyama et al., 1994; Furey et al., 2000). Ginkgo biloba has been shown to have neuro-protective effects on brain neurons against oxidative stress induced by peroxidation, Accepted 2 October 2001

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in some recent studies (Maitra et al., 1995; Oyama et al., 1996; Ni et al., 1996; Hoyer et al., 1999). More recent evidence has shown that Ginkgo biloba also acts as an inhibitor of the monoamine metabolising enzymes, monoamine oxidase A and B, which may also contribute to its free-radical scavenging and neuroprotective effects (White et al., 1996). In addition, evidence suggests that both acute and chronic doses of Ginkgo biloba may modulate the cholinergic system (Nathan, 2000), with direct effects of choline uptake and acetylcholine release (Kristo®kova and Klaschka, 1997) and increase in cholinergic muscarinic receptors (Taylor, 1986). Pre-clinical animal studies have shown that Ginkgo biloba has nootropic effects in established models of learning and memory (Winter, 1991; Chopin and Briley, 1992; Gajewski and Hensch, 1999). Supporting the pre-clinical evidence, positive effects of chronic Ginkgo biloba have also been shown in patients with age-related memory impairment with diagnosis of cerebral insuf®ciency (see review by Soholm, 1998), and a modest but signi®cant effect has been shown in patients with Alzheimer's disease (see review by Oken et al., 1998). Our recent study also showed that chronic (1 month) Ginkgo biloba (120 mg) may improve speed of information processing, working memory and executive processing, in healthy young subjects, ®nding signi®cant improvements in digit span backwards, working memory speed, Rey auditory verbal learning test and inspection time (Stough et al., 2001) The research into the acute effects of Ginkgo biloba has been rather sparse with studies thus far con®ned to healthy populations. Subhan and Hindmarch (1984) found signi®cantly improved scores on the Sternberg memory scanning test 1 h after treatment with 600 mg of Ginkgo, indicating improved short term memory scanning speed and reaction time to visual stimuli. Similarly Kennedy et al. (2000) also found improved measures of cognitive performance as indicated by sustained improvement in attention, after an acute 600 mg dose. While lower doses (120 mg) have been shown to have minimal effects in younger subjects (Kennedy et al., 2000), improvements in cognitive functioning, particularly working memory have been reported with the 120 mg doses in elderly subjects (over 50 years of age) (Rigney et al., 1999). However, one of the limitations of past research is the limited range of tests used to examine Ginkgo biloba's acute effects, particularly in relation of memory. Using a wide battery of memory tests, the current study aimed to examine the acute effects of Ginkgo biloba (120 mg) on memory in healthy older subjects. Copyright # 2002 John Wiley & Sons, Ltd.

METHODS Subjects The subjects were 11 healthy volunteers (6 females, 5 males; mean age  SD ˆ 58.46  10.92 years (range 50±70)). The study was approved by the Swinburne Research Ethics Committee. All subjects gave written consent before taking part in the study and underwent a medical screening at the Brain Sciences Institute to ensure their suitability. Subjects were required to ®ll the following criteria to ensure that a `normal healthy' old population was selected for the study: (1) no history of dementia, psychiatric disorders or neurological diseases; (2) no history of bleeding disorders, gastrointestinal disorders; (3) not taking anticoagulants, anti-depressants, anti-psychotics, anxiolytics, ACE inhibitors or antiParkinsons medication, or any cognitive enhancing drugs or herbs; (4) non-smoker. Design The study was a repeated measures, double-blind, placebo-controlled design, in which all participants underwent testing in both treatment conditions (120 mg GinkgoforteTM (Blackmore's Ltd) and a placebo). The drugs and testing order was randomised to minimise order effects. The study consisted of two sessions, held 1 week apart to allow a 7 day washout period. In both sessions subjects were given the opportunity to practise the computerised tests to eliminate practice effects and to familiarise themselves with the equipment. The subjects were instructed not to consume caffeine containing food or drinks on the testing days. They were also instructed to eat two pieces of toast at home 2 h before their baseline testing began to standardise food intake for all subjects. On the ®rst day of testing the subjects were asked to perform a series of memory tests to obtain a baseline measure. Following this, subjects were instructed to orally take three tablets of Ginkgoforte (3  40 mg dose) or three identical placebo tablets. The dose was three 2000 mg (equivalent to dry leaf) tablets of Blackmore's Ginkgo Biloba Forte containing 120 mg of active ingredient. The active compounds of the extract were standardised to contain ginkgo ¯avonglycosides 10.7 mg and ginkgolides and bilobalide 2.7 mg. Testing was repeated 90 min after administration of the drugs. This time frame was chosen to coincide with peak plasma Ginkgo biloba levels (Moreau et al., 1986). Identical procedures were carried out for the second session. Hum Psychopharmacol Clin Exp 2002; 17: 45±49.

acute nootropic effects of ginkgo biloba Memory tests CDR computer tests. The Cognitive Drug Research computerised assessment system tasks were chosen to test memory as these are speci®cally designed to assess enhancement and impairment of human cognitive performance in drug trials. They are suf®ciently reliable, precise and sensitive to predict the potential behavioural effects of a drug (Wesnes et al., 1989). Numeric working memory. A sequence of ®ve digits was presented on the PC screen at a rate of one per second. The subject was then required to identify from the following list of random digits, also presented at one per second, which digits had appeared in the initial sequence. This tests the sub-vocal rehearsal of digit sequences and the articularly loop sub-system of working memory. Spatial working memory. A house with nine windows arranged as a grid shape was presented on the PC to the subject for 15 s. Of the nine windows, four were lit up. Following this, images of the same house were presented, with one of the windows lit up. Subjects were required to indicate whether or not that particular window had been lit up in the original image. This tests the ability to temporarily retain spatial information and the visuo-spatial sub-loop of working memory. Picture recognition. Subjects were presented with a number of different images on the PC screen, at intervals of 1 s. Approximately 15 min later they were presented with some of the same images again, as well as some new images that were not presented the ®rst time. The subjects were required to indicate which images they recognised from the initial list of images, and which ones they did not recognise. This tests the ability to discriminate novel from previously presented pictorial information and episodic secondary non-verbal visual recognition. Simple reaction time. The word `yes' was ¯ashed up on the PC screen at random intervals. Subjects were to press a button as quickly as possible when they saw the word appear. This is a test of alertness and power of concentration and tests the primary stage of information processing. Choice reaction time. The words `yes' or `no' were ¯ashed up on the PC screen at random intervals. Subjects were required to press a corresponding `yes' Copyright # 2002 John Wiley & Sons, Ltd.

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or `no' button as quickly as possible when they saw the words appear. This also tests alertness as well as being a test of stimulus discrimination and response organisation. AVLT. The Rey auditory verbal learning task was administered to the subjects. It consisted of ®ve separate presentations of a list of 15 words. Subjects were required to recall as many words as they could from the list immediately following each presentation. The test measures verbal learning (Trial 5), short-term memory, following an interference list (Trial 7) and long-term memory (Trial 8, 20 min after Trial 7) (Ryan, 1986). Analysis and statistics The data were analysed using a 2 (treatment) by 2 (time) repeated measures ANOVA. The main effects of treatment over time were examined by analysing the differences between baseline (pre-drug) scores and post-drug scores. RESULTS The data revealed no evidence of acute effects of Ginkgo biloba on cognitive functioning. The repeated measures ANOVA showed no signi®cant drug interactions for either the accuracy (%), response speed (ms) measure of spatial working memory, numeric working memory, picture recognition, choice reaction time or simple reaction time. Similarly no signi®cant drug interactions were found for the auditory verbal learning tests of verbal learning and short and long-term memory. Table 1 shows the means and standard deviations of the maximum effects (post-drug) of each drug condition relative to baseline (pre-drug), with F statistics and signi®cance levels. DISCUSSION The current study investigated the acute nootropic effects of 120 mg Ginkgo biloba in healthy older subjects. The results indicated no signi®cant effects at this dosage for any of the memory tests examined. This ®nding is consistent with the studies of Subhan and Hindmarch (1984) and Kennedy et al. (2000) who also showed no acute effects of Ginkgo biloba at the 120 mg dose. However, in the latter studies acute memory enhancing effects were observed with higher doses of Ginkgo biloba. Subhan and Hindmarch (1984) and Kennedy et al. (2000) both found an enhancement of working memory and serial storage with an acute 600 mg dose of Ginkgo biloba. These Hum Psychopharmacol Clin Exp 2002; 17: 45±49.

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Table 1. Means and standard deviations of the change in performance (from baseline (pre-drug) to post-drug) of accuracy and speed, for non-signi®cant results Placebo Non-signi®cant results Accuracy (original) % Spatial working memory Numeric working memory Picture recognition Choice reaction time Accuracy (new) % Spatial working memory Numeric working memory Picture recognition Speed (original) (ms) Spatial working memory Numeric working memory Picture recognition Choice reaction time Simple reaction time Speed (new) (ms) Spatial working memory Numeric working memory Picture recognition Choice reaction time Auditory verbal learning Trial 5 (verbal learning) Trial 7 (short-term memory) Trial 8 (long-term memory)

Ginkgo biloba (120 mg)

M

SD

12.50 0.20 1.36 0.91

27.81 5.92 13.43 1.58

2.27E 3.43 1.36 0.727

7.73 1.62 4.55

24.02 2.24 13.31

3.18 7.23E 2.73

14.74 85.14 96.63 2.56 12.37

499.23 170.56 258.62 53.07 77.09

12.40 54.65 175.62 12.37 0.64 2.36 1.55

SD 16

F

Sig

9.68 9.4 16.29 0.407

2.18 0.812 0.00 1.16

0.17 0.39 1.00 0.30

5.6 3.30 12.92

0.35 1.38 0.23

0.16 0.27 0.64

130.64 53.67 137.89 3.40 8.10

249.13 99.53 246.96 30.67 27.17

0.64 0.20 0.46 0.14 1.01

0.46 0.66 0.51 0.71 0.34

476.09 184.13 301.47 77.09

190.56 88.01 166.78 8.10

246.19 93.21 188.93 27.17

0.96 0.33 0.01 1.01

0.35 0.58 0.919 0.34

2.62 2.91 2.58

1.73 0.82 2.09

2.05 2.86 2.74

1.85 1.20 0.17

0.20 0.30 0.68

®ndings suggest that there is a dose-response relationship with regards to the acute effects of Ginkgo biloba, with memory enhancing effects observed with higher doses. While acute improvements have been observed with 600 mg, a recent study showed that memory enhancement may also be observed with subchronic administration of the lower doses (120 mg taken on two consecutive days) (Rigney et al., 1999). The latter ®nding suggests that at lower doses more prolonged administration may be required to enhance memory. Supporting this, our recent study showed memory and cognitive enhancing effects with chronic (1 month) administration of lower doses of Ginkgo biloba (120 mg) in healthy normal subjects (Stough et al., 2000). It must also be noted that as yet an optimal time frame, in which to test subjects for nootropic effects, has not been established. Although the present time frame (90 min) was chosen to coincide with peak plasma Ginkgo biloba levels as de®ned by Moreau et al. (1986), testing times have not been consistent in previous studies, with effects found from 1 h to 6 h post-dose, and several intervals in between. The time of testing may be an important consideration Copyright # 2002 John Wiley & Sons, Ltd.

M

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as previous behavioural studies have shown that maximum effects do not always coincide with maximum plasma concentration of the drugs (Lader, 1986). While the mechanisms involved in Ginkgo biloba's memory enhancing effects remain unclear, it might be possible to explain the acute effects with reference to Ginkgo biloba's effects on the cholinergic system (Nathan, 2000). Previous studies have shown that acute modulation of the cholinergic system improves different memory processes (Drachman and Leavitt, 1971; Safer and Allen, 1971; Weingarnter, 1985; Warburton et al., 1986; Levin, 1992). The chronic effects of Ginkgo biloba may be due to a combination of pre and post-synaptic cholinergic modulation, platelet activating factor antagonistic effects, monoamine oxidase inhibitory effects and free radical scavenging activity (Nathan, 2000). In general there are a number of inconsistencies within the limited amount of research conducted thus far. In interpreting the observations, careful consideration should be given to factors such as subject groups (young vs old), the doses used (low vs high), the time frame in which testing is conducted and acute versus chronic effects. Hum Psychopharmacol Clin Exp 2002; 17: 45±49.

acute nootropic effects of ginkgo biloba In summary, the current study found no evidence of memory enhancing effects with an acute 120 mg dose of Ginkgo biloba in healthy older subjects. However, one cannot rule out a possible nootropic effect at either higher doses, or as recently shown by Stough et al. (2001), with more chronic administration. ACKNOWLEDGEMENTS Authors wish to thank Blackmore's Ltd for providing Ginkgo biloba and placebo tablets for this study. REFERENCES Chopin P, Briley M. 1992. Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine induced amnesia in rats. Psychopharmacology 106: 26±30. Del Cerro S, Arai A, Lynch O. 1990. Inhibition of long-term potentiation by an antagonist of platelet activating factor receptors. Behav Neurol Biol 54: 213±217. Drachman DA, Leavitt J. 1974. Human memory and the cholinergic system. Arch Neurol 30: 113±121. Furey ML, Peitrini P, Alexander GE, Schapiro MB, Horwitz B. 2000. Cholinergic enhancement improves performance on working memory by modulating the functional activity in distinct brain regions: a positron emission tomography regional cerebral blood ¯ow study in healthy humans. Brain Res Bull 51: 2143±2218. Gajewski A, Hensch SA. 1999. Ginkgo biloba and memory for a maze. Psychol Rep 84: 481±484. Hoyer S, Lanner H, Noldner M, Chatterjee SS. 1999. Damaged neuronal energy metabolism and behaviour are improved by Ginkgo biloba extract (Egb 761). J Neural Transm 106: 1171±1188. Kennedy DO, Scholey AB, Wesnes KA. 2000. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology 151: 416±423. Kristo®kova Z, Klaschka J. 1997. In Vitro effect of Ginkgo biloba extract (Egb 761) on the activity of pre-synaptic cholinergic nerve terminals in rat hippocampus. Dement Geriatr Cogn Disord 8: 43±48. Lader M. 1986. The use of hypnotics and anxiolytics in the elderly. Int Clin Psychopharmacol 1: 273±283. Levin ED. 1992. Nicotinic systems and cognitive function. Psychopharmacology 108: 417±431. Maitra I, Marcocci L, Droy-Lefaix MT, Packer L. 1995. Peroxy radical scavenging activity of Ginkgo biloba extract Egb761. Biochem Pharmacol 49: 1649±1655. Moreau JP, Eck CR, McCabe J, Skinner S. 1986. Absorption, distribution and elimination of a labelled extract of Ginkgo biloba leaves in the rat. Presse Med 15: 1458±1461.

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Hum Psychopharmacol Clin Exp 2002; 17: 45±49.