a double-masked study of the effects of ginseng on cognitive functions

CURRENT THERAPEUTIC RESEARCH” VOL. 57, NO. 12, DECEMBER 1996

A DOUBLE-MASKED STUDY OF THE EFFECTS OF GINSENG ON COGNITIVE FUNCTIONS

HENRIK S0RENSEN’ AND JESPER SONNE’

‘Health Center of Skodsborg, Skodsborg, and ‘Department of Internal Medicine and

Gastroenterology, Gentofte University Hospital, Hellerup, Denmark

ABSTRACT

The effects of a pure ginseng preparation on a variety of cognitive functions was compared with those of placebo in a double-masked, randomized, test-retest design. The subjects were healthy volunteers older than 40 years of age who were given the ginseng preparation or placebo for 8 to 9 weeks. Of the 112 subjects who completed the study, 55 received ginseng and 57 received placebo. The ginseng group showed a tendency to faster simple reactions and significantly better abstract thinking than the controls. However, there was no significant difference between the two groups in concentration, memory, or subjective experience.

INTRODUCTION

In clinical and experimental investigations in animals and humans, ginseng has been shown to have favorable effects on physical achieve- ments,le3 subjective well-being,4 and mental functions. The subjective effects include an increased feeling of well-being, decreased fatigability, increased stamina, and increased alertness.‘*4,5 The effects of ginseng on organisms have been described as adaptogenic and resistogenic; however, ginseng’s pharmacologic actions are not fully understood.‘,5 Ginseng has been used to revitalize sick or elderly persons; such persons appear to benefit more from ginseng than do healthy subjects.5

Improvement has been reported in a variety of mental functions, par- ticularly in psychophysical reactions and ability to concentrate.1,3 Im- provements in higher cognitive functioning have been reported in case studies and field studies involving small numbers of subjects.

There have been only a few randomized, double-masked, placebo- controlled clinical studies of the effects of ginseng on cognitive function. Branth and Gruber3 studied the effects of ginseng on healthy, middle-aged subjects who participated in a cancellation test, which required strict concentration, and that measured one cognitive function. Similarly, in a dou-

Address correspondence to: Henrik Sorensen, Skodsborg Sundhedscenter, Skodsborg, Strandvej 125/7, 2942 Skodsborg, DK-Denmark. Received for publication on October 15, 1996. Printed in the U.S.A. Reproduction in whole or part is not permitted.

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EFFECTS OF GINSENG ON COGNITIVE FUNCTIONS

ble-masked study of 120 persons, Forgo et al2 observed improved simple reaction times in the 40- to 60-year-old subjects but not in the 30- to 39-year-old group.

Few studies have used more comprehensive batteries of tests. In a crossover study of 49 elderly persons acting as their own controls, Fulder et al6 found that ginseng had an effect on psychophysical functioning but not on memory or concentration; however, this study had some method- ologic problems. D’Angelo et a1,7 in a study of 32 young, healthy students, found no effect on pure motor function (tapping test), recognition (digit symbol substitution), or visual reaction time, while a slight improvement was seen in the results of certain psychomotor and concentration tests. A number of studies have reported the results of combination preparations containing ginseng, minerals, and vitamins. The findings in these studies cannot be compared with studies in which ginseng was used alone.

The objective of the present study was to test, by using a standard battery of neuropsychological tests in a clinically controlled design, the effect of a pure ginseng preparation on the entire spectrum of cognitive functions.

SLJBJECTSANDMETHODS

Subjects

An advertisement for healthy subjects aged 40 to 70 years was placed in a weekly paper. All individuals who volunteered underwent a medical interview. Exclusion criteria were as follows: serious illness, diseases of the central nervous system, and abuse of alcohol or drugs. Persons receiv- ing psychoactive medication that might interact with ginseng were also excluded. The study was approved by the local ethics committee, and written consent to participate was obtained from the subjects after they received oral and written information about the trial.

The subjects were randomized into two groups; both groups received identical-looking tablets. During the experimental period, the ginseng- treated group received 400-mg standardized ginseng extract,* while the placebo group received an inactive, heavily soluble calcium preparation. Neither the subjects nor the study manager knew which tablets contained which preparation.

At the first appointment, all subjects underwent a baseline cognitive test of 1 to 1.5 hours’ duration and then received the pills. Retesting was done after 8 to 9 weeks of treatment. Before the 2-day examination, the subjects were told to avoid stimulants and alcohol. As far as possible, each subject was tested at the same time of day on both occasions. During the

* Trademark: Gerimax Ginseng Extract (Dansk Droge A/S, Ishoj, Denmark)

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H. S43RENSEN AND J. SONNE

retest, the subjects completed a demographic questionnaire and a second questionnaire concerning subjective changes and side effects, if any.

Methods

The battery of cognitive tests consisted of psychomotor tests, attention and concentration tests, learning and memory tests, and tests to assess abstract thinking.

Psychomotor Tests

The Simple Auditive Reaction Times Test according to the computer test program (Brain WorkTM, Byron Brooks, Farum, Denmark) is used to measure how quickly subjects are able to depress a key in response to a high, clear sound coming at irregular intervals. After a practice series of five stimuli, 60 consecutive measurements are made. This test measures elementary, sustained attention and arousal in the auditory canal.

The Simple Visual Reaction Times Test (Brain Work) is similar to the auditive test, except that the stimulus is a white square approximately 0.4 x 0.6 cm in diameter, which appears intermittently in one of the four corners of a dark-blue screen. The subjects are instructed to watch the entire screen and to depress a key in response to the stimulus. After five practice stimuli, 60 consecutive measurements are made. This test re- quires sustained attention and concentration to detect the stimuli.

The Finger-Tapping Test (Brain Work) measures how many times a subject is able to depress a reaction key in 10 seconds. Ten measurements, five on each side, are made in immediate succession. This test measures the speed of central and peripheral neuromuscular coordination of the hands.

Attention and Concentration Tests

The D2 Test is a cancellation test using a 29.5 x 20.9 cm sheet with 14 lines, each containing various combinations of 47 ds and ps. One to four apostrophes are placed in the four spaces above and below each letter. The subject is instructed to analyze the letters in consecutive order, as quickly as possible, and to underline the ds that are accompanied by two apostrophes. After 20 seconds the line is changed. This test measures the complex analytical rate and the maintenance of concentration during almost 5 minutes of intensive cognitive analysis.

Another test of attention and concentration is the Fluency Test. Sub- jects are asked to name as many different types of animals as possible in 1 minute. The test measures the ability to rapidly and systematically mobilize information from long-term memory.

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Learning and Memory Tests

Three different tests were used to measure learning and memory. In one of these, the Selective Reminding Test (Brain Work), 10 unrelated words are read, and the subject is asked to list as many of the 10 words as possible, without regard to sequence. Any words that the subject missed are read again, and again the subject attempts to list all of the words. This process is repeated up to 10 times or until the subject correctly lists all 10 words. This test is used as a measure of learning and memory.

In the Logical Memory and Reproduction Test, a text of 18 meaning units are read to the subject, who immediately and again at 1 hour reproduces as many of the units as possible. This test is used to assess the learning and memory of linguistically meaningful material.

In the Rey-Oestrich Complex Figure Test, a figure is shown to the subject, who reproduces the figure as accurately as possible while it is visible. The figure is then removed, and after an undisturbed, 3-minute interval the subject is asked to reproduce the figure as accurately as possible from memory. This test is used to assess visual learning and memory.

Abstraction Tests

The Wisconsin Card Sorting Test (Brain Work) is used to assess abstract thinking. Four cards marked with different symbols appear at the top of a computer screen. The symbols vary in shape, color, and number. An additional card is shown at the bottom of the screen; the subject is instructed to place that card underneath one of the four cards above. Im- mediately after the card is moved a message appears on the screen indi- cating whether the card has been placed correctly or incorrectly, but no explanation is given. Another card then appears at the bottom of the screen for the subject to place. When the subject places 10 consecutive cards correctly, the sorting criterion is changed without explanation. A total of 58 cards is shown. No explanations are given at any point through- out the test. Further details on this test are given in the Discussion.

Several changes were made in the testing procedure during retesting. To minimize the retest effect, parallel versions of the learning and memory tests were used (eg, the Taylor Complex Figure Test replaced the Rey- Oestrich Complex Figure Test). Because the Fluency Test and the Wiscon- sin Card Sorting Test are not suited for retesting, they were not included in the baseline testing.

Scoring Procedure

The individual tests were scored according to current clinical princi-

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H. S0RENSEN AND J. SONNE

ples, with adjustments made to account for the fact that two treatments were being compared and that the subjects were healthy individuals.

The psychomotor tests, which involve the subject’s sense of competi- tion, were scored in terms of absolute rapidity (the tenth percentile was used, rather than the fastest time, to rule out spurious excess reactions) to comply with the way a healthy person would regard the test and to test whether ginseng has an arousal effect, which may enhance a subject’s ability to react as quickly as possible. We also used the median score as a measure of central tendency. The measure of variation, which is of interest in clinical settings, is not considered relevant in this study. Prior to the study, the 10th percentile was chosen, since it is a known value, which is used as the fastest time in expressing the range of variation tie, the 10th percentile minus the 90th percentile).

The Selective Reminding Test was used as a verbal learning test. Because the two tests (ie, the test used at baseline and the test used at retesting) have a slightly different degree of difficulty, this test was used only as a pure memory test, measuring how many units were lost between the immediate recall and later reproduction. The same is true for the two figures.

Statistical Analysis

The primary outcome was the change score on each test from baseline to retesting. The distribution of change scores was evaluated with regard to skewness and kurtosis. When relevant, Student’s two-sample t test was used to analyze the mean change score between the two treatment groups. Because there have been no reports of a negative effect of ginseng on cognitive functions, and to enhance the power of the study, a one-tailed test for the effect of the active substance was used.

RESULTS

Of the 156 volunteers interviewed, 127 met the study criteria and were included in the baseline testing. A total of 112 subjects completed the study, while 15 (12%) dropped out-6 due to illness and 9 for unknown reasons.

Compliance was assessed by querying the subjects and by counting the tablets returned. In no case did the returned tablets exceed 5% of the total number distributed to the subject.

The demographic characteristics of the two treatment groups are given in Table I. The groups were similar with respect to age, years of schooling, and advanced education but not with respect to sex. The placebo group included a disproportionately large number of men.

Table II presents a comparison of the cognitive change scores for the

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Table I. Demographic characteristics.

Ginseng Placebo (n = 55) (n = 57)

Sy&

Female Age (y)t Schooling (y)t Advanced education (%)

* P = 0.04 versus number of males t Mean + SD.

ginseng and the placebo groups. For all of the tests except the Selective Reminding Test, the baseline values for the two groups were similar and corresponded to the high end of expected values for normally functioning persons.‘,’ On the Selective Reminding Test, the placebo group scored significantly higher than the ginseng-treated group at baseline. Therefore, the results of this test were excluded from further analysis.

In nine of the 10 baseline comparisons, there were no significant differences between the placebo group and the ginseng group. The difference in the Selective Reminding Test scores was not considered large enough to compromise the overall comparability of the two groups, as this test measures only one aspect of verbal learning and because neuropsychological functions, as measured by these tests, are known to be independent of each other.’

It is well known that the degree of residual effect (experience) varies for different psychological tests.’ In general, the simple psychomotor tests, such as tests of reaction time, show little or no retest effect, while the more strategy-dependent or complex tests may show a considerable retest effect. The D2 Test showed a large retest effect for both groups, presumably because of the complex nature of the procedure.

A comparison of the two treatment groups shows that the ginseng- treated group performed significantly better in the most rapid auditive reaction times (10th percentile), whereas the median (50th percentile) performance was not significantly different. To a lesser extent, the same tendency was found for the test of visual reaction times. The greatest difference was found for the fastest times, whereas the median values approached each other. Furthermore, there was a significant difference between the two groups in the results on the Wisconsin Card Sorting Test, with the ginseng-treated group making fewer errors. No significant differences in performance between the ginseng and the placebo groups were noted for any of the other tests.

At retesting, the subjects were questioned concerning changes during the treatment period in general well-being, energy level, speed of reactions, concentration, and memory. Both treatment groups reported a

964

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slight, but not significant, subjective improvement in general well-being and energy but hardly any change in speed, concentration, or memory. These answers must be regarded in the light of several factors. First, the tablets were distributed in unmarked bottles under neutral conditions; this helped to counteract the placebo effect that is part of any drug ther- apy.” Second, the fact that the subjects knew that objective testing was to follow the questioning appears to have moderated responses to questions regarding the functions that were going to be analyzed. Also, the mechanism of adaptation would be expected to have minimized the perception of change-so-called normalization-over the &week treatment period between baseline and retesting. Thus a number of the subjects described an immediate subjective change during the first weeks of treatment, but later began to doubt the existence of actual change. Finally, many subjects were in doubt as to whether to ascribe a possible change in subjective well-being to the treatment or to other events, such as holidays, that may have oc- curred during the 8 weeks.

At the retesting, the subjects were asked about any side effects they may have experienced. No side effects were identified.

DISCUSSION AND CONCLUSIONS

A comprehensive battery of cognitive tests was used to investigate cognitive functioning in healthy, middle-aged subjects. The group that had received ginseng for 8 to 9 weeks showed slightly faster reaction times than the placebo group. Similarly, the subjects who received ginseng performed significantly better on an abstraction test. Concentration and memory were similar in both groups. Improvements in reaction times have been reported in a number of previous studies’T2,6; this finding conforms to the assumption that ginseng causes increased alertness and arousal.

In previous studies1 of the effects of ginseng, actual abstraction tests were not used. In this study, we employed the Wisconsin Card Sorting Test, which uses an unstructured task to test the ability to analyze a situation on an abstract level; the ability to solve problems in a controlled, deductive manner; and the degree of mental flexibility under changing conditions.i1.12 This test measures mental organization, reasoning, and control, all of which are essential, complex functions performed in the frontal lobe of the brain. The fact that the test cannot be validated by retesting should be remembered; we did not administer the test at baseline. If our findings can be reproduced in other studies, interesting discus- sions concerning the mechanism of effect could result.

A disproportionate ratio of men to women was seen in the two treatment groups, with the placebo group having substantially more men and

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H. SQRENSEN AND J. SONNE

fewer women than the ginseng-treated group. This disparity may have affected the results of the various tests. For instance, on the Wisconsin Card Sorting Test, men made an average of 1.4 more errors than women. However, this unequal distribution can only explain part of the difference in performance between the groups, with the placebo group averaging 3.8 more errors than the ginseng-treated group after the &J-week treatment period.

To date, only a couple of methodologically acceptable studies have used a comprehensive battery of cognitive tests to investigate the effects of ginseng.6*7 The results of the present study support the findings of Fulder et al6 in a geriatric population in which the ginseng-treated group was “somewhat better at the coordination and speed test, but tests of concentration and memory . . . gave equivocal results.” D’Angelo et al7 found that ginseng had an effect on the ability of subjects aged 20 to 24 years to perform mental arithmetic.

The composition of the study population must be assumed to play an important role in the magnitude of an effect. Several findings5 have indi- cated that the effect of ginseng appears to be most marked in sick or elderly persons with lower levels of physical and mental functioning. The present study comprised healthy, middle-aged persons with sufficient initiative to volunteer for the study. In this respect, the study population must be characterized as a positive section of the population, and, as such, perhaps less susceptible to a potential effect of ginseng.

The results of cognitive testing cannot be compared with physical or physiologic measurements. Cognitive functions are variable and are influ- enced by various factors, both in the person being tested and in the testing situations. Thus a major effect is required to be reflected in the results of cognitive tests. This may contribute to the differences in findings reported in various investigations. Psychometric properties, such as floor and ceil- ing effects, and the statistical phenomenon of regression toward the mean (ie, on repetition of a test, extreme scores tend to progress to a less extreme score) may be confounding factors.

In our study, the length of the treatment period (8 to 9 weeks) and the dosage of the ginseng extract (400 mg daily) are matters for discussion. There are no valid guidelines for a connection between treatment period, dose, and effect. Branth and Gruber3 administered 170 mg per day of ginseng extract for 8 weeks, Forgo et al2 200 mg for 12 weeks, D’Angelo et al7 200 mg for 12 weeks, and Fulder et al6 X00-mg Korean red ginseng (corresponding to approximately 300-mg ginseng extract) for 10 days. Ful- der recommended a dosage of 2000 to 3000 mg (corresponding to approximately 400 to 600 mg ginseng extract) in future investigations. Several reviews’*‘3 of studies, doses, and side effects of ginseng have been written. These are complicated issues involving pharmacologic and psychologic mechanisms of effect. For instance, the perception of changes in subjective

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phenomena (eg, an alteration in well-being) must be assumed to de- crease in the course of a lengthy period of treatment, due to psychologic adaptation.

Acknowledgment

This study was supported by a grant from Dansk Droge A/S, Ishej, Denmark.

References:

1. Sonnenborn U, Proppert Y. Ginseng (Panax ginseng C.A. Meyer). 2 Phytother. 199O;ll: 35-49.

2. Forgo I, Kayasseh L, Staub JJ. Einfluss eines standardisierten Ginseng-Extraktes auf das Allgemeinbefinden, die Reaktionsfahigkeit, Lungenfunktion und die gonadalen Hor- mone. Med Welt. 1981;32:751-756.

3. Branth S, Gruber P. Ginseng fdrbattrar prestationen! Biomed. 1990;3:14-17.

4. Wiklund I, Karlberg J, Lund B. A double-blind comparison of the effect on quality of life of a combination of vital substances including standardized ginseng G115 and placebo. Curr Ther Res. 1994;55:32-42.

5. Knipschild P. Ginseng: Trick or treat? A review of experiments among elderly people with vitality problems. Pharm Weekbl. 1988;123:1-11.

6. Fulder S, Kataria M, Gethyn-Smith B. A double-blind clinical trial of Panax ginseng in aged subjects. In: Proceedings of the 4th International Ginseng Symposium, Daejeoni

Korea. Seoul: Korea Ginseng & Tobacco Research Institute; 1984:215-223.

7. D’Angelo L, Grimaldi R, Caravaggi M, et al. A double-blind, placebo-controlled clinical study on the effect of a standardized ginseng extract on psychomotor performance in healthy volunteers. J Ethnopharmacol. 1986;16:15-22.

8. Lezak MD. Neuropsychological Assessment. New York: Oxford University Press; 1976.

9. Brickenkamp R. Handbuch Psychologischer und Pddagogischer Tests. Gottingen, Ger- many: Hogrefe; 1975.

10. Kaada B. Placebo-gaten mot sin lesning? Tidsskr Nor Laegeforen. 1986;8:635-641.

11. Berg EA. A simple objective technique for measuring flexibility in thinking. J Gen

Psychol. 1948;39:15-22.

12. Axelrod BN, Woodart JL. Analysis of an abbreviated form of the Wisconsin Card Sorting Test. Clin Neuropsychol. 1992;6:27-31.

13. Owen RT. Ginseng: A pharmacological profile. Drugs Today. 1981;8:343-351.

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