By David Kiefer, MD, Editor

Clinical Assistant Professor, Department of Family Medicine, University of Wisconsin; Clinical Assistant Professor of Medicine, Arizona Center for Integrative Medicine, University of Arizona, Tucson

Dr. Kiefer reports no financial relationships relevant to this field of study.

SYNOPSIS: Cognitive improvement in women after treatment with Ginkgo biloba may be mediated by changes in cardiovascular reactivity.

SOURCE: Ong Lai Teik D, Lee XS, Lim CJ, et al. Ginseng and Ginkgo biloba effects on cognition as modulated by cardiovascular reactivity: A randomised trial. PLoS One 2016;11:e0150447.

SUMMARY POINTS

  • Two different doses of Panax ginseng did not affect cognition.
  • Ginkgo biloba affected some aspects of cognition (executive functioning), but only in women.
  • It appears that some of Ginkgo biloba’s cognitive effects can be explained due to changes in cardiovascular measurements, a correlate for cardiovascular reactivity.

What’s the magic bullet to stave off cognitive decline or help people with dementia to regain some of their mental function? There is likely no such cure, but research from many different disciplines has found treatments of varying efficacy for sufferers of dementia. This study examined two herbal medicines, Ginkgo biloba (ginkgo) and Panax ginseng (“ginseng,” Asian or Korean ginseng), with a history of use for improvement of mental function in the context of both health and disease; the authors provided numerous references to these effects. Specifically trying to establish a mechanism of action for these two plants, the authors used changes to the cardiovascular system as a proxy for stress and stress management to connect those effects to concomitantly administered cognitive analyses. They provided a methodological framework for the connection between stress and adverse cognitive effects, as well as cardiovascular changes (i.e., heart rate variability and blood pressure reactivity) that purportedly tie into stress and stress management. This model seems like a viable way to comment on each plant’s mechanism of action, even if it has not been corroborated previously. The research question is compelling: Essentially, could these two plants moderate stress, which then could improve executive functioning?

Undergraduate student volunteers were recruited in Helsinki for this study, but were excluded if they regularly consumed caffeine, ginkgo, or ginseng; if they took medications that interacted with ginkgo or ginseng; or if they had hormone-sensitive conditions, autoimmune disorders, diabetes, heart conditions, or bleeding disorders. A total of 48 participants (28 women, 20 men) then were included in this study, and were randomized in a crossover, double-blind, placebo-controlled fashion to ginkgo (n = 24) or ginseng (n = 24). Within each herbal arm, the study participants received two different doses of the herbal medicine or placebo over three different days. The ginkgo dose was either 120 mg or 240 mg of a patented ginkgo extract (GBE24/6) standardized to 24% flavone glycosides and 6% terpene lactones. The ginseng dose was either 500 mg or 1,000 mg of an extract (GNC) standardized to 3% ginsenosides. On the three testing days, the authors administered a battery of tests. (See Table 1.) To analyze the results, the researchers used a complicated procedure that repeated the cognitive tests until improvement was less than 5% on a subsequent test. This allowed the researchers, as per validated prior research, to ascribe changes in testing to ginkgo or ginseng, rather than learning of the testing regimen. In addition, blood pressure and heart rate were measured both before and after the cognitive testing during each testing day.

Table 1: Testing of Study Participants

Given on three separate testing days for the three treatment arms (placebo, herbal dose 1, herbal dose 2)

Cognitive Tests (Function Analyzed)

Cardiovascular Testing

Visual search (selective attention, working memory)

Psychomotor vigilance task (selective attention, simple reaction time)

Stroop task (selective attention, impulsivity, cognitive flexibility)

Bechara’s gambling task (decision making, impulsivity)

Berg’s card sorting test (complex executive functioning)

Tower of London (overlapping cognitive domains)

Blood pressure

Heart rate

With respect to results, for all of the cognitive tests, there was no difference compared to placebo for either of the doses of ginseng. In the case of ginkgo, there was a statistically significant decrease in the number of errors committed in the Berg’s and Stroop tests (P = 0.004-0.011, and P = 0.017, respectively), for both doses, but only for women. In men taking ginkgo, either there was no effect (for most cognitive measures), or, in one subset of the Berg’s card sorting test, a small increase in errors (P = 0.004).

The next set of analyses addresses the primary aim of the study, namely “…to understand whether the effects of [ginseng] and [ginkgo] on cognitive performance may be associated with changes in cardiovascular reactivity.” As a start, the authors noted that during some of the cognitive tests (mostly the Stroop and Bechara’s gambling tasks), the placebo group showed an increase in systolic blood pressure, likely due to the difficulty of the tests. During these same tests, high-dose ginkgo was shown to reduce diastolic and systolic blood pressure. Also, in women, high-dose ginkgo reduced diastolic blood pressure after Berg’s testing. In contrast, for high-dose ginseng, after visual search and the psychomotor vigilance task, there was an increase in diastolic blood pressure and an increase in heart rate (considered “somewhat surprising” by the authors.) These latter tests are considered less difficult, and, as such, had less of an increase in cardiovascular parameters from baseline; the authors weren’t surprised that there wasn’t an improvement in these values with herbal treatment, although the ginseng-caused increase in blood pressure was a surprise (see below).

Of note, the above-mentioned effects are relative, not absolute, changes in cardiovascular reactivity. The authors noted surprise “baseline” herbal cardiovascular effects that varied for ginkgo compared to ginseng. (See Table 2.) For example, 60 minutes after treatment but before the cognitive effects, the higher dose of ginkgo raised blood pressure (diastolic and systolic), whereas the higher dose of ginseng lowered only diastolic blood pressure. Compared to placebo, other parameters remained unchanged.

Table 2: The Effect of Ginkgo and Ginseng on Blood Pressure and Heart Rate

The effect of ginkgo and ginseng, both doses, on blood pressure and heart rate when compared to placebo, 60 minutes after treatment but before the cognitive testing (considered a “baseline”). Only statistically significant effects are mentioned.

 

Low-dose Ginkgo

High-dose Ginkgo

Low-dose Ginseng

High-dose Ginseng

Diastolic blood pressure

 

Higher

 

Lower

Systolic blood pressure

 

Higher

   

Heart Rate

       

COMMENTARY

The interpretation of this study, and teasing out possible cause-effect explanations is difficult. What we can say for sure is that both plants had cardiovascular effects (see Table 2), which were not generally observed in prior studies, although it is unclear why ginkgo raised blood pressure at baseline. The authors venture detailed, and referenced, mechanism of action research about ginkgo, not unlike reviews on the topic.1 The positive effects for dementia and memory better support another conclusion found in this paper: ginkgo improved subsets of cognitive testing and reduced blood pressure after some, but not all, cognitive tests.

We also know that ginseng did not fare well in this study. A well-known adaptogen that affects the hypothalamus-pituitary-adrenal axis, and its resultant “stress hormones,”2 ginseng would be expected to improve post-testing cardiovascular reactivity, just as it did during the baseline testing (lower diastolic blood pressure). However, not only did ginseng have no effect on the cognitive tests when compared to placebo, but it increased cardiovascular reactivity after some of the less anxiety-provoking tasks. This “surprising” finding could be due simply to the minimal overall change documented; less difficult tasks caused less of a response in the placebo group, making it difficult to elicit a treatment effect with the herbal medicines. These subtleties might need more extreme conditions to generate positive effects. Also, rarely would single doses of herbal medicine be expected to change symptoms in a clinical practice. The next step for these researchers, hopefully, will be to expand the length of the trial to weeks or months, more in line with how these medicines are prescribed typically, as well as to recruit patients of a variety of ages perhaps to examine the plants’ preventive effects.

The gender effect deserves mentioning, not only because the authors correctly state that it is the first published study of a gender difference in cognitive effects to ginkgo treatment. But why did this happen? The authors mention different gender responses to psychological stressors as one possible explanation for the herbal effects and the cardiovascular reactivity. Their references to prior work, as well as cerebral foci correlates, support this. Overall, it seems like there was a lot of discussion for a few data points (and low study participant numbers) that will be much more convincing, and clinically interesting, when this is repeated on a larger scale, perhaps with a less-complicated study design. Overall, these results are interestng in the context of stress management and cognitive performance, but the herbal medicine effects are too piecemeal to generate much clinical optimism. It does tie herbal medicine effects to both cognition and cardiovascular effects, which partly corroborates their traditional and more modern clinical use. A cure-all for dementia? Probably not. Something to be recommended to all women patients? Not yet, but wait for follow-up research to refine this. And, for men? Talk to your patients about individualized integrative therapeutics that may be better suited (in this study we saw a worsening of symptoms) to their cognitive symptoms than ginkgo or ginseng, but, again, for now.

REFERENCES

  1. Hashiguchi M, Ohta Y, Shimizu M, et al. Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia. J Pharm Health Care Sci 2015;1:14. doi: 10.1186/s40780-015-0014-7.
  2. Kiefer D, Pantuso T. Herbal medicines: Panax ginseng. Am Fam Physician 2003;68:1539-1542.