In our study, treatment with ginkgo did not result in any improvement in cognitive performance. Our study had sufficient power to detect effects thought to be clinically significant. Smaller effects could have been missed, but the confidence intervals suggest that they would be relatively small (at most 0.3 SD for the corresponding normative data). We did not observe an interaction between baseline performance and treatment effects that could suggest a benefit restricted to those who were more severely impaired. Ginkgo was well tolerated; the 2 serious AEs were isolated and were not previously seen in trials with ginkgo.
Our study had several methodologic strengths. We used a high-quality product with a standardized concentration of active compounds. Our subjects were very motivated to complete the trial and compliant with the protocol, and we had very few subjects lost to follow-up. Our primary outcome analyses were intent-to-treat, and we included susceptibility analyses limited to the completers, all of which showed no significant differences.
There are some limitations to this study. Minorities were underrepresented, limiting the generalizability of our results mainly to Caucasians. Subjects received ginkgo for only 12 weeks. Although we believe this was long enough to detect symptomatic improvement in cognitive performance, it was not long enough to determine whether ginkgo had any disease-modifying effects. Our subjects had a long disease duration (median 20 years), and, thus, it is possible that Ginkgo may improve cognitive performance early in the disease process. Our sample had mild impairment overall and mainly were impaired on the PASAT and mostly below average on the CVLT-II. Although we did not see interactions with baseline performance or in the post hoc subgroup analyses to suggest so, it is possible we could have seen a positive effect if we had recruited a sample of subjects more impaired on attention and verbal fluency tests or with impairment in verbal learning.
Our current study did not show a significant effect on cognitive performance, whereas our pilot study did show an effect restricted to the Stroop Test. In our pilot study, we enrolled 43 subjects with MS who scored between 0.5 and 2.5 SDs below the mean on the PASAT or the CVLT-II total score. Thus, very impaired subjects in these 2 tests were excluded in our pilot study, whereas they were eligible for our current study. It is unlikely that this change in classification accounted for our findings because we did not see any differences in the post hoc analyses that restricted the sample to only impaired subjects. The cognitive test battery used in the pilot study included the same tests used in this study plus the Symbol Digits Modalities Test and the Useful Field of View Test, neither of which showed a difference in the pilot study, so the difference in the batteries is not a likely explanation for the different outcomes.
Subjects in our pilot study were randomly assigned to receive either placebo or the same dose of ginkgo as used in our current study and the duration of treatment was the same; however, the manufacturer of the products used in our pilot and current studies were different. Both products had similar concentrations of the active compounds, so it is unlikely that a difference in the products was responsible for the different outcomes.
A more likely explanation for the difference in findings between the pilot and the present study is that there is really no effect and the pilot study results were due to chance. With a p level of 0.05, 1 in 20 trials will produce false-positive results. In addition, the sample size of our pilot study was relatively small, and we used parametric statistics in the analyses. The effect in the pilot study was limited to the Stroop Test and was much more prominent in participants with the greatest impairment. The Stroop Test does not have a normal distribution, and, thus, the results of the pilot study might have been more influenced by extreme observations, whereas the effects of outliers are smaller when a larger sample is used, as in the current study.
In our pilot study, we had 2 practice sessions before the baseline assessment to minimize the effects of practice. In the analysis of the pilot data, we noted there was still some residual practice effect between the third (baseline) and fourth (exit) visits because the placebo group continued to improve. In addition, the performance on the CVLT and PASAT in the pilot approached the ceiling for these measures, limiting our ability to see an effect. For these reasons we chose a harder version of the PASAT and omitted the practice visits. It is possible that the elimination of the practice visits could account for the different results.
Our test battery was limited, and it is certainly possible that we did not include a test for which ginkgo would have an effect. However, we assessed the most important cognitive domains that are affected in MS. A larger battery might have been more informative but would have also required a larger sample size.
We included self-report measures that assessed the reports of the subject's cognitive function from both the participant's and caregiver's perspectives and that did not show any treatment effect. It is possible that additional functional assessments that measure performance in real-life situations could have detected an effect that we missed by limiting the outcome measures to cognitive tests and questionnaires.
This study represents the third large double-blind placebo-controlled trial of a therapy thought be effective in AD that has failed to improve cognitive performance in MS. Donepezil, memantine, and now ginkgo all have Class I data indicating that they are ineffective in improving cognitive performance in MS.5,6
In AD, donepezil is believed to improve cognitive impairment by increasing acetylcholine, whereas memantine works by antagonizing glutamate effects on the NMDA receptors in a use-dependent manner. Ginkgo antagonizes PAF and thus may have an effect similar to that of memantine on glutamate neurotransmission. Based on the negative results of these 3 studies, it is tempting to hypothesize that the biochemical underpinnings of cognitive dysfunction in AD and MS differ and neither an acetylcholine deficit nor an excess glutamate may be critical to cognitive dysfunction in MS. Better understanding of the pathophysiology of cognitive dysfunction in MS is needed to rationally design therapeutic strategies for this significant complication of MS.