Forget to take your Ginkgo biloba? Turns out, it doesn’t matter

Among the natural products on pharmacy shelves, I was rooting for Ginkgo biloba for the prevention of dementia. For one, dementia is a horrible illness. Secondly, currently available drugs for Alzheimer’s disease (AD) have little meaningful effect. Thirdly, preliminary data with ginkgo for AD looked encouraging. I recall reading this systematic review back in 2000. One sentence jumped out at me (the bolding is mine):

We conclude that for selegiline, vitamin E, lecithin, linopirdine, and propentofylline the published data do not provide support for efficacy. Based on the evidence we reviewed, it is our conclusion that donepezil, metrifonate and rivastigmine, however, all provide statistically significant modest benefit on cognitive performance and global functioning to the elderly with probable AD who are eligible for inclusion in clinical trials. The magnitude of the effect is similar for all of the medications. The results from the trials of ginkgo biloba are promising but the effects are smaller than those from the above mentioned therapies.

So the effect, while weak, was just about as bad as the prescription alternatives. For a “natural” remedy, that’s pretty good. But as with most small clinical trials, what appears to be clinically and statistically significant usually disappears when larger, more rigorous trials are conducted. And that seems to be the case now, with a publication in the December 23, 2009 issue of the Journal of the American Medical Association. But before we dive into the trial, let’s look at why ginkgo is even being studied at all.

The Background

 Ginkgo biloba is a popular product – it’s the most prescribed supplement in Germany (and apparently the treatment of choice for dementia), and is #9 in sales among herbals in the United States ($99 million in 2008).

Ginkgo trees are not only attractive, but their leaves are used to make the medicinal product, usually in the form of an extract. (Ginkgo seeds contain a toxin and are considered unsafe for consumption.) Ginkgo leaves contain several biologically active compounds including flavonoid glycosides and terpinoids. With respect to prevention or treatment of dementia, it’s been proposed that the constituents might work by reducing oxidative damage to neurons, or from providing general anti-inflammatory effect. It has also been proposed that ginkgo improves circulation, perhaps through an antiplatelet effect. Another possible mechanism is that ginkgo might have direct effects by reducing cell death – though this has not been established.

Ginkgo biloba supplements are usually well tolerated. Side effects are typically mild, with stomach upset the most common complaint.  Spontaneous bleeding is the most concerning rare side effect reported with treatment, and there are several case reports of bleeding in the brain and eye that are associated with ginkgo treatment. It’s not certain that ginkgo is the cause, but it’s troubling. Clinical trial results have been reassuring on this point, with reported side effects largely equivalent to placebo. Still, the known antiplatelet effects, and the bleeding case reports, have led to warnings about use in combination with other antiplatelet drugs. It’s not recommended for people with a history of bleeding problems, or in combination with  medications that can increase bleeding risks (warfarin, anti-inflammatories, etc.) Ginkgo seems to reduce the action of some liver enzymes, so it can indirectly affect other drugs as well. Combining ginkgo with any medications, in the absence of consultation with a pharmacist, is not advised.

Ginkgo has been studied extensively, albeit in small, short-duration trials. The Natural Medicines Comprehensive Database rates it “Possibly Effective” for age-related memory impairment, cognitive function, dementia, diabetic retinopathy, peripheral artery disease, premenstural syndrome, Raynaud’s syndrome, and vertigo.

Digging into the dementia research, the issue of poor trial quality is repeatedly cited as a confounder in interpreting the data. Indirect comparisons, like the systematic review cited above, have suggested that if ginkgo does has an effect, it’s more modest than drug treatment.

Before we look at the latest trial, let’s consider how what we’re studying and how we look for an effect. Alzheimer’s is the most common form of dementia in adults. It is progressive, and non-reversible. From the National Institute of Neurological Disorders and Stroke,

Initially, people experience memory loss and confusion, which may be mistaken for the kinds of memory changes that are sometimes associated with normal aging. However, the symptoms of AD gradually lead to behavior and personality changes, a decline in cognitive abilities such as decision-making and language skills, and problems recognizing family and friends. AD ultimately leads to a severe loss of mental function. These losses are related to the worsening breakdown of the connections between certain neurons in the brain and their eventual death.

Evaluating whether a drug (or “natural” remedy) works to prevent dementia is challenging. The disease course is a progressive decline in function – the intent with treatment is to prevent, slow, or delay, that decline. Randomized, controlled, double-blind trials are essential – it is impossible to determine if any treatment has an effect without comparisons to a control group. Because of the challenges with diagnosis, the slow onset, and the gradual decline in function, clinical trials need to be designed carefully. A good trial would follow a large number of patients for a long period. It would also study a large population, so that even a modest effect could be detected. We’d also want to study a population that’s healthy – without dementia, but we might include those with mild cognitive impairment. This would help us answer whether ginkgo useful to prevent dementia.

And that’s exactly what this study set out to answer.

The Study

The Snitz et al study was a follow-on study to the DeKosy et al study published in JAMA in 2008. Briefly, DeKosy established that Ginkgo biloba was not effective in reducing the incidence of dementia or Alzheimer’s disease. This newest study reports on cognitive decline, a pre-defined secondary outcome in the same population as the DeKosy study. The authors sought to determine if Ginkgo biloba affected the rated of cognitive change, and if it had specific effects on different cognitive functions (e.g., memory, language, attention, etc.)

Volunteers aged 75 or older were recruited in four US cities. Those with dementia were excluded, though mild cognitive impairment was acceptable. If you weren’t taking drugs that could interact with ginkgo, and were generally healthy, you were probably eligible for the study. It was a good generalizable sample of the elderly population. This was a huge study: 3069 patients were randomized. The population size was selected to accommodate for patients that would drop out, yet still be large enough to detect a clinically meaningful difference from the ginkgo.

Patients were randomized to either Ginkgo biloba 120mg  twice daily (“EGb 761“, donated by Schwabe Pharmaceuticals) or an identical placebo. This brand of ginkgo biloba is standardized to the main active ingredients, and the dose was chosen based on results from prior clinical trials. Both patients and researchers were blinded to the actual treatment given.

Patients were evaluated when they entered the trial, and regularly with two validated dementia screening test, the 3MSE and the ADAS-Cog. Comprehensive neurological testing was conducted annually starting in the third year of the study. Patients were followed, on average, for 6.1 years in total.

The results can be summarized simply: There was no significant difference between the groups, either overall or in any of the specific cognitive areas tested. There is no evidence that ginkgo has any effect on those that develop dementia, or on cognitive effects of normal aging.

To see if “pre-treating” patients with ginkgo had any effect, the researchers compared results from years 3 to 4 to year 6. Again, no effect.

Criticisms of the Study

The manufacturer of the ginkgo supplement used, Schwabe, dismisses the results. Their criticisms can be summarized as follows, with my comments in [brackets]:

• The placebo group barely declined in function. Ginkgo cannot be shown to be effective when the control group declines so little. [Because of a lower than expected dementia rate in the trial, the trial was extended until the required number of dementia cases occurred that would be sufficient to detect a difference. No difference was noted between the groups.]
• Cognitive performance was measured using a blunt dementia-screening tool. Specific testing didn’t start until 500 patients had left the study. [The authors note this, and did a secondary analysis which was consistent with the primary analysis.  The “blunt” screening tools are validated evaluation tools for dementia (3MSE and ADAS-Cog. No difference was noted between groups.]
• Of patients that remained in the study, only 60% (placebo and ginkgo) were taking the product.  [The study was powered to adjust for this, as non-adherence was evaluated in the intention-to-treat analysis. Notably, adherence was slightly lower (though not significantly) in the ginkgo group.]

Conclusion

The largest and best-designed study to examine Ginkgo biloba has found it ineffective in reducing the incidence of dementia, Alzheimer’s disease, or in reducing the rate of cognitive decline in older adults. This is a persuasive study. In a population that is very close to the “real world” that might consider taking the product, no effect of ginkgo has been shown. The product studied was the most-evaluated ginkgo product and one standardized for active ingredients. Given the documented risks of bleeding with ginkgo, the risk-benefit calculation now tilts strongly away from treatment: There are risks, and no demonstrated benefits.  It’s time for pharmacists to start recommending against self-treatment with Ginkgo biloba for the treatment or prevention of dementia or cognitive decline.

References

Snitz, B., O’Meara, E., Carlson, M., Arnold, A., Ives, D., Rapp, S., Saxton, J., Lopez, O., Dunn, L., Sink, K., DeKosky, S., & , . (2009). Ginkgo biloba for Preventing Cognitive Decline in Older Adults: A Randomized Trial JAMA: The Journal of the American Medical Association, 302 (24), 2663-2670 DOI: 10.1001/jama.2009.1913.

Up-To-Date. Ginkgo Biloba. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2009.

Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2010 [cited 2 Jan 2010] Available from: http://www.naturaldatabase.com. Subscription required to view.