Having trouble remembering to take your Ginkgo supplement? The pills themselves might not help with that forgetfulness—or any other age-related cognitive decline, according to a new study published online Tuesday in JAMA, The Journal of the American Medical Association.

"Compared with placebo, the use of G. biloba, 120 milligrams twice daily, did not result in less cognitive decline in older adults," the authors of the study concluded.

The randomized, double-blind, placebo-controlled study is the largest of its kind, having followed 3,069 older adults (72 to 96 years old) who started the trial with no or only mild cognitive impairment. After following the individuals for six years, administering regular testing and interviewing people close to them, the researchers found that those who had been given gingko pills performed the same in memory, language, attention, visuo-spatial judgment and executive function tests as those in the placebo group.

The authors, whose research was supported by the National Institutes of Health's National Center for Complementary and Alternative Medicine among other government groups, expected to see at least minor benefits in the ginkgo cohort. "We're a bit surprised [ginkgo is] as ineffective as it turned out to be," says Steven DeKosky, vice president and dean of the University of Virginia School of Medicine in Charlottesville and study co-author. Laboratory tests of the substance have shown "biological effects that give you a pretty good rationale" for expecting it to help shield neural cells, he says. And given the herb's antioxidant properties, many researchers have anticipated positive findings in human subjects.

An analysis published last year in JAMA using the same data pool, the Ginkgo Evaluation of Memory (GEM) study, found that the herbal supplement was ineffective in preventing Alzheimer's disease. Still, DeKosky and his colleagues thought they might uncover more specific cognitive functions, such as language or executive function, that were being aided by ginkgo. In many treatment studies, he explains, differences often emerge on a small scale, "but we didn't see any differences."

The ginkgo plant has been used in traditional Chinese cooking and medicine for at least 1,500 years, and the tree itself dates back some 270 million years. In modern form, extracts from the Ginkgo biloba's leaves are often ground up into pill capsules and taken for everything from memory loss to tinnitus (ringing in the ears). In the GEM study, a standard ginkgo extract—manufactured by German-based Schwabe Pharmaceuticals—was given alongside an identical placebo made by the same company.

Although regimented scientific studies have felled one herbal treatment after the next in recent years (including the popular Echinacea supplement), many researchers maintain that they are not simply out to debunk these complementary treatments. "We're always hoping to find something," says DeKosky, who studies Alzheimer's disease.

Williams College professor Paul Solomon, who did not contribute to this study, agreed, saying he would be "delighted" if gingko works, adding: "It's relatively inexpensive, and it has relatively benign side effects." It is always possible a future study will show benefits, he says, but he thinks that, "the likelihood of that is remote."

The new paper did not examine other purported benefits of the supplement, such as improved vascular functioning or reductions in tinnitus. And those in the herbal products industry have noted that these older adult studies do not show whether such supplements can have benefits if they are taken starting in young or middle age. But in such long-term studies—following people from their 50s to their 80s, for example—it can be difficult to maintain strict monitoring and blinds, DeKosky says.

Early studies in the 1990s, which were broadly embraced by the media and public, reported positive cognitive results from ginkgo supplements. But none of these studies have stood up to scrutiny over time, says Solomon, who co-authored a paper earlier this year in Evaluation & the Health Professions proposing more rigorous guidelines for evaluating the cognitive benefits of alternative medicines.

As for the placebo effect, says DeKosky, it is unlikely to play much of a role in long-term studies like GEM. Rather it is something that researchers are more likely to encounter "very early on" in treatment or short studies. Although the follow-up intervals of this study were not designed to detect such an effect, it is unlikely it would persist for several years, he says. Additionally, notes DeKosky, if patients are thinking about the supplement logically, they wouldn't expect to see results right away. "It wouldn't be logical for a drug that has lots of antioxidants to have a short-term effect of increasing your thinking function. We take them for the longer term."

For his patients, Solomon does not recommend the supplement to treat or prevent Alzheimer's disease or to help with age-related memory problems. DeKosky has similar advice. He notes that "it makes more sense to eat better, exercise and do all of the other things we already know are good for cognitive health" rather than popping unproven pills.

Although DeKosky admits he was disappointed to not find even a hint of help from this herbal supplement, he calls the study itself a success. Recruiting and maintaining such a large group of community-based elderly—and their willing proxies to interview—for six years was no small feat. More of these studies will come, he says, and in the meantime, the research group will continue parsing the data collected from GEM. Next on the list will be to see if the ginkgo had any impact on cardiac disease rates or peripheral vascular disease. The group also plans to image the brains of hundreds of individuals to look for clues and follow some into their late old age.

Solomon, for one, isn't holding his breath for good news from this supplement as a brain booster. "I think it's probably time to throw in the towel for ginkgo," he says. "I think it's time to look for something else."