Why the big black hole of uncertainty? It all
comes down to the quality of the studies conducted so far. By understanding
what makes a drug
study tick, you can get some insight into what counts as convincing
evidence in medical research-and
why ginkgo biloba hasn't yet moved from the dietary
supplement racks to the prescription pads of U.S. doctors.
Double blinding. This
insures that neither the patients nor the researchers know who received
the drug until the final results are tallied. Otherwise, the knowledge
of who did and didn't get the drug could influence the scientists
or the study participants.
2. Careful selection of subjects
In a well-done clinical trial, all the participants are screened
carefully for the disease that the drug is supposed to treat.
This sounds obvious, but a lot of health problems have similar
symptoms. For example, both early Alzheimer's disease and depression
can both cause memory impairments.
3. Measuring what matters
In any drug trial, researchers have to choose an appropriate way
to measure the effect of the drug. In trials for Alzheimer's drugs,
for instance, participants undergo standard tests to determine
if the drug reduces memory impairment and other symptoms. The
best clinical trials also check for "clinical
significance," or whether the treatment made a meaningful
difference in patients' lives. If patients taking a new Alzheimer's
drug show a small improvement in a laboratory test of memory,
this is all well and good. But does this improved test score translate
into a decrease in forgetfulness or confusion in everyday life-a
meaningful benefit? Typically, a doctor determines this during
individual meetings with patients. Information from family members
is also included in many studies.
Not many studies of ginkgo have met these standards.
A few years ago, several researchers in Oregon reviewed all the
studies they could find of ginkgo biloba as a treatment for dementia,
focusing on those studies involving people with Alzheimer's disease
(the leading cause of dementia). Out of 50 studies, only four
met the minimum standards for a clinical
trial of a drug for Alzheimer's.
Together, the four studies included 212 subjects
treated with ginkgo and 212 subjects given a placebo. The Oregon
researchers concluded that daily treatment with 120 to 240 mg
of ginkgo for three to six months brought about a small improvement
in test scores, but it did not appear that the change was clinically
There were other problems, too. Past studies
of ginkgo and dementia
(Alzheimer's and other types) were often conducted by a single
scientist, or team of scientists, on patients recruited in one
location. These "single-site" studies cannot be trusted as much
as those conducted at different locations around the country,
explains Lon Schneider, MD, a professor of psychiatry, neurology,
and gerontology at the University of Southern California in Los
Angeles. Single-site studies "are hugely subject to bias, because
at one site the investigator is holding all the cards," Schneider
says. "These are never as compelling as multicenter studies."
trials, any errors or bias contributed by a particular research
group has less of an impact.
Another weakness has been the reliance on small
groups of research subjects. In the clinical trials to test current
Alzheimer's drugs, hundreds of research subjects were involved.
When a study involving a dozen or two subjects claims to show
that ginkgo helps people with dementia, people like Schneider
get suspicious. Was the improvement in one or two people misreported
or mismeasured, which then bumped up the average? "You can show
improvement with 20 people only when there is an exaggeratedly
large and unrealistic effect," he adds. More typically, hundreds
of participants are required just to distinguish drug effects
from those of the placebo.
The JAMA study: almost but not quite
One recent study of gingko for Alzheimer's avoided
some of these pitfalls-the study published in JAMA in 1997. Hundreds
of patients with early Alzheimer's took 120 mg of ginkgo per day
for a full year, and were tested periodically. The study suggested
that ginkgo delayed the progression of the symptoms for up to
six months. These widely-publicized findings influenced many people
to take ginkgo in hopes of preventing or treating Alzheimer's
But when other researchers took a close look,
they found flaws-some fairly serious. For one thing, some of the
people in the placebo group did not worsen as much as they should
have without treatment. "It was not as it ought to be, and it
leaves you wondering if these are truly patients with dementia,"
observes Paul Solomon, Ph.D., a professor of psychology at Williams
College in Massachusetts. Also, the change in mental skills detected
by the study was small-about 25 percent of what would be expected
in a patient treated with existing Alzheimer's drugs, Solomon
The real kicker was the fact that researchers
could not tell the difference between treated subjects
and those on placebo. In other words, the study could not prove
that the effect of ginkgo on these people was clinically significant.
Based on information provided by caregivers and family members,
the researchers did document a difference, although it was relatively
small: for every seven people treated with ginkgo, caregivers
and family members detected improvement in one person on ginkgo.
"The outcome measure that is required in the
United States is that observers who are blinded can notice a difference
in the patients, and no one could notice any difference," Solomon
notes. "If that study was submitted to the FDA
to have a drug approved, it would not be acceptable."
The next wave
Despite all the flaws of past studies, the evidence
was good enough to launch two new and improved studies of ginkgo
for dementia in the United States. In 1999, the National Institutes
of Health (NIH) in Bethesda, Maryland, started a $15 million multicenter
study to determine if treatment with ginkgo either prevents or
delays the onset of Alzheimer's in older people at risk of the
disease. The six-year study will involve 2,000 people recruited
at four locations around the country.
Another large study of ginkgo for dementia concluded
this year. The study is led by Schneider and financed by Dr. Willmar
Schwabe Pharmaceuticals, a company based in Germany. Schwabe is
also supplying the daily doses of ginkgo 240 mg/day) for the NIH
study. The Schwabe trial is a "regulatory
quality" study on the level of the trials on which the FDA
approved current Alzheimer's drugs, Schneider says. It involved
about 500 people with Alzheimer's disease at dozens of different
centers who were given 120 or 240 mg of either ginkgo or a placebo
and followed for six months. The study concluded earlier this
year, and the first results may be announced this summer.
Leaping over the counter
Today, U.S. manufacturers of over-the-counter
ginkgo supplements can make general claims that the herb "helps
memory" or "improves concentration." The brass ring for a pharmaceutical
giant like Schwabe would be to get approval by the FDA to make
so-called "health claims," such as "Delays progression of Alzheimer's
The NIH and Schwabe studies may not provide
the final word on ginkgo and dementia. Clinical trials are so
complex and difficult, it's unusual for a single study, however
well-conducted, to settle a medical controversy like the one swirling
around ginkgo biloba. Often it takes many years for evidence to
pile high enough for experts to reach a consensus. In the meantime,
Alzheimer's treatment will continue to rely on what works: skilled
and compassionate caregivers and the handful of medications that
won a place in physician's formulary by playing by the rules of
The Physician's Desk Reference for Nutritional
Supplements, by Sheldon Saul Hendler Ph.D., M.D., and David
Rorvik. (Montvale, NJ: The Medical Economics Company, Inc., 2001,
700 pp., $59.95). This frank and science-based book reviews the
scientific evidence for ginkgo biloba and other herbal remedies.
The US governments Food
and Drug Administration (FDA) maintains a website with information
on drugs and supplements, as well as information about what claims
a specific product may make: http://www.fda.gov.
To learn more about proven therapies for Alzheimer's
Disease as well as research
on new ones, contact the Alzheimer's Disease Education and Referral
(ADEAR) center. It can answer questions about the disease, provide
free brochures, and offer referrals to patients and caregivers.
Tel: 800-438-4380, or visit the website: http://www.alzheimers.org.
The study by Oregon researchers that reviewed
existing gingko studies:
B. Oken and others, "The efficacy of ginkgo
biloba on cognitive function in Alzheimer disease," in Archives
of Neurology, November 1998, vo. 55, no. 11, pp. 1409-1415.
A few of the many conflicting studies testing
the effects of ginkgo on Alzheimer's disease and dementia, including
the JAMA article cited in the text:
"A placebo-controlled, double-blind,
randomized trial of an extract of ginkgo biloba for dementia,"
by the North American EGb Study Group, in Journal of the American
Medical Association, October 1997, vol. 278, no. 16, pp. 1327-1332.
"The efficacy of ginkgo for elderly people with
dementia and age-associated memory
impairment: new results of a randomized clinical trial," by M.
van Dongen and others, in Journal of the American Geriatric
Society, October 2000, vol. 48, no. 10, pp. 1183-1194.
"A 26-week analysis of a double-blind, placebo-controlled
trial of the ginkgo biloba extract EGb 761 in dementia," by P.
Le Bars and others, in Dementia and Geriatric Cognitive Disorders,
July-August 2000, vol. 11, no. 4, pp. 230-237.
(c) 2001 Corbis