The March 2013 National Toxicology
Program’s (NTP) technical report on toxicology and carcinogenesis studies of a particular Ginkgo biloba extract (GBE) in animals1 elicited a number of widely varying
responses from news, nonprofit, and herb and dietary supplement industry
organizations. The NTP is a division of the National Institutes of
Environmental Health Sciences (NIEHS) of the US National Institutes of Health. Media
reports seized upon the authors’ findings of cancer in rats and mice after two
years of being force-fed high doses of GBE;2 various nonprofit and industry
organizations produced press releases criticizing the studies’ relevance to
humans and test material used;3-5 the Center for Science in the
Public Interest (CSPI) downgraded ginkgo’s classification from “safe” to
“avoid” in its Chemical Cuisine guide;6 and consumers were left with
more confusion than clarity.
In June 2013, CSPI took additional action against the herb, calling on the US
Food and Drug Administration (FDA) to ban ginkgo from all foods and dietary
supplements.* The organization urged the FDA to “inform the dietary supplement
industry that Ginkgo poses a substantial and unreasonable risk to consumers,
provides no benefit to consumers, and [should] be removed from the market
within a specified period of time.”7
At the time of this writing, the FDA has
not officially responded to CSPI’s ginkgo letter; however, since the
publication of the NTP report, the FDA issued a warning letter to a company that
sells a Ginkgo biloba-containing
product. In a letter dated March 28, 2013 to Stewart Brothers, Inc., FDA warned
that the company’s SuperBerry Fruit Juice Drink Blend was adulterated because
ginkgo is not currently classified as “generally recognized as safe,” or GRAS,
and it “bears or contains an unsafe food additive.” The FDA referenced the
NTP’s findings of “carcinogenic activity in animals,” which, according to the
letter, renders it adulterated under Section 402(a)(2)(C) of the Federal Food,
Drug, and Cosmetic Act.8
Despite
the warning letter, FDA press officer Tamara Ward — who works with the Office
of Dietary Supplements and Food Enforcement Actions — said the FDA is not
likely to take any immediate drastic action based on the findings of the
toxicology and carcinogenicity report.
“While
FDA is concerned about the findings of the studies, and will consider the
implications it may have for the safety of dietary supplements containing Ginkgo biloba, it is not scientifically
valid to conclude with certainty that dietary supplement products containing Ginkgo biloba are unsafe based solely on
data from the new NTP study,” Ward wrote (email, July 25, 2013).
Other
major regulatory bodies, such as the European Medicines Agency (EMA), have been
hesitant to draw strong conclusions from the NTP study. After the publication
of the report, the EMA’s Committee on Herbal Medicinal Products (HMPC) delayed
the publication of its Ginkgo biloba
extract monograph and consulted with a panel of toxicologists to review the
NTP’s findings (W. Busse email to M. Blumenthal, July 31, 2013). According to a
report from the Working Party on Community Monographs and Community List, which
convened in July 2013, “[t]he HMPC concluded that at present there is no proof
for an increased cancer risk identified for patients taking Ginkgo medicinal
products at their approved posology [dosage].”9
Toxicology studies, such as
the recent NTP report, undoubtedly play a useful role in determining the
potentially harmful nature of substances from synthetic or natural chemicals to
food additives to, less frequently, herbal extracts. The latest report from the
NTP is the first such report to address the potential hazard of the specific
GBE used in the studies. In fact, according to NTP’s records of such studies,
which date back to 1976, only a handful of herbs or herbal extracts has even
been analyzed by the program (see Tables 1 and 2).10
Table 1. National Toxicology Program Carcinogenicity and/or
Toxicology Studies on Herbs
|
Year
|
Common Name
|
Latin binomial & Family
|
Plant Part & Preparation
|
Subjects
|
2010
|
Aloe vera
|
Aloe vera,
Xanthorrhoeaceae (Syn. A. barbadensis)
|
Gel, whole-leaf, or decolorized
whole-leaf extracts
|
Mice
|
2013
|
Aloe vera
|
Aloe vera,
Xanthorrhoeaceae
(Syn. A. barbadensis)
|
Nondecolorized whole-leaf
extract
|
Mice, Rats
|
2010
|
Goldenseal
|
Hydrastis canadensis, Ranunculaceae
|
Root powder
|
Mice, Rats
|
2011
|
Milk thistle
|
Silybum marianum, Asteraceae
|
Fruit extract
|
Mice, Rats
|
2011
|
Ginseng (Asian)
|
Panax ginseng, Araliaceae
|
Root extract
|
Mice, Rats
|
2012
|
Senna
|
Senna alexandrina, Fabaceae
|
Pod extract
|
Genetically Modified Mice
|
2012
|
Kava
|
Piper methysticum, Piperaceae
|
Root extract
|
Mice, Rats
|
2013
|
Ginkgo
|
Ginkgo biloba, Ginkgoaceae
|
Leaf extract
|
Mice, Rats
|
Table 2. Reported Levels of Carcinogenic Activity in NTP Herbal
Studies
|
Herb
|
Conclusions
|
Aloe vera (2010)30
|
Slightly enhanced
photocarcinogenic activity
|
Aloe vera (2013)31
|
Clear evidence of carcinogenic
activity in male and female rats
No evidence of carcinogenic
activity in male and female mice
|
Goldenseal32
|
Clear evidence of carcinogenic
activity in male and female rats
Some evidence of carcinogenic
activity in male mice
No evidence of carcinogenic
activity in female mice
|
Milk thistle33
|
No evidence of carcinogenic
activity
|
Ginseng34
|
No evidence of carcinogenic
activity
|
Senna35
|
No evidence of
carcinogenic activity in male and female mice
|
Kava36
|
Equivocal
evidence of carcinogenic activity in male rats
No evidence of
carcinogenic activity in female rats
Clear evidence of
carcinogenic activity in male mice
Some evidence of
carcinogenic activity in female mice
|
Ginkgo37
|
Some
evidence of carcinogenic activity in male and female rats
Clear
evidence of carcinogenic activity in male and female mice
|
The independent nonprofit ABC, plus herb and dietary supplement industry
organizations including the American Herbal Products Assocation (AHPA) and Natural
Products Assocation (NPA), cited numerous limitations, potential flaws, and
other issues with the NTP studies and report, many of which fall into three general
areas of primary concern: (1) the application of toxicology and carcinogenicity
studies in rodent models has questionable and debated relevance to actual human
use (the NTP report itself notes that the results are not applicable to other
species of animals other than rodents, particularly humans, per below); (2) the
extract used in the studies does not appear to conform to the GBEs available in
the US marketplace or those listed in internationally recognized pharmacopeias
or other compendia; and (3) such GBEs that have been the subject of numerous
preclinical studies and dozens of human clinical trials have a reasonably long
history of safe use and known benefits.3-5
The NTP Ginkgo Studies
In
hazard-identification toxicology studies, scientists feed animals — in this
case, laboratory mice and rats — higher-than-normal doses of the ingredient in
question in order to determine if a material should be evaluated for potential
toxicity to humans. According to an April 29th, 2013 New
York Times article about the NTP report, “It is a valid criticism, as
doses used in toxicology studies tend to be very high. In the new ginkgo study,
mice were given up to 2,000 milligrams of extract per kilogram of body weight,
or just over 900 milligrams per pound of body weight, five times a week.”
“Dosages sold for human consumption,” the Times author noted,
“range from 30 to 120 milligrams, regardless of body size.”2
ABC, in
its public response to NTP on the draft ginkgo report submitted in February
2012, noted that the doses given to the rodents were 55-108 times higher than
the normal human levels of consumption of standardized GBE.3,11
The NTP
makes this point in its “Explanation of Levels of Evidence of Carcinogenic
Activity” in the report, in which it states, “Positive results demonstrate that
a chemical is carcinogenic for laboratory animals under the conditions of the
study.” It continues, “Thus, the actual determination of risk to humans
from chemicals found to be carcinogenic in laboratories requires a wider
analysis that extends beyond the purview of these studies”1 [emphasis
added].
The four
main conclusions drawn by the NTP study authors from the two-year gavage
studies include the following:
(1) [T]here was some
evidence of carcinogenic activity of Ginkgo biloba extract
in male F344/N rats based on increased incidences of thyroid gland follicular
cell adenoma;
(2) There was some
evidence of carcinogenic activity of Ginkgo biloba extract
in female F344/N rats based on increased incidences of thyroid gland follicular
cell neoplasms;
(3) There was clear
evidence of carcinogenic activity of Ginkgo biloba extract
in male B6C3F1/N mice based on increased incidences of hepatocellular carcinoma
and hepatoblastoma; and
(4) There was clear
evidence of carcinogenic activity of Ginkgo biloba extract
in female B6C3F1/N mice based on increased incidences of hepatocellular
adenoma, hepatocellular carcinoma, and hepatoblastoma.1
Interestingly,
the New York Times article also noted
that “[i]n some instances, the number of cancers exceeded the numbers ever seen
in mice in the lab.”2 According to Robin Mackar of the Office of
Communications and public liaison for NTP and NIEHS, this comment was referring
specifically to “the incidences of hepatoblastoma [a rare, undifferentiated variant
of hepatocellular carcinoma] in the livers of male and female mice, [which]
were among the highest observed in NTP studies” (email, July 17, 2013). The exact
reasons for this unusually high incidence level are unknown.
Ginkgo biloba Extract Used in NTP Studies
In its
early 2012 comments submitted to NTP regarding a draft copy of the report
(which was released in late 2011 for public comment), ABC voiced concern
over the specific GBE used in the studies: Shanghai Chinese Ginkgo Biloba
Extract (SC-GBE), manufactured by the Shanghai Xing Ling Science and Technology
Pharmaceutical Company, Ltd., China.11
SC-GBE
has a different chemical profile from what is commonly considered the gold
standard of GBEs — Willmar Schwabe Pharmaceutical Co.’s EGb 761® (Karlsruhe,
Germany), which is manufactured in a way that is consistent with numerous
“official and authoritative monographs and compendia,” including the American
Herbal Pharmacopoeia, the German Commission E Monograph, the United States
Pharmacopeia, the Pharmacopoeia Europa, and the World Health Organization.11
Specifically, the SC-GBE used in the NTP trial was stated in the report to have
31.2% flavonol glycosides, 15.4% terpene lactones, and 10.45 +/- 2.40 parts per
million (ppm) ginkgolic acids, a potentially allergenic compound. EGb 761 is
standardized to 22-27% ginkgo flavonol glycosides, 5.4-6.6% terpene lactones,
and less than 5 ppm of ginkgolic acids.11
In an
email response to HerbalEGram, lead NTP study scientist Dr. Cynthia Rider, PhD,
explained the committee’s decision to use SC-GBE. “When we were unable to
procure bulk EGb761 (our originally intended test article) from Schwabe, the
previous study scientist for Ginkgo biloba extract (GBE),
contacted colleagues in industry to ask for reputable sources of bulk GBE,” she
said (email, April 29, 2013). “He received information from an industry contact
that recommended Shanghai Xing Ling as a source of bulk GBE that was sold in
the US and Europe.”
Despite
the use of SC-GBE instead of the intended EGb 761, the NTP report’s authors
classified the extract as “comparable to the Schwabe extract.” Dr. Rider noted,
“One thing that I have not seen in the media is a discussion of the variability
in the concentrations of constituents in GBE products available in the
marketplace. There are no enforced standards for constituents in dietary
supplements and there have been several studies that have compared constituents
of GBE products in the US and Europe that have found varying levels of marker
components and a lack of conformation to label claims (Fransen et
al. 2010; Kressmann et al. 2002; Sloley et
al. 2003).”
However,
AHPA’s former Chief Science Officer Steven Dentali, PhD, in a chart showing
percentages of flavonol glycosides and terpene lactones in various GBEs on the
market from NTP references, demonstrated that the SC-GBE used in the NTP
studies (identified as “NTP 578” on AHPA’s graph) falls well outside the range
of the typical concentrations of these two GBE constituent classes.4
“I had to
add a quadrant just to fit it in,” Dentali was quoted as saying in a
NutraIngredients-USA article.12 “This is an outlier. Their study
results are specific to the material they studied.”
Further,
in its analysis submitted in early 2012, during the public comment period for
the original draft report, AHPA was unable to find evidence that SC-GBE is sold
anywhere in the US marketplace.13 An additional point of
consideration raised by both ABC and AHPA in their public comments regarding
the nonconformity of SC-GBE to other well-known GBEs was the use of corn oil as
the vehicle of administration in the NTP rat and mice studies.
“NTP has
long-used corn oil as a vehicle,” said Bill Gurley, PhD, a professor of
pharmaceutical sciences at the University of Arkansas for Medical Sciences
College of Pharmacy and a co-author of ABC’s 2012 comments to NTP regarding its
draft report (email, April 29, 2013). “Several studies have shown that
prolonged administration of corn oil can produce some unexpected toxicities.
The problem is that botanical extracts are not consumed in conjunction with
corn oil by humans on a chronic basis. This alone makes the study results
applicable only to this group of [animals]. In general, corn oil can improve
the oral bioavailability of many phytochemicals and thus may increase the
toxicity and/or carcinogenicity of certain phytochemicals (e.g., ginkgolic acids).”
Dr. Rider
responded by noting that the NTP studies used a group of control animals that
were fed corn oil alone. The use of a control measure is one way to ensure that
the ingredient in question is the cause of any cancers or toxicities, not the vehicle
itself.
“Water,
methylcellulose, and corn oil were explored as potential ‘vehicles’ for GBE,”
Dr. Rider wrote in an email to HerbalEGram. “The best suspension was achieved
with corn oil, which is the reason it was selected as the vehicle. In all NTP
studies the effects of a given test article are always compared versus animals
exposed to the ‘vehicle’ (in this case corn oil) alone. The concurrent vehicle
control group for the GBE studies, as well as the ‘corn oil gavage’ historical
control database (past studies of where corn oil was used as the vehicle),
provides a basis for observing the effects of GBE treatment.”
However,
some experts, like Dr. Gurley, remain unconvinced. “If the Shanghai [GBE]
contained higher levels of ‘actives’ and ‘toxic’ agents, then you would expect
it to be more problematic, especially when administered with corn oil, which
will dramatically improve the bioavailability of most of these phytochemicals,”
he said. “In my opinion, the Shanghai extract is an anomaly that is not reflective
of most of the ginkgo extracts consumed in Europe or the US.”
Although
much industry attention has focused on SC-GBE, some see the NTP report’s
applicability to humans as a more significant issue.
“Despite
concerns over whether or not the appropriate test material was selected, the
bigger question remains,” said
Rick Kingston, PharmD, clinical professor at the College of Pharmacy at the
University of Minnesota and president of regulatory and scientific affairs at
SafetyCall International. “Why is it so difficult for people to understand that these results
have no applicability in determining the likelihood of humans developing cancer
after using these products? Unfortunately, a number of scientists involved
in discussing or interpreting the results of these studies have done nothing to
make this point clear. And, in some cases, they have clearly
misrepresented the findings which has added more confusion to the issue”
(email, October 10, 2013).
A History of Safe Use and Demonstrated Benefits
Despite
multiple concerns about the specific extract used in the NTP studies, various
experts and industry organizations have expressed concern that the widely
circulating reports of potential “Ginkgo biloba” toxicity and
carcinogenicity will deter individuals from consuming supplements that have
shown very few serious adverse effects and have demonstrated benefits in
clinical trials conducted on other GBEs, such as EGb 761.
“Such
health benefits are relevant in both clinical medicine as well as in selfcare,
as documented by numerous published clinical trials,” ABC’s Founder and
Executive Director Mark Blumenthal, and other co-authors, wrote in ABC’s early 2012
public comments on the NTP draft report.11 “We are deeply
concerned that any final report from NTP based on the toxicology of the
Shanghai Chinese GBE used in the NTP studies — which we have adequately shown
is not consistent with the proprietary ginkgo extract that has been employed in
most of the published pharmacological and clinical trials, and which is not
consistent with the specifications established and officially recognized in
numerous government monographs on ginkgo — will have an erroneous, undeserved,
and unwarranted adverse effect on professional and public perceptions of the
relative safety of the appropriately manufactured ginkgo extract.”
Interestingly,
NTP noted a number of historic uses of various parts of the ancient ginkgo
tree in its final report introduction.1 “Seeds from the ginkgo tree
have been used medicinally dating back thousands of years. In Chinese
medicine, Ginkgo biloba seeds have been used to treat
pulmonary issues, alcohol abuse, and bladder infections, while ginkgo leaves
came into use later to treat skin infections, as well as heart and lung
disease,” the authors wrote. “Current use of Ginkgo biloba extract
centers on leaf-based preparations for the promotion of circulation and brain
function, and the treatment of tinnitus.”
In
2009, Reiner Kaschel, PhD, clinical neuropsychologist at the University of
Osnabrueck in Germany, undertook a literature review of 29 published clinical
trials to assess the effects of GBE — most of which were EGb
761 — on various aspects of mental performance.14 According
to Schwabe’s website, “[Twenty nine] studies with a total of 2,414 participants
being either healthy old adults or patients showing first signs of cognitive
decline provided the database for the review. In total, 209 Ginkgo-placebo
comparisons were analyzed with the result that in all cognitive functional
areas examined, Ginkgo extract showed significant positive effects compared to
placebo.” Beneficial effects “could thus be proven in areas including but not
limited to short- and long-term memory, concentration, attention and executive
functions with a probability 4-8-fold higher than expected purely by chance.”15
Dr.
Kaschel concluded, “There is consistent evidence that chronic administration
(of Ginkgo extract) improves selective attention, some executive processes, and
long-term memory for verbal and non-verbal material.”15
The
professional and public perception of the efficacy of ginkgo has been
confounded by the results of two large-scale, long-term clinical trials of GBE
in recent years, which failed to find such robust results in the area of prevention of
dementia and related cognitive function, including Alzheimer’s disease (AD).
The Ginkgo Evaluation of Memory (GEM) Study — co-funded by five branches
of the US National Institutes of Health (NIH), including the National Center
for Complementary and Alternative Medicine (NCCAM); the National Institute on
Aging; the National Heart, Lung, and Blood Institute; the National Institute of
Neurological Disorders and Stroke; and the Office of
Dietary Supplements — “failed to find an effect of Ginkgo biloba on
prevention of dementia (DeKosky et al., 2008), prevention of
cognitive decline (Snitz et al., 2009), reduction in cardiovascular
disease-related events or mortality (Kuller et al., 2010), or
decreases in blood pressure or hypertension (Brinkley et al.,
2010),” according to the NTP report.1 EGb 761, however, is
marketed in some countries where it has been approved for the treatment of
AD symptoms, rather than the prevention of AD.
More
recently, results of the GuidAge clinical trial on EGb 761,16 conducted
in France and published in 2012 by Vellas et al., found
that the extract did not reduce elderly participants’ risk of developing AD,
despite the fact that EGb 761 is marketed for the treatment of
symptoms. A more detailed analysis of the trial, including criticisms of the
study, was published in HerbalGram 97.17
Further,
the GuidAge trial reported that there was indication of a reduction in the risk
for dementia in those who continued treatment for at least four years.16 This
ties in with findings from the PAQUID Study, which suggested slower cognitive
decline during the course of 20 years in those who took EGb 761 compared to
those who did not.18
Additional
randomized, placebo-controlled trials published recently have confirmed the
beneficial effects of EGb 761 on memory in healthy people19 and
those with mild cognitive impairment,20 as well as in the
symptomatic treatment of dementia.21,22
Despite
the mixed results of clinical trials, adverse effects of GBE from such studies
were found to be minor and infrequent. According to Medline Plus, a service of
the US National Library of Medicine, ginkgo leaf extract is considered “likely
safe when taken by mouth for most people. It can cause some minor side
effects such as stomach upset, headache, dizziness, constipation, forceful
heartbeat, and allergic skin reactions.”23
Authors of the GuidAge trial wrote, “Incidence of adverse events was much the
same in both groups [experimental {i.e., EGb 761} and control], with no
significant difference in the incidence of serious adverse events, including
death, hemorrhagic events, stroke (ischaemic or haemorrhagic), or cardiac
disorders…. Long-term administration of standardised Ginkgo biloba extract
at 240 mg daily did not affect vital signs, physical function, or neurological
function.”16
Similarly,
as the NCCAM press release on the GEM study stated, “In analyzing safety data,
the GEM study did not find significant adverse effects from ginkgo, in
particular there was no evidence for increased bleeding risk in persons
taking ginkgo.”24
To date,
The Cochrane Collaboration — an independent, international network that
produces systematic reviews and meta-analyses of randomized, controlled trials
on materials from herbs to pharmaceutical drugs and other medical interventions
— has published two reviews focusing on ginkgo. In 2009, authors from the
University of Oxford analyzed 36 randomized, double-blind human clinical
studies of ginkgo extract for cognitive impairment and dementia.25 Although
the results of the studies were largely “inconsistent” and “unreliable,” the
authors concluded that “[g]inkgo biloba appears to be safe in use with no
excess side effects compared with placebo.”25
In the
second review published in early 2013, researchers from the Royal Devon and
Exeter Hospital and National Health Service Trust in the UK published an
analysis of four studies looking at Ginkgo
biloba for the treatment of tinnitus.26 In one study that looked
at dementia patients with or without tinnitus, there was a statistically
significant reduction of symptoms in a subgroup of participants with vascular
dementia and Alzheimer’s disease. And, similar to the 2009 study, the incidence
of side effects among the 1,543 participants was low.
Conclusions
According to dietary supplement safety and poison control expert Rick Kingston,
a member of the ABC Advisory Board and a co-author of the ABC comments to NTP,
“It is worth considering that one of the original reasons for GBE’s being
singled out for review is the fact that it contains quercetin, a compound
previously studied within the NTP and initially found to be ‘potentially
carcinogenic,’ subsequently identified as a ‘known mutagen,’ and a substance of
concern for the NTP. Still, there are few, if any, scientists calling for a ban
on fruits, vegetables and other plant based food sources that ubiquitously
contain naturally occurring quercetin. This demonstrates that the utility of
these NTP studies are often times simply hypothesis generation — that is,
looking for possible substances that under unusual or specific circumstances of
use might contribute to, or cause adverse effects. As such they are simply the
first step in ongoing investigation” (email, May 2, 2013).
As Gary
Gutting, PhD, a professor of philosophy at the University of Notre Dame,
recently wrote in a New York Times “Opinionater” piece, “As
any regular reader of news will know, popular media reports ‘scientific
results’ nearly every day. … How seriously should we take them?”27 Prof.
Gutting discussed the ever-relevant issue of correlation versus causality in
science — the idea that, in many cases, results simply show that a change in
one variable is correlated with a change in another, not necessarily caused by
(or even related to) that change — and totes the golden standard of randomized
controlled trials (RCTs) in science, which aim to limit the number of
confounding variables in a well-designed study.
Science
reporting, Gutting wrote, often doesn’t “explain the specific limited role such
studies usually play in the overall scientific process.… In fact, most
scientific results are of no immediate practical value; they merely move us one
small step closer to a final result that may be truly useful.”27
According
to Dr. Gurley at the University of Arkansas, readers should be hesitant to draw
any strong conclusions from the recent NTP report on GBE. “The overriding point
to consider is that rats are not humans,” he said. “Their metabolism … is
different from humans and their response to many carcinogens is different from
that of humans. The conclusions drawn from the study are, in my opinion,
not translatable to other ginkgo extracts or to humans.”
Dr. Rider,
in her comments to HerbalEGram, noted that NTP provides information to the
government and the public about potential carcinogenicity or toxicology of
compounds suggested by various individuals or organizations — in this case, by
the National Cancer Institute — that are in need of more data.
“Our purpose is to provide the best possible toxicity and
carcinogenicity data on agents with significant exposure potential to the
public and other government agencies,” Dr. Rider wrote. “In addition, at this
time, we do not know which specific chemical constituent(s) or combination of
constituents of GBE is responsible for the carcinogenic effects of GBE in rats
and mice. Further research is needed to determine this."
*
Shortly after CSPI’s ginkgo press release, the organization similarly condemned Aloe vera (Xanthorrhoeaceae) by
downgrading the plant’s safety rating to “avoid” in its Chemical Cuisine guide.28
This consumer warning was based on the August 2013 publication of NTP’s
toxicology and carcinogenicity report on a preparation derived from Aloe vera, the findings of which have
been questioned by some experts and organizations. In particular, the
NTP used nondecolorized (unpurified, unfiltered) A. vera, which contained 10,000-13,000 ppm aloin, a stimulant
laxative. According to a statement by the International Aloe Science Council,
this is roughly 2,000 times more than what is found in aloe products available
to consumers.29
—Tyler Smith
References
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Chan PC, Rider CV, Nyska A et al. NTP Technical Report on the Toxicology
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Accessed April 23, 2013.
2.
Rabin RC. New doubts about Ginkgo biloba. New
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3.
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5.
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DC: Natural Products Association; April 30, 2013. Available here.
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National Institutes of Health website. Available here.
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12.
Schultz H. Ginkgo cancer results flawed because extract used is not
representative, observers say. NutraIngredients-USA website. Available here.
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13. Draft NTP TR 578: Analysis of the
specific Ginkgo biloba extract used in 2-year gavage studies. American Herbal
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Accessed April 30, 2013.
14. Kaschel
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Psychopharmacol. 2009;24(5):345-370. Available here. Accessed
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15.
Ginkgo biloba extract is effective for cognitive decline [press release].
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Available here.
Accessed April 30, 2013.
16. Andrieu S, Ousset PJ, Coley N, Ouzid
M, Mathiex-Fortunet H, and Vellas B. GuidAge study: a 5-year double blind,
randomised trial of EGb 761 for the prevention of Alzheimer's disease in
elderly subjects with memory complaints. Curr Alzheimer Res. 2008;5(4):406-415.
Available here. Accessed
April 29, 2013.
17. Smith T. Ginkgo and Alzheimer’s Disease
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