HerbalEGram: Volume 10, Number 5, May 2013

The March 2013 National Toxicology Program’s (NTP) technical report on toxicology and carcinogenesis studies of Ginkgo biloba extract (GBE) in animals¹ elicited a number of widely varying responses from news, nonprofit, and herb and dietary supplement industry organizations. Media reports seized upon the authors’ findings of cancer produced in rats and mice after two years of being force-fed high doses of one specific GBE;² the consumer health and food safety organization Center for Science in the Public Interest (CSPI) in its Chemical Cuisine guide to food additives downgraded the classification of ginkgo from “safe” to “avoid”³; the American Botanical Council (ABC),⁴ the American Herbal Products Association (AHPA),⁵ and the Natural Products Association (NPA)⁶ each produced press releases criticizing the studies’ relevance to humans; and consumers were left with more confusion than clarity.

Toxicology studies, such as the recent NTP report, undoubtedly play a useful role in determining the potentially harmful nature of substances from 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 herbal or herb-derived chemicals or extracts has even been analyzed by the program.⁷

The nonprofit ABC, plus herb and dietary supplement industry organizations such as AHPA and NPA, cited numerous limitations, potential flaws, and other issues with the NTP studies and report, many of which fall into three areas of primary concern: (1) the application of toxicology and carcinogenicity studies in rodent models has questionable and debated relevance to actual human use; (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 pharmacopoeias 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.^4-6

The NTP Ginkgo Studies

In hazard-identification toxicology studies, scientists feed animals — in this case, laboratory mice and rats — higher-than-normal dosages 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 New York Times article about the recent NTP report, “It is a valid criticism, as doses used in toxicology studies tend to be very high. In the new gingko 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.^4,8

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

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),⁸ ABC voiced concern over the specific GBE used in the studies: Shanghai Chinese Ginkgo Biloba Extract (SC-GBE), procured by the Shanghai Xing Ling Science and Technology Pharmaceutical Company, Ltd.

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 (2003), German Commission E Monograph (1994), the United States Pharmacopeia (2011), and the data from the World Health Organization.⁸

Specifically, SC-GBE was stated in the report to have 31.2% flavonol glycosides, 15.4% terpene lactones, and 10.45 +/- 2.40 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.⁸

In an email response to HerbalEGram, lead NTP study scientist Dr. Cynthia Rider 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 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 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 the graph) falls well outside the range of the typical concentrations of these two GBE constituent classes.⁵

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.⁹ An additional point of consideration 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.”

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 self-care, 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.⁸ “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 biloba 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 (Mahady, 2002; Smith and Luo, 2004),” 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.¹⁰ 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.”¹¹

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.”¹¹

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 761,¹² 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 97.¹³

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.¹² 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.¹⁴

Additional randomized placebo-controlled trials published recently confirmed the beneficial effects of EGb 761 on memory in healthy people¹⁵ and those with mild cognitive impairment,¹⁶ as well as in the symptomatic treatment of dementia.^17,18

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.”¹⁹

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.”¹²

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.”²⁰

Conclusions

According to dietary supplement safety and poison control expert Rick Kingston, PharmD — clinical professor at the College of Pharmacy at the University of Minnesota, president of Regulatory and Scientific Affairs at SafetyCall International in Minneapolis, 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?”²¹ Prof. Gutting discusses 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 writes, 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.”²¹

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."

—Tyler Smith

References

1. Chan PC, Rider CV, Nyska A et al. NTP Technical Report on the Toxicology and Carcinogenesis of Ginkgo Biloba Extract in F334/N Rats and B6C3F1/N Mice (Gavage Studies). National Toxicology Program website. Available at: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/TR578_508.pdf. Accessed April 23, 2013.

2. Rabin RC. New doubts about Ginkgo biloba. New York Times. Available at: http://well.blogs.nytimes.com/2013/04/29/new-doubts-about-ginkgo-biloba/. Accessed April 29, 2013.

3. Consumers urged to avoid ginkgo in wake of new cancer concerns [press release]. Washington DC: Center for Science in the Public Interest; April 18, 2013. Available at: http://cspinet.org/new/201304181.html. Accessed April 18, 2013.

4. Many ginkgo extracts safe, says herbal science group [press release]. Austin, TX: American Botanical Council; April 18, 2013. Available at: http://cms.herbalgram.org/press/2013/ABC_Response_Ginkgo_NTP_Report.html. Accessed April 18, 2013.

5. AHPA comments on unique ginkgo extract used in NTP study [press release]. Silver Spring, MD: American Herbal Products Association; April 18, 2013. Available at: www.ahpa.org/Portals/0/pdfs/13_0418_AHPANTPNoteTable_FINAL.pdf. Accessed April 29, 2013.

6. NPA disputes New York Times story on Ginkgo biloba [press release]. Washington DC: Natural Products Association; April 30, 2013. Available at: www.npainfo.org/NPA/NewsRoom/NewsReleases2013/NPADisputesNewYorkTimesStoryonGinkgoBiloba.aspx. Accessed April 30, 2013.

7. Long-term study reports and abstracts. National Toxicology Program website. Available at: http://ntp.niehs.nih.gov/?objectid=D16D6C59-F1F6-975E-7D23D1519B8CD7A5. Accessed April 30, 2013.

8. Blumenthal M, Gurley BJ, Kingston R, Low Dog, T, and MacKay D. American Botanical Council revised public comment on NTP draft toxicology report on Ginkgo biloba extract. National Institutes of Health website. Available at: http://ntp.niehs.nih.gov/NTP/About_NTP/TRPanel/2012/February/PublicComm/Blumenthal20120125.pdf. Accessed April 29, 2013.

9. Draft NTP TR 578: Analysis of the specific Ginkgo biloba extract used in 2-year gavage studies. American Herbal Products Association website. Available at: http://ntp.niehs.nih.gov/NTP/About_NTP/TRPanel/2012/February/PublicComm/AHPAAnalysis.pdf. Accessed April 30, 2013.

10. Kaschel R. Ginkgo biloba: specificity of neuropsychological improvement-a selective review in search of differential effects. Hum Psychopharmacol. 2009;24(5):345-370. Available at: www3.interscience.wiley.com/journal/122465029/abstract. Accessed May 1, 2013.

11. Ginkgo biloba extract is effective for cognitive decline [press release]. Karlsruhe, Germany: Willmar Schwabe Pharmaceuticals Co.; December 8, 2009. Available at: www.schwabepharma.com/international/media-relations/press-releases/items/2009_12_08_Kaschel.php. Accessed April 30, 2013.

12. 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 at: www.ncbi.nlm.nih.gov/pubmed/18690838. Accessed April 29, 2013.

13. Smith T. Ginkgo and Alzheimer’s Disease Prevention: Researchers, herbal experts interpret results of the five-year GuidAge clinical trial. HerbalGram. 2013;97:32-37. Available at: http://cms.herbalgram.org/herbalgram/issue97/hg97-resrvw-ginkgo.html. Accessed April 30, 2013.

14. Amieva H, Meillon C, Helmer C, Barberger-Gateau P, Dartigues JF. Ginkgo biloba extract and long-term cognitive decline: a 20-year follow-up population-based study. PLOS One. 2013;8(1): e52755. Available at: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0052755. Accessed May 2, 2013.

15. Kashel R. Specific memory effects of Ginkgo biloba extract EGb 761 in middle-aged healthy volunteers. Phytomedicine. 2011;18(14):1202-2017. Available at: www.ncbi.nlm.nih.gov/pubmed/21802920. Accessed May 2, 2013.

16. Grass-Kapanke B, Busmane A, Lasmanis A, Hoerr R, Kaschel R. Effects of ginkgo biloba special extract EGb 761^® in very mild cognitive impairment (vMCI). Neuroscience and Medicine. 2011;2:48-56. Available at: www.scirp.org/journal/PaperInformation.aspx?paperID=4279. Accessed May 2, 2013.

17. Ihl R, Bachinskaya N, Korczyn AD, et al. Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: a randomized controlled trial. Int J Geriatr Psychiatry. 2011;26(11):1186-1194. Available at: http://onlinelibrary.wiley.com/doi/10.1002/gps.2662/abstract. Accessed May 2, 2013.

19. Herrschaft H, Nacu A, Likhachev S, Sholomov I, Hoerr R, Schlaefke S. Ginkgo biloba extract EGb 761® in dementia with neuropsychiatric features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res. 2012;46(6):716-723. Available at: www.ncbi.nlm.nih.gov/pubmed/22459264. Accessed May 2, 2013.

19. Ginkgo. Medline Plus website. Available at: http://www.nlm.nih.gov/medlineplus/druginfo/natural/333.html. Accessed April 30, 2013.

20. Ginkgo Evaluation of Memory (GEM) Study Fails To Show Benefit in Preventing Dementia in the Elderly [press release]. Washington DC: National Center for Complimentary and Alternative Medicine; November 18, 2008. Available at: http://nccam.nih.gov/news/2008/111808.htm. Accessed April 29, 2013.

21. Gutting G. What do scientific studies show? New York Times website. Available here. Accessed April 25, 2013.