Is Ginkgo biloba Safe?

[This is a repeat of a Q&A published in the August 2013 issue, reprinted because of further questions.]

Q. Dear Dr. Dean,

I have been a long-time user of your Ginkgo biloba product. However, I recently read a report of a government-sponsored toxicology study that concluded that Ginkgo biloba extract had carcinogenic (cancer-causing) effects in rats and mice. Consequently, I am reluctant to continue using this product. Have you seen the study, and what do you think about it?

I do not want to take something that is supposed to be beneficial, but which may cause cancer.

Lou, Port Angeles, WA

A. Dear Lou,

I understand your concern. The report referenced is from NIH’s National Toxicity Program.1 There were four parts to this undertaking: 1) 3-month study in mice; 2) 2-year study in mice; 3) 3-month study in rats; and 4) 2-year study in rats. In each part of the study, the animals were gavage-fed (i.e., force-fed by tubes) doses of the Ginkgo extract (in corn oil), ranging from 0 mg/kg (control), and groups fed doses ranging from 125–2,000 mg/kg (3-month mouse study); 200–2,000 mg/kg (2 year mouse study); 62.5–1,000 mg/kg (3-month rat study); and 100–1,000 mg/kg (2 year rat study).

The four main conclusions drawn by the NTP study 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

Exceeding Normal Human Doses by 55–108 Times!

Not surprisingly, the worst results were in the highest dose groups. For example, the two year study with rats found that 1,000 mg/kg of body weight found the greatest toxicity, with virtually no toxicity noted in the lowest doses tested. The human equivalent dose of the highest doses used in these studies would be just over 900 milligrams per pound of body weight, five times a week for 50–60 years (rats generally live 2–3 years).2 It should be noted that the most common dose used by humans (240 mg/70 kg [“average” human bodyweight]) is only a fraction of even the lowest dose tested (62.5 mg/kg in the 3-month rat study). The American Botanical Council confirmed that the doses given to the rodents were 55–108 times higher than the normal human levels of consumption of standardized GBE!3,5

There are even more distortions that are not apparent from reading the “mainstream media” reports of this study. First, of all, the announcement and publicity given to this study comes from what is perhaps the most anti-supplement group anywhere, the Center for Science in the Public Interest.4

Ginkgo biloba Extract Used in NTP Studies

The American Botanical Council noted that the GBE used in the studies was Shanghai Chinese Ginkgo biloba extract (SC-GBE), procured by the Shanghai Xing Ling Science and Technology Pharmaceutical Company, Ltd.5 SC-GBE is known to have 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.5

Although the report’s authors classified the SC-GBE extract as “comparable to the Schwabe EGb 761 extract,” the American Herbal Products Association was unable to find evidence that SC-GBE is sold anywhere in the US marketplace.6

Use of Corn Oil Complicates Dosing Levels

An additional factor to consider regarding the discrepancy of SC-GBE to other standardized 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. “Several studies have shown that prolonged administration of corn oil can produce some unexpected toxicities. 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).” According to Dr. Gurley, readers should be hesitant to draw any strong conclusions from the 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.”7

A History of Safe Use and Demonstrated Benefits

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.8 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.”9 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.”9

Additional randomized placebo-controlled trials published recently confirmed the beneficial effects of EGb 761 on memory in healthy people10 and those with mild cognitive impairment,11 as well as in the symptomatic treatment of dementia.12,13

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.”14

Although Ginkgo is most commonly used for its widely tested cardiovascular, and cognitive enhancing benefits, other promising indications for its use include intermittent claudication (peripheral vascular disease), depressed mood, anxiety, tinnitus, and headache.15 Not surprisingly, in view of its history of improving blood flow throughout the body, another little known indication for Ginkgo is the potential to alleviate male erectile dysfunction.

Ginkgo Improves Erectile Rigidity

In a 1991 study, fifty patients with proven arterial erectile impotence were treated with 240 mg of GBE daily for nine months.16 The patients were divided into two groups. The first group had achieved sufficient erections with intracavernous papaverine injections before beginning treatment with GBE. The second group had not achieved sufficient erections with high-dose papaverine injections. In the first group (n = 20), all patients regained spontaneous and sufficient erections after six months of oral GBE treatment. Arterial flow rates were actually improved after three months and continued to improve at six months. Rigidities at the penile tip and base were significantly improved after six months and remained constant during the nine-month duration of the study. In the second group (n = 30) (this was the group that did not respond to high-dose papaverine injections—i.e., a very severe state of ED), improved arterial penile flow rates and rigidities were noted at six and nine months. Nineteen patients responded to intracavernous PGE1 (prostaglandin E1) following GBE treatment. Of these 19 patients, 9 required a minimal dose of 5 mcg PGE1, while the other 11 required a maximal dose of 20 mcg. The remaining 11 patients remained impotent. Thus, it appears that Ginkgo biloba extract at a dose of 240 mg per day may also greatly assist those with ED.

Bottom line: I think the NTP “study” was just another fraudulent government-sponsored “take-out piece,” designed to discredit a time-honored natural supplement with a wide range of clinical uses. As for me, I’ll continue to take 240 mg of Ginkgo daily for its plethora of beneficial effects.

Ward Dean, M.D.

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.
  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/.
  3. 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.
  4. 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.htmlv.
  5. Blumenthal M, Gurley BJ, Kingston R, Low Dog T, 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
    .
  6. 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
    .
  7. Smith, Tyler. Experts Question Relevance of Ginkgo Toxicology Report. HerbalEGram: Volume 10, Number 5, May 2013.
  8. Kaschel R. Ginkgo biloba: specificity of neuropsychological improvement — a selective review in search of differential effects. Hum Psychopharmacol. 2009;24(5):345-70. Available at: www3.interscience.wiley.com/journal/122465029/abstract.
  9. 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.
  10. Kashel R. Specific memory effects of Ginkgo biloba extract EGb 761 in middle-aged healthy volunteers. Phytomedicine. 2011;18(14):1202-17. Available at: www.ncbi.nlm.nih.gov/pubmed/21802920.
  11. 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.
  12. 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.
  13. 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.
  14. Ginkgo. Medline Plus website. Available at: http://www.nlm.nih.gov/medlineplus/druginfo/natural/333.html.
  15. Kleijnen, Jos, and Knipschild, Paul. Ginkgo biloba. The Lancet, November 7, 1992; 340:1136-9.
  16. Sohn M, Sikora R. Ginkgo biloba extract in the therapy of erectile dysfunction. J Sex Educ Ther. 1991;17:53-61.

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