by Kerry Bone, MCPP, FNHAA, FNIMH, DipPhyto BSc(Hons)
During my 20-plus years of reviewing the phytotherapy scientific literature, I cannot recall a more bizarre episode than the reported occurrence of colchicine in ginkgo (Ginkgo biloba L., Ginkgoaceae). A group of scientists at Wayne State University, Michigan, while investigating natural anti-inflammatory substances in pooled placental blood, found a compound that they identified as colchicine.1 Naturally, the scientists were curious as to the origins of this plant chemical, so they decided to examine individual blood samples from the 24 pregnant women in the study. Only five of these appeared to contain colchicine and the researchers reported that all of the colchicine-containing blood samples came from women who used herbal supplements. For some reason they next tested ginkgo and echinacea (Echinacea spp., Asteraceae) products from local retail outlets and found that one of the ginkgo samples contained significant levels of colchicine (26 mg per tablet). The authors concluded that due to its potential harmful effects from the colchicine, it would appear that ginkgo should be avoided by women who are pregnant or trying to conceive.
“A grin without a cat”
Colchicine is an alkaloid that was originally isolated from the autumn crocus (Colchicum autumnale L., Liliaceae), a plant native to the Mediterranean that has been used since ancient times to treat gout and other inflammatory conditions. Colchicine is highly toxic and the effective dose is quite close to a toxic dose. Toxic effects include nausea, vomiting and bone marrow suppression.2 Colchicine inhibits normal cell division (mitosis) and has also been linked to Down’s syndrome. Clearly, it is contraindicated in pregnancy.3
Before critiquing the actual scientific merit of the study, some common sense, logical questions arise that were not answered (i.e., no information was provided) by the study (and obviously not asked by peer reviewers of the publishing journal, Chemical Research in Toxicology). These include:
Were the five women with the colchicine levels taking ginkgo?
• If not, what herbs were they taking, if any?
• Why would researchers select just echinacea and ginkgo for analysis?
• How many ginkgo products were tested?
• Why were ginkgo leaves not tested as well?
• Do the findings match the known safety record of ginkgo?
Questions about the research from a scientific perspective are:
• Is ginkgo known to contain colchicine?
• From a phytochemical perspective, what basis holds that ginkgo should contain colchicine?
• How conclusively was colchicine identified in ginkgo?
• Could the levels of the “colchicine” found in the ginkgo sample account for the levels found in placental blood?
• Are these levels of “colchicine” toxic? If so, what effects were observed on the mother and child?
In fact, colchicine has never before been reported in ginkgo. A comprehensive literature search by Norman R. Farnsworth, Ph.D., of the University of Illinois at Chicago (conducted at the request of the American Botanical Council) found no evidence of colchicine in ginkgo.4 According to Professor Farnsworth: “Based on biogenetic considerations, colchicine should never be found outside of the Monocotyledoneae (e.g., Araceae, Liliaceae). Thus, colchicine has never been reported as a normal constituent of Ginkgo biloba nor would it be expected or predicted to be present.”
Farnsworth also questioned the scientific validity of the study and the editorial review process it underwent to be published. “Anyone who thinks that colchicine can be found naturally in ginkgo is not qualified to be a peer reviewer of this paper,” he said, referring to the editorial process for scientific journals in which papers are reviewed by independent experts to determine their scientific merit and the accuracy of their conclusions prior to publication.
The W. Schwabe Company, the German manufacturer that researched and developed a ginkgo extract that has become an industry and research benchmark, tested three separate samples of ginkgo leaf and failed to find colchicine. This finding was confirmed by testing by the American Herbal Products Association and the Council for Responsible Nutrition.4
The Australian Therapeutic Goods Association (TGA), which is equivalent to the U.S. Food and Drug Administration, recently tested five ginkgo products. No colchicine was found in any (detection limit 1 µg/g). Interestingly, using a method similar to the study in question, a substance was found in the ginkgo products that had similar analytical properties to colchicine. However, it is unlikely that the substances had similar pharmacological properties (otherwise the women would either no longer be pregnant or alive). Although its identity was not determined, further analysis demonstrated conclusively that this was not colchicine.5
Could the levels of colchicine in ginkgo account for those reportedly observed in the pregnant women? The Wayne State researchers claimed to have found 49 to 763 µg/L of colchicine in the placental blood of the women allegedly taking herbal supplements.1 They claim to have found 26 µg of colchicine per ginkgo tablet. In a multiple dose study of the pharmacokinetics of colchicine, 1 mg per day achieves plasma concentrations in human subjects in the range of 0.3 to 2.5 µg/L.6 Hence, to achieve a level of 49 µg/L of colchicine (the lowest value in the reported range) a person would need to consume around 50 mg of colchicine per day. Since each ginkgo tablet, purportedly contains only 26 µg, this equates to nearly 2,000 ginkgo tablets per day. In their defense the authors claimed that placental tissue is known to concentrate ingredients from the mother’s blood. But even assuming a concentration factor of 50, this is still 40 tablets per day to achieve the lowest reported concentration of colchicine, when the normal dose is typically 2 to 4 tablets per day (assuming a 60 mg tablet, i.e., 120–240 mg ginkgo extract per day, in accord with the German Commission E recommended dosage).7
Perhaps most astounding of all, the reported levels of colchicine would have been lethal to the unborn children. Several cases involving suicide by the ingestion of colchicine tablets have been reported in the literature. In one case, the plasma level of colchicine 24 hours after ingestion was 4.5 µg/L,8 in another the femoral blood level was 62 µg/L.9 Autumn crocus is probably the richest plant source of colchicine. Yet a case report of a man who consumed 17.1 g of flowers found that his maximum colchicine level was just 4.34 µg/L, at 13 hours after ingestion of the flowers.10 Nonetheless, he was hospitalized with nausea, vomiting, and abdominal pain.
The purported link between herbal supplements and colchicine in placental blood is hardly Nobel-Prize-winning material. But the authors and the journal involved made sure that their study received due attention by releasing their findings to the press in advance to actual publication of the journal. And despite the many shortcomings of the study, the press had a field day. Press releases and articles ran headings such as:
Ginkgo and Pregnancy Don’t Mix11
Ginkgo Biloba Compound May Affect Fetus12
Mag Warns Pregnant Women About Herbal Supplement13
Despite criticism from science organizations, such as the American Botanical Council and trade groups associated with the botanicals industry, the researchers and journal editor involved in the publication of the study were reported to be unrepentant.14 Moreover, after going to great lengths to raise the specter of a public health issue related to their work, the principal investigators from Wayne State have shown no willingness to cooperate with sincere efforts by the botanicals industry to investigate the possible contamination of one or a few lots of ginkgo products — the only remaining, however remote, possible explanation for the alleged colchicine being in a ginkgo product. Efforts to secure disclosure of the identity of the supposedly colchicine-tainted ginkgo product from the Wayne State principal investigators, the vice president for research, the university counsel, and the president of the university have all failed. It seems incumbent upon an institution of higher learning that reports and seeks publicity for a matter of public health to work with any and all legitimate agencies seeking to resolve that concern; Wayne State has not lived up to that responsibility.
Perhaps the next time, before chemists and biologists report on the potential harmful effects of herbs, they shall enlist advice from a phytochemist and a toxicologist (and maybe even a phytotherapist)!
What the world press has been noticeably silent about is the increasing evidence of harm attributed to the use of conventional pharmaceuticals during pregnancy, based on actual case studies. A superficial scan of recent literature has revealed a link between anticonvulsant drugs and birth defects,15 and non-steroidal anti-inflammatory drugs and increased risk of miscarriage: topics for another day.16
Kerry Bone is a practicing clinical herbalist who also serves as Director of Research and Development at MediHerb, an herbal extract manufacturer based in Warwick, Queensland, Australia. His collaboration with Simon Mills, Principles and Practice of Phytotherapy: Modern Herbal Medicine, has been adopted as a textbook at many herbal and naturopathic colleges throughout the world.
1. Petty HR, Fernando M, Kindzelskii AL, et al. Identification of colchicine in placental blood from patients using herbal medicines. Chem Res Toxicol Web release date August 4, 2001. http://pubs.acs.org/subscribe/journals/crtoec/browse_asap.html.
2. Hood RL. Colchicine poisoning. J Emerg Med 1994;12(2):171-7.
3. Levy M, Spino M, Read SE. Colchicine: a state-of-the-art review. Pharmacotherapy 1991;11(3):196-211.
4. American Botanical Council. Herbal science group debunks research suggesting presence of toxin colchicine in ginkgo [news release]. 2001 August 30.
5. Therapeutic Goods Administration. TGA questions validity of colchicine report. 2001 October 11. http://www.health.gov.au/tga/docs/html/colchicine.htm.
6. Chappey O, Scherrmann JM. [Colchicine: recent data on pharmacokinetics and clinical pharmacology]. Rev Med Interne 1995;16(10):782-9.
7. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW, Rister RS, editors. Klein S, Rister RS, translators. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin, TX: American Botanical Council; Boston: Integrative Medicine Communication; 1998. pp.136-8.
8. Dehan B, Chagnon JL, Vinner E, et al. Colchicine poisoning: report of a fatal case with body fluid and post-mortem tissue analysis by high-performance liquid chromatography. Biomed Chromatogr 1999;13(3):235-8
9. Kintz P, Jamey C, Tracqui A, et al. Colchicine poisoning report of a fatal case and presentation of an HPLC procedure for body fluid and tissue analyses. J Anal Toxicol 1997;21(1):70-2.
10. Danel VC, Wiart JD, Hardy GA, et al. Self-poisoning with Colchicum autumnale L. flowers. Clin Toxicol 2001;39(4):409-11.
11. Foster R. Ginkgo and Pregnancy Don’t Mix [press release]. http://www.yahoo.com. 2001 September 21.
12. Anon. Ginkgo Biloba Compound May Affect Fetus. Reuters News Service. 2001 August 29.
13. Anon. Mag Warns Pregnant Women About Herbal Supplement. Reuters News Service. 2001 August 29.
14. Borman S. Toxin reported in supplements. Chemical & Engineering News 2001;79(33):33-4.
15. Holmes LW, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132-8.
16. Nielsen GL, Sorensen HT, Larsen H, et al. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ 2001;322:266–70.