Phytotherapy review & commentary
Ginkgo and Bleeding Tendency: Guilt by Association?
Ginkgo biloba as the 50:1 standardized extract (EGb) has been used as an herbal treatment for “cerebral insufficiency” and intermittent claudication for almost 40 years.(1) It is often assumed that, given these vascular indications, Ginkgo has a clinical impact on bleeding parameters (in other words it is a “blood thinning” agent). This assumption is fuelled by the significant in vitro and in vivo activities of EGb and the isolated ginkgolides against PAF (platelet activating factor). (1) Platelet activating factor has several important biological properties, including the promotion of platelet aggregation under pathological conditions.
Journals now abound with articles attributing antiplatelet or even anticoagulant properties to Ginkgo, warning against its concurrent use with aspirin or warfarin and advising that it should be discontinued prior to surgery. For a recent example, see the article published in The Journal of The Royal Society for the Promotion of Health. (2) Cases of spontaneous bleeding (3-8) and adverse interactions with warfarin (4) and aspirin (5) have been reported. The use of Ginkgo is most widespread in Germany, where it is commonly prescribed by medical doctors. Until recently, the German authorities were largely silent on the issue of increased bleeding tendency, suggesting they were not concerned. However, last year an “Important Notice” was released from the Pharmaceutical Commission of German Pharmacists. (6) This was in turn based on the publication of a summary of reports concerning Ginkgo from the German adverse reactions database. By 2002 there were 185 reports of adverse reactions to Ginkgo in Germany, (7) of which 20 reports were connected to coagulation disorders. The Commission warned that patients using Ginkgo extracts are in danger of suffering spontaneous bleeding or complications during surgery and there is an increased danger of bleeding with concomitant use of anticoagulant drugs.
But the case against Ginkgo is far from proven. The herb is one of the most popular in the Western world (for example more than five million units of Ginkgo products were sold in Germany alone in 1998) (8) and, because of its indications, Ginkgo is largely taken by older people. So the risk of spontaneous bleeding and the use of warfarin and aspirin are relatively high in the population taking Ginkgo. The possibility therefore exists that hemorrhagic episodes are inappropriately attributed to Ginkgo, when it is not the causative agent at all. In other words, a combination of Ginkgo’s reputation, its popularity and the demographics of its use leads to a self-fulfilling prophecy: that the herb is a risk for bleeding tendency.
There are in fact, findings from several clinical studies which challenge the assumption that Ginkgo significantly alters bleeding parameters or interacts with antiplatelet or anticoagulant drugs. While a few early studies showed mild and probably insignificant effects, later studies failed to find any activity at all.
In studies with healthy volunteers, acute oral administration of standardized Ginkgo extract (15 mL probably corresponding to 600 mg dry extract) and a ginkgolide mixture (80 mg and 120 mg) inhibited PAF-induced platelet aggregation. (9), (10) The effect with the Ginkgo extract was only transient and there were no concomitant changes in coagulation, skin bleeding time, hematological and biochemical laboratory tests, blood pressure or pulse. (14) Longer-term oral administration with the standardized extract (120 mg/day for 3 months) resulted in inhibition of collagen-induced platelet aggregation, but failed to inhibit three other inducers, including PAF (1 [micro]mol/L), ex vivo. (11) Oral administration of standardized extract (112.5 mg) to healthy volunteers has been shown to reduce erythrocyte aggregation, but had no effect on plasma viscosity, platelet aggregation or blood pressure. (12) Another study reported a significant decrease in both diastolic and systolic blood pressure in healthy volunteers ingesting standardized extract (120 mg/day at bedtime) for 3 months. Bleeding times and fibrinogen levels showed no change. (13) Recently a double-blind, placebo-controlled study carried out in 32 healthy young male volunteers found that doses of EGb from 120 to 480 mg/day for 14 days had no effect on platelet function or coagulation parameters. (14)
Concomitant treatment with standardized Ginkgo extract (100 mg/day) for 4 weeks in patients who were stabilized on long-term warfarin therapy had no significant influence on their response to warfarin in a randomized, double blind, placebo-crossover trial (average age of patients was 64.5 years). The stability of international normalized ratio (INR) values was confirmed and major bleedings or thromboembolic events were not observed. (15) Administration of standardized Ginkgo extract (240 mg/day) for 7 days, alone or concomitantly with aspirin (500 mg/day), had no influence on bleeding parameters in a controlled trial involving 50 patients. (16)
In conclusion, objective studies suggest that safety concerns regarding Ginkgo and increased bleeding tendency are exaggerated. The association of Ginkgo with a few isolated events does not imply causality and, given its widespread use, the scarcity of such reports is testimony to its safety. No matter how often these concerns are reflected in biased or uncritical reviews, the objective reality is that the case is not proven. As a recent review of Ginkgo drug interactions concluded: (17) “While caution and close monitoring of patients comedicating with ginkgo (or other herbal product or drug) is recommended, the reporting of G. biloba-drug interactions appears exaggerated based upon the available evidence.” A more critical and objective evaluation of case reports is required to understand the safety issues for this important herb.
Boswellia Effective for Osteoarthritis
An extract of Boswellia serrata standardized to 40% boswellic acids by HPLC has yielded dramatic results in the treatment of osteoarthritis. (1) A randomized, double-blind, placebo-controlled, crossover study was conducted to assess the efficacy, safety and tolerability of Boswellia extract in 30 patients with osteoarthritis of the knee, 15 each receiving active treatment or placebo for 8 weeks. After the first intervention, washout was given and then the groups were crossed over to receive the opposite intervention for 8 weeks. All patients receiving herbal treatment reported a significant decrease in knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was substantially decreased, but radiologically there was no change. The dose used was 1000 mg of extract per day. Boswellia was well tolerated by the patients, except for minor gastrointestinal adverse reactions.
Since the boswellic acids are specific, non-redox inhibitors of 5-lipoxygenase and hence leukotriene biosynthesis, (2) research attention has focussed on the effects of Boswellia in inflammatory joint diseases such as rheumatoid arthritis. In an uncontrolled trial, Boswellia extract was administered to 30 patients with rheumatoid arthritis (RA). After 6 months of treatment the number of patients with detectable C-reactive protein (an inflammatory marker) was reduced from 63% to 47%, suggesting that Boswellia may have a modifying effect on RA. (3)
In a review of 12 clinical trials (conducted in Germany or India) on the use of Boswellia in the treatment of RA the following results were observed: (4)
* Boswellia treatment was superior to placebo in patients suffering RA for several years and in patients who responded poorly to conventional treatments.
* Boswellia was as effective as gold therapy for RA.
* In some children with chronic juvenile arthritis, Boswellia proved beneficial.
* Boswellia was well tolerated, with few mild side effects (diarrhea, urticaria).
Other studies have shown the benefit of Boswellia in the treatment of RA. (5-7) Despite this research focus on rheumatoid arthritis, herbal clinicians have also favored the use of Boswellia in osteoarthritis. The results of the above clinical trial now provide significant evidence to support this application.
What is striking about the trial is the substantial clinical benefit observed. Results were highly statistically significant (p<0.001) and changes in the treatment parameters were quite large. For example, in the first 8-week treatment period before crossover the pain index in the Boswellia group fell from 2.7 [+ or -] 0.45 to 0.26 [+ or -] 0.45, the loss of movement index was reduced from 2.8 [+ or -] 0.41 to 0.30 [+ or -] 0.48 and the swelling index went from 1.1 [+ or -] 0.91 to zero. The group receiving the placebo treatment after crossover showed substantial deterioration over the ensuing 8 weeks, suggesting that the 21-day washout period before crossover was insufficient. Although this is a flaw in the experimental design, it suggests a substantial residual therapeutic benefit after stopping Boswellia.
New Clinical Developments for Ginseng
Several clinical studies have been published which support novel or new uses for Korean or Asian ginseng root (Panax ginseng). However, many of these new applications are not surprising, since they logically follow from the whole-body tonic properties of the herb.
A group of Korean scientists have followed on from their earlier research which found that Korean red ginseng boosted CD[4.sup.+] T cell counts in HIV-1-infected patients. They investigated whether 5.4 g per day of ginseng root powder taken long term had any impact on the development of resistant HIV-1 strains in patients treated with the drug zidovudine. (1) Nine patients were treated with both ginseng and the drug; another nine acted as controls and received only the drug. In samples after 24 months of therapy the incidence of six resistance mutations to zidovudine was 21.7% for the ginseng group, versus 56.3% for the controls (p<0.01). The authors concluded that the observed maintenance of CD[4.sup.+] T cell counts by the zidovudine and Korean ginseng combination might be indirectly due to the delayed development of resistance to zidovudine.
In another long-term Korean study, the impact of red ginseng therapy on postoperative immunity and survival was investigated in patients with gastric cancer. (2) Forty-nine patients who had undergone gastric resection with lymph node removal by the same surgeon for histologically-proven AJCC (American Joint Committee on Cancer) stage III gastric adenocarcinoma were enrolled in the trial. After the application of predefined exclusion criteria, 22 patients were given ginseng (4.5 g/day) for the first 6 months after surgery and 20 acted as placebo controls. All patients were also treated with chemotherapy each month for 6 months after surgery. Flow cytometry for peripheral T-lymphocyte subsets showed that the ginseng powder restored CD[4.sup.+] T cell levels to the initial preoperative values during chemotherapy. Depression of CD[3.sup.+] lymphocytes was also inhibited. The study demonstrated five-year disease-free survival and overall survival rates which were significantly higher in patients taking ginseng compared to controls (68.2% versus 33.3%; 76.4% versus 38.5% respectively, p<0.05). In other words, the ginseng treatment significantly prolonged survival and reduced the incidence of metastases.
Ninety-two patients with moderately severe chronic obstructive pulmonary disease (COPD) were randomly given either ginseng (300 mg/day of extract, equivalent to 1500 mg of root) or placebo for 3 months. (3) Measures of both pulmonary function and exercise capacity improved only in the group receiving ginseng, and the values were significantly above placebo at the end of the trial. For example, compared to baseline readings at the start of the trial, forced expiratory capacity in one second was up by 27.0%, peak expiratory flow rate improved 27.5%, maximum voluntary ventilation was up by 40.4% and maximum oxygen consumption improved 37.5%. No side effects were observed during the study.
Also recently announced were the results of a study on a formulation containing Panax ginseng and Panax notoginseng in patients with mild to moderate dementia (due to a number of small strokes). (4) Twenty-five patients took the ginseng combination while another 15 took a drug for dementia containing almitrine plus raubasine, which is thought to improve oxygen delivery to the brain. The scientists based at the University of Beijing conducted a battery of tests that measured patients’ ability at recall and verbal and visual recognition. Patients taking the ginseng compound showed more improvement in overall memory than those taking the drug combination. However, such results are preliminary and placebo-controlled studies are now needed.
These are exciting developments which suggest a key role for ginseng in the management of several major chronic diseases. The improved survival and lower rate of metastases after surgery and chemotherapy is particularly valuable information. Perhaps if the ginseng had been given for longer than 6 months the outcomes may have been even more striking.
Controversy Over Ginkgo and Epilepsy
In 2001 a letter was published in Annals of Internal Medicine by Dr. Philip Gregory drawing attention to anecdotal reports of seizure in association with the use of Ginkgo biloba. (1) According to the letter, the US FDA’s database has described seven reports of which four were linked to multi-ingredient products containing Ginkgo and three were associated with single-ingredient Ginkgo products (each from different manufacturers). The author also mentions other anecdotal reports from Internet discussion boards and electronic mailing lists (some of dubious credibility) and speculates that this phenomenon might be an inherent property of Ginkgo leaf or due to product contamination with Ginkgo seed (apparently associated with seizure in Japan).
The closing paragraph of the letter is as follows: “On the basis of these limited data, it is impossible to determine causality with any certainty. Until more is known, ginkgo should be used cautiously or avoided in patients who might be predisposed to seizure or who are using other medicines known to incite seizure. This letter is meant to put health care professionals on the lookout for similar cases and to prompt more thorough communications about possible ginkgo-related seizure.”
This letter invoked a stinging rebuttal entitled Scientific reporting of unscientific data–A case of Ginkgo biloba being miscredited from Dr. Jan G. Bruhn who is a member of the ESCOP (European Scientific Cooperative on Phytotherapy) Scientific Committee. (2) In his letter Dr. Bruhn quite correctly points out that the quality of the cases is very poor and that herbal product manufacture in the US does not require proper pharmaceutical manufacturing standards or quality control. Hence, results and reports based on US products should be handled cautiously because of quality issues. He laments that the known anticonvulsant effects of Ginkgo were not highlighted in Dr. Gregory’s letter. Dr. Bruhn concludes his letter with: “To evaluate the possibility of adverse effects we need unambiguous data concerning the products involved, and also precise information on the extent and manner of use as well as about comedications and the patient’s profile. That is the only way to perform a qualified benefit-risk assessment. Anecdotes from the Internet are not scientific data!”
Although the critique of Dr. Bruhn is absolutely valid, there is the danger of missing the essential issue: that Ginkgo might genuinely (and perhaps rarely) be linked to epileptic seizures. In order for such associations to come to light, anecdotal reports do have a valid role, provided they are only regarded as possibilities requiring further investigation.
There is one key flaw in Dr. Bruhn’s rebuttal. He has ignored, or been unaware of, a paper published in 2001 by a UK-based scientist which could explain the connection between Ginkgo and epilepsy. The publication in question describes two patients with well-controlled epilepsy who presented with recurrent seizures within 2 weeks of commencing Ginkgo extract. Ginkgo was discontinued and both patients were seizure-free several months later. Both patients were taking the anticonvulsant drug sodium valproate in combination with other medications. (3) While Ginkgo could not be identified as the causative agent, intraperitoneal injection of Ginkgo (50 mg/kg) has been shown to reduce the effectiveness of sodium valproate and carbamazepine in mice. (4)
So in other words the association of Ginkgo with epilepsy could be an herb-drug interaction. Until further information becomes available, Ginkgo should be avoided by epileptic patients taking anticonvulsant drugs.
FNIMH = Fellow, National Institute of Medical Herbalists (UK)
FNHAA = Fellow, National Herbalists Association of Australia
The contribution of Michelle Morgan in the preparation of this article is gratefully acknowledged.
P.O. Box 713 * Warwick QLD 4370, Australia +61 7 4661 0700 * Fax +61 7 46610788 * www.mediherb.com
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(1.) Kimmatkar N, Thawani V, Hingorani L et al. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee–a randomized double blind placebo controlled trial. Phytomedicine 2003; 10(1): 3-7
(2.) Safayhi H, Mack T, Sabieraj J et al. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. J Pharmacol Exp Ther 1992; 261(3): 1143-1146
(3.) Eleventh European Congress of Rheumatology, Vol 5, supplement issue, 1987; p 175
(4.) Etzel R. Special extract of Boswellia serrata (H 15) in the treatment of rheumatoid arthritis. Phytomedicine 1996, 3(1): 91-94
(5.) Singh, Hardayal, Singh GP et al. Abstract presented at International Conference on Clinical Pharmacology and Therapeutics, Bombay, 20-22 November 1987
(6.) Proceedings of The Symposium of Recent Advances in Mediators of Inflammation and Anti-inflammatory Agents. Councel of Science and Industrial Research, Regional Researck Laboratory, Jammu, 1984.
(7.) Gupta VN, Yadav DS, Jain MP et al. Chemistry and pharmacology of gum resin of Boswellia-serrata salai guggal. Indian Drugs 1987; 24 (5): 221-231
(1.) Cho YK, Sung H, Lee HJ et al. Long-term intake of Korean red ginseng in HIV-1-infected patients: development of resistance mutation to zidovudine is delayed. Int Immunopharmacol 2001; 1: 1295-1305
(2.) Suh SO, Kroh M, Kim NR et al. Effects of red ginseng upon postoperative immunity and survival in patients with stage III gastric cancer. Am J Chin Med 2002; 30(4): 483-494
(3.) Gross D, Shenkman Z, Bleiberg B et al. Ginseng improves pulmonary functions and exercise capacity in patients with COPD. Monaldi Arch Chest Dis 2002; 57(5-6): 242-246
(4.) Tian J, Yin J, Yang C et al. A randomized pilot study of compound of Chinese ginseng treatment of memory impairment in patients with mild and moderate dementia after stroke. 28th International Stroke Conference, Phoenix, Arizona, February 14, 2003. Abstract P327
(1.) Gregory PJ. Seizure associated with Ginkgo biloba? Ann Intern Med 2001; 134(4): 344
(2.) Bruhn JG. Scientific reporting of unscientific data–A case of Ginkgo biloba being miscredited. Phytomedicine 2003; 10: 358
(3.) Granger AS. Ginkgo biloba precipitating epileptic seizures. Age Ageing 2001; 30(6): 523-525
(4.) Manocha A, Pillai KK, Husain SZ. Influence of Ginkgo biloba on the effect of anticonvulsants. Indian J Pharmacol 1996; 28(2): 84-87
by Kerry Bone, FNIMH, FNHAA
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