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by Mark Blumenthal
In early January the American Botanical Council received numerous requests from members for a response to a recently-published meta-analysis of milk thistle clinical trials. This popular herbal dietary supplement, the study concluded, is ineffective for various disorders of the liver. ABC issued a Media Alert to select Sponsor Members, the contents of which are contained in this article. 1
A review and meta-analysis of 13 clinical trials (11 published and two conference abstracts) on the concentrated and standardized extract of milk thistle seed (Silybum marianum) was published December 2005 in the American Journal of Gastroenterology. 2 Milk thistle extract (MTE) is a popular herbal dietary supplement in the U.S., used primarily for its reputed beneficial effect on the liver. (In 2004 MTE was the 10th largest-selling herbal dietary supplement in mainstream retail markets. 3)
ABC and some of its scientific colleagues and medical advisors reviewed the paper and found anomalies in its contents. ABC also noted that there are discrepancies in the published analysis and the publicity from the journal’s publisher.
First, ABC emphasized that the published meta-analysis concluded that MTE is safe and was well tolerated in the clinical trials of various durations. Second, the ABC review determined that the conclusion questioning MTE’s efficacy is based primarily on the results of only one of the 13 trials reviewed by the paper’s authors. At least 2of the 4 authors have previously conducted systematic reviews of the literature on MTE; thus they appear quite familiar with the clinical and pharmacological literature on MTE.
Safety Obfuscated
A press release from Blackwell Publishing 4, publisher of the American Journal of Gastroenterology, resulted in a short Reuters news report 5 and other brief articles on various websites, although to date (January 26) this article does not appear to have been reported in other major media.
Despite numerous positive statements made by the authors in the original paper about the safety and efficacy of MTE, the press release from Blackwell Publishers focuses primarily on the negative. The press release quotes Dr. Christian Gluud of the Copenhagen Trial Unit, Center for Clinical Intervention Research at the Copenhagen University Hospital, one of the study’s authors, as saying, “The ironic fact is that even though milk thistle and milk thistle extracts have been widely examined, we are still not in a situation where we can exclude a potential beneficial or harmful effect.”
Dr. Gluud’s equivocation about the safety of MTE in the press release is directly at odds with the results of the paper itself where several statements regarding the lack of adverse effects of MTE are made. For example, the authors write, “…among the randomized clinical trials reporting adverse drug events, MT appeared safe and well tolerated.” 2
Commenting on the meta-analysis, ABC Advisory Board member Mary Hardy, MD, the former associate director of the UCLA Center for Human Nutrition, stated, “This meta-analysis did not show that MTE had significant adverse events, nor did it increase all-cause mortality in the majority of trials.” [Hardy M. Personal communication to M. Blumenthal (e-mail), Jan. 6, 2006.]
Using authoritative reviewers, ABC previously published an extensive Safety Assessment Report on MT. 6 This report found what most other authoritative reviewers have concluded: the safety of MTE is well established in extensive animal testing and human clinical trials, as well as a significant level of use in Germany and other parts of Europe where adverse events, if they occur, would have been reported to health authorities as part of the normal practice of pharmacovigilance for nonprescription medications. (ABC Sponsor Members and others are invited to contact ABC for information about licensing the MT Safety Assessment Report for labeling or use as educational content on websites.)
Efficacy Questions
“The methodology employed in this meta-analysis is sound,” noted Dr. Hardy, “but, like all meta-analyses, it is limited by the material in the review. The medical conditions examined are widely varied - everything from alcoholic liver disease (primarily what appears to be end-stage cirrhosis) to steatosis (accumulation of fatty tissue in an organ) to viral disease (both Hepatitis B and C).These diseases have different etiologies [sources] and lots of confounding variables, such as whether or not patients stop drinking alcohol.”
The primary outcome measured was all-cause mortality - a difficult variable to test in trials as short as 6 months (the average length of treatment for the pooled studies) and which generally requires studies with a large number of subjects to show a difference.
There were only enough trials to make a comment in alcoholic liver disease (e.g., “Liver-related mortality was significantly reduced [emphasis added] by MT in ALL trials.”). Dr. Hardy notes that “almost all of the deaths occur in only two studies. We don't have adequate details about the patients in these trials to comment about why so many deaths were reported here (were the patients more severely ill, still drinking, etc.?).”
Dr. Hardy added, “The more specific outcome, death related to liver disease, reportedly shows that MTE is protective if all trials are taken into account. The conclusion that this meta-analysis arrives at ‘based on high quality trials, MT does not seem to significantly influence the course of patients with Alcoholic and/or Hepatitis B or C liver disease.’ is therefore based on ONE article. Many of these patients also had Hepatitis C antibodies and may have been sicker.”
Dr. Hardy also noted that the methodological quality of the trials reviewed were fair, especially since many of these were relatively older trials. She summarized her thoughts on this meta-analysis as follows:
“The meta-analysis employs a good methodology, but the primary outcome variable would be difficult to assess with this set of trials, and, in fact, the main negative conclusion ends up resting on the results of one trial. A second trial, which is smaller, older and of somewhat less quality, shows a benefit for MTE. Further, including all trials again shows a benefit for the more specific outcome, mortality related to liver disease. Also, the average duration of treatment is short for a mortality trial. Therefore, the authors’ conclusion about the efficacy of MTE needs to be viewed with qualifications.” It should be noted that the quality of some of the studies is relatively poor and additional studies, especially in the area of viral hepatitis, may be warranted.
Other Considerations about Milk Thistle
MT has a long history of safe use in traditional folk medicine as an herbal remedy for the liver. There are an impressive number of experimental and animal pharmacology research studies, plus the body of clinical trial data, that suggest a positive benefit of MTE on liver function. The totality of all this evidence suggests the efficacy of MTE for various applications related to liver function. For example, the ABC Clinical Guide to Herbs reviews 21 clinical trials, most of which show some positive results for liver-related disorders. 7 In addition, the German government’s Commission E reviewed the available literature on MT and concluded that it is safe and effective for “toxic liver damage and for supportive [i.e., adjunct, not primary] treatment in chronic inflammatory liver disease and hepatic cirrhosis.” 8
Additional therapeutic monographs have been published by the World Health Organization 9, recognizing the therapeutic value of MTE.
The bulk of scientific evidence shows that MTE concentrated extract is safely tolerated in both animals and humans; MTE extract has demonstrated strong antioxidant effects; MTE extract increases RNA synthesis in helping to create new hepatocytes, i.e., helping to rebuild the liver tissue. 7,8 In fact, the authors of the meta-analysis write, “…we found that MT significantly improved two liver biochemical variables, s-bilirubin and GGT.” 2
Further, several recent clinical trials have attempted to determine whether MTE produces any adverse drug interactions; the clinical literature to date has shown that no interactions are known, 10, 11 and in one trial, MTE actually had a beneficial effect on a hepatotoxic psychopharmaceutical drug. 12
In summary, in view of the preponderance of scientific and medical evidence it is the view of ABC and its advisors that some of the conclusions of the meta-analysis are flawed and have been misinterpreted and misreported in subsequent media reports.
References
1. Blumenthal M. ABC Clarifies Recent Meta-analysis of Milk Thistle Clinical Trials. Media Alert. American Botanical Council, Jan. 11, 2006.
2. Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Milk Thistle for alcoholic and/or hepatitis B or C diseases - A systematic Cochrane hepato-biliary group review with meta-analyses of randomized clinical trials. Am J Gastroenterol. 2005;100:2583-2591.
3. Blumenthal M. Herb sales down 7.4 percent in mainstream market: garlic is top-selling herb; herb combinations see increase. HerbalGram. 2005; 66:63.
4. Anon. Common Alternative Treatment for Liver Disease is Found to be Ineffective [press release]. Blackwell Publishing, Dec. 14, 2005.
5. Harding A. Milk thistle ineffective for liver disease. Reuters, Dec. 26, 2005.
6. Milk Thistle Safety Assessment Report. Austin, TX: American Botanical Council; 2004.
7. Blumenthal M, Hall T, Goldberg A, Kunz T, Dinda K, Brinckmann J, et al, eds. The ABC Clinical Guide to Herbs. Austin, TX: American Botanical Council; 2003.
8. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine: Expanded Commission E Monographs. Austin, TX: American Botanical Council; Newton, MA: Integrative Medicine Communications; 2000.
9. Fructus Silybi Mariae. World Health Organization Monographs on Selected Medicinal Plants. Volume 2. Geneva: WHO; 2002.
10. Mills E, Wilson K, Clarke M, et al. Milk thistle and indinavir: a randomized controlled pharmacokinetics study and meta-analysis. Eur J Clin Pharmacol. 2005;61:1-7
11. DiCenzo R, Shelton M, Jordan K, et al. Co-administration of milk thistle and indinavir in healthy subjects. Pharmacother. 2003;23(7):866-870.
12. Palasciano G, Portinacasa P, Palmieri V, et al. The effect of silymarin on plasma levelsof malondialdehyde in patients receiving long-term treatment with psychotropic drugs. Curr Therapeut Res. 1994; 55(5):537-545.
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