(CHINESE) HERB NEWS
Herbs in this issue:
St. John’s wort
Jingjie (Herba Schizonepetae)
A Note From Dr. Leung
Are we headed the right direction?
Last May, I attended a one-day colloquium in Washington DC sponsored by the National Center for Complementary and Alternative Medicine (NCCAM). The topic was on complementary and alternative medicine. However, after listening to the experts from government and industry give their presentations, I came away with the impression that most of the experts were barking up the wrong tree. First of all, what is complementary or alternative medicine? Is it simply using a modern drug derived from natural sources to treat diseases? As a naturally derived drug is from an ‘alternate’ (‘complementary’) source to the usual synthetic origin of conventional pharmaceuticals, it must be a CAM therapeutic. Is that how it goes? Throughout the colloquium, except for comments by an acupuncturist (Bill Schoenbart) in the audience, which pointed out the importance of taking traditional usage and administration into
Dr. Leung is author of the Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics (Wiley-Interscience), which was published in 1980 and revised in 1996. He is also creator of PHYTOMED, a prototype computer database on Chinese herbal medicine developed under contract with the National Cancer Institute.
consideration when investigating CAM therapeutics, all the expert speakers were treating herbal drugs as if they were conventional pure-chemical drugs. And in a short period devoted to pre-submitted comments by Colloquium participants, mine regarding the problem of herb/drug definition, citing St. John’s wort’s failure in a recent clinical trial for major depression as an example, were not mentioned. At that time, I thought we were really headed towards the wrong direction. But I was later proven wrong. Read on.
Small Business Innovation Research (SBIR) grants to study herbal supplements
In November last year, the NCCAM issued requests for applications (RFAs) for the characterization, standardization, and production of reproducible preparations of 4 widely used dietary supplements for clinical trial. The 4 herbs were: feverfew (Tanaceti Folium), milk thistle (Cardui Fructus), valerian (Valerianae Radix), and echinacea (?). These RFAs were earmarked for SBIR. However, being disappointed 15 years earlier with my database project (an SBIR contract with the National Cancer Institute) whose second phase was not funded allegedly due to lack of funds, despite the review panel’s recommendation for funding, I had not paid any attention to NIH grant/contract activities with small business because I believed that those were mostly political favors to ‘professional/habitual’ grantees. Hence I didn’t know about these RFAs until my colleagues approached me with the news only about 3 weeks before the deadline and asked me if I wanted to go for one of them as there was not enough time to write more than 1 proposal. We were qualified because our company, Phyto-Technologies, Inc., is a small business and we specialize in the manufacture of herbal products. I decided to give it a try and we went for the feverfew grant because my friend and colleague, Dr. Dennis Awang, who is a well-known feverfew expert (especially its chemistry), was interested in applying for this one. We then pulled together a consortium of expert colleagues that included Allison McCutcheon (botanist), Greg Pennyroyal (agronomist/generalist), Ezra Bejar (bioassay expert), and Bunki Bunkaitis-Davis (gene expression profiling expert). Over a weekend at my house, Dennis, Greg, Darin Smith (Phyto-Tech’s director of operations), and myself, tried to put the proposal together. But it turned out to be much more than we bargained for. It ended up I had to spend another 5 days and nights to put the proposal together, with further help from Darin in the business area and from Greg, especially in the marketing area. Because our approach is multifaceted in the characterization and standardization, I had to first understand what each aspect (botanical, physicochemical, bioassay, gene expression, etc.) was all about before I could put together the research plan in a logical and understandable manner. That process was very painstaking and tortuous because I was no expert in all those fields. But since we all had started it and our company had committed resources to it, I was obligated to finish it myself. I just can’t imagine how ‘professional’ proposal writers can be experts in all subjects and write proposals like these. Do they actually understand the subject matter, especially its nuances that can only be learned by years of actual practice in the particular field? Or do they know what the reviewers look for and write the proposals to fit a preformed mold of thinking? I still can’t figure that out. But I did later find out that even some of our reviewers didn’t seem to understand our proposal, judging by their critique of it. Nevertheless, after those several tortuous days, the application was completed and submitted to the NCCAM. It was such a relief! Now, the work had been done, all we needed to do was wait. Once in a while, the possibility of the grant being awarded to us crossed my mind. Other than that, I was just too busy to have any time to think about it. Six months had elapsed with absolutely no word from NCCAM when the May colloquium was held in Washington DC. Before the colloquium, participants were asked to submit comments that were supposed to be addressed at the colloquium. After sitting there all day listening to experts make their presentations and express their views on dietary supplements, without hearing a single word about my submitted comments or related views submitted by others, I thought the government was up to its usual practice again. Then, a month later when I received the review panel’s critique of our proposal which pointed out numerous ‘deficiencies,’ I realized that even some experts like the ones on our review panel didn’t seem to get it. My guess was that they either didn’t have time to digest our proposal or simply didn’t understand the subtlety of it. I began to resign to the fact that that was another one of those whom-you-know and not what-you-know type of deals with the government. Nevertheless, I responded to all their questions which I later learned that the reviewers did not have a chance to review. It turned out that it was actually the NCCAM staff who appeared to have understood our research plan, because several weeks later we received the good news that our proposal was fully funded. That certainly revived my faith in our federal government and has given me a chance to put my theory and experience in integrating science and traditional medicine to work.
For your information, I am reproducing below the exact comments I submitted to the Colloquium before it was held last May because I thought you might be interested in the issues involved in the research in alternative and complementary medicine.
My comments apply to different aspects of CAM therapeutics, hence I place them all under this first question. The following are my 3 general comments:
(1) It appears to me scientists and practitioners in the natural therapeutics field each has his/her own ideas of what a natural therapeutic is. But most speak of it as if it were a conventional synthetic single-chemical pharmaceutical that can be chemically characterized and readily quality controlled. Little attention has been paid to clearly define the diversity of these natural CAM therapeutics. I believe many of our clinical trials have produced ambiguous and/or meaningless results because we have failed to clearly identify and define the test therapeutics as well as clearly define their indications. For example, Asian ginseng has no single well-defined indication (there are many), yet we frequently refer to the ‘therapeutic effects’ of ‘ginseng,’ often as due to its ‘ginsenosides’ (there are many). We are scientists and practitioners, the ones who supposedly should know better, yet we don’t seem to clearly know what we are talking about. No wonder the general public is confused.
Take another example - the well-publicized clinical trial of ‘St. John’s wort’ published in a recent issue of JAMA. I am sure there will be a spate of critical reviews from others regarding its design deficiencies. But my opinion is that there are 2 major problems with it.
One, the drug is simply identified as a ‘standardized 300-mg tablet extract of St. John’s wort’ from Lichtwer Pharma GmbH, Berlin, Germany. It is presumably standardized to hypericin. But there is no other information given on this ‘drug.’ Since hypericin is only one of an X number of chemicals in St. John’s wort, which has shown activity in minor depression, what else does this ‘drug’ contain that was originally present in the St. John’s wort herb? Without having this kind of information, all we can conclude from this clinical trial is that Lichtwer Pharma’s ‘St. John’s wort’ (whatever that is), and NOT St. John’s wort, is ineffective in treating major depression. This Lichtwer Pharma product may still work in minor depression. But if this same ‘drug’ is submitted to a clinical trial for minor depression, no matter the outcome, it will still be only Lichtwer Pharma’s ‘St. John’s wort.’ No other St. John’s wort product can match it unless the Lichtwer Pharma’s product is clearly defined (solvents used, amount of hypericin & related naphthodianthrones, flavonoids, xanthones, etc. per TLC and/or HPLC patterning, etc.) as compared to chemicals present in the original herb, otherwise no one can duplicate its composition. And the trial results cannot be held to be representative of St. John’s wort’s effects. Since St. John’s wort for depression is not the same as cascara for laxation (the former’s antidepressive principles are still not clearly known while the latter’s cathartic principles are anthraglycosides), we can’t yet equate its antidepressive activity to a ‘standardized’ extract.
Two, my understanding is the indication for St. John’s wort is minor depression, not major depression. Hence, irrespective of the test drug used (total extract, the pure hypericin chemical, or mixture of equal parts of naphthodianthrones & flavonoids, or whatever) the outcome of the study would not reflect on the true effects of St. John’s wort.
(2) Before we consider a clinical trial on a CAM therapeutic, we must first clearly identify what it is. In the case of natural medicines, they can be classified into 3 main types: (1) those that are well characterized chemicals with specific bioactivities; (2) those with well-characterized chemicals that may or may not be responsible for the activity of the natural medicine; and (3) those with no clearly identified active chemical components, whose activity lies in one or more compounds present in the natural medicine. With the above distinction, when we talk about clinical trial on a CAM therapeutic, we can then clearly and intelligently refer to it either as: (1) an isolated chemical (e.g., ephedrine, huperzine A, or caffeine) that can be easily measured; (2) a “standardized” extract with specific amounts of an identified chemical or chemical groups whose activities may be due to any one or more of these compounds (e.g., ginsenosides, hypericin, or parthenolide) as well as most of the chemical components present in the original herb; and (3) a total extract (aqueous, alcoholic, hydroalcoholic, etc.) containing a wide spectrum of chemical constituents, any one of which can be responsible for the bioactivity, but which so far has not been clearly identified.
So far, we have been too lax in accepting a CAM therapeutic without paying attention to its actual nature. Most frequently we speak of it as if it were the first type – a pure chemical drug that is no different than any conventional synthetic pharmaceutical, yet in fact it could be the third type with no specifically identified active components. Therefore, in order for any clinical trial to be successful, we must clearly define what we are going to study and for what indication(s). A clinical trial can yield meaningful results ONLY when the test therapeutic is clearly defined and the indication correctly assigned. With conventional single-chemical drugs, there is no problem with their identity, because they are always pure chemicals, but not so with CAM therapeutics!
(3) A considerable portion of the rapidly growing literature on natural CAM therapeutics is worthless due to the ambiguity and misidentification of the natural medicines being studied or described. The DSHEA of 1994 has not helped this situation because of its equal treatment of palliative herbs and food herbs as dietary supplements. Yet the fact is that we have pure (or almost pure) chemicals at one end of the spectrum (e.g., catechins, huperzine A, ephedrine, and synephrine) and relatively undefined herbal extracts at the other end (e.g., astragalus, fo-ti, and ginseng) whose active principles have not yet been clearly characterized. Then there are other ‘therapeutics’ in between, which have at least some, but not all, of their active components defined (e.g., feverfew, St. John’s wort, and echinacea), and which are often ‘standardized’ arbitrarily to marker compounds. Instead of trying to clearly distinguish among different types of ‘dietary supplements’ or CAM therapeutics, we somehow consider all the above types as if they were single-component drugs that can be chemically ‘standardized’ and quality controlled. Hence, when we talk about the activity of an ‘herbal medicine’ (be it caffeine in coffee, catechin in green tea or in catechu, chlorogenic acid in echinacea, ginsenoside Rb-1 in Asian ginseng, or schizandrins in schisandra), we too often equate the chemicals with the herbs and consider the herbs as if they were conventional single-component pharmaceuticals with well-defined chemical characteristics. The result is massive confusion in the literature.
In order to arrest the continued rapid growth of useless and misleading data on CAM therapeutics and to pave the way for future meaningful research in the CAM field, existing literature with such information needs to be identified and made known to the CAM and biomedical communities. Simply identifying publications with ill-defined natural medicines can avoid further dissemination and perpetuation of wrong or dubious information and misinformation. Criteria for identifying such medicines and articles containing information on such CAM therapeutics* can be promulgated with support of the NCCAM, both financially and technically. It is important that NCCAM recognize the difference between pure single-chemical pharmaceuticals (synthetic or natural) and not-yet-chemically-defined natural medicines, as well as others in-between, so that it can assume the leadership in spending US taxpayers’ money wisely and with beneficial results. Failing to recognize this but continuing to support research with natural CAM therapeutics that are of dubious identity or origin would continue to contribute to the disarray and confusion in the CAM field. It is encouraging to note that NCCAM appears to have recognized this fact and I hope it will take concrete steps towards rectifying the current situation in herb research, as the conventional medical and drug communities have no incentive to see that the CAM field undertake its research correctly which will generate results beneficial to the general public.
*(1) A.Y. Leung, “Scientific studies and reports in the herbal literature: What are we studying and reporting?” Leung’s Chinese Herb News No. 18: 1-2(1999); reprinted in HerbalGram 48: 63-64(2000). (2) A.Y. Leung, “Criteria for evaluating research on herbs and other natural products.” Leung’s Chinese Herb News No. 19: 2-3(1999).
A migraine remedy
The causes of migraine continue to be studied and debated. There are numerous clues but no clear answers. Some women suffer all their lives from debilitating migraine, and then, all of a sudden, it disappears after menopause. This indicates a hormonal factor in migraine. Clearly, there is much to learn in this area, and an open mind is required. In that spirit, I want to report the following:
This is from a report published in a journal dealing with Chinese folk remedies using egg and jingjie or schizonepeta [Herba Schizonepetae; Nepeta tenuifolia Benth. or Schizonepeta tenuifolia (Benth.) Briq.].1 It is simple and appears to be quite effective (according to the author) that I can’t resist bringing it to your attention. The physician (Dr. Liu) who reported this was from the Hebei Provincial Qinglong Manchurian Autonomous County People’s Hospital. Among the 21 patients Dr. Liu treated, 12 were male and 9 were female, between 17 and 55 years old. Duration of illness was from 6 months to 6 years. After treatment with this remedy, the migraine in 9 patients was completely relieved, which did not recur after 1-year follow up; the symptoms in another 9 patients were significantly mitigated, but occasionally recurred; and the symptoms in the remaining 3 patients were not relieved.
Method: Make a hole about 2 cm in diameter at the bigger end of an egg. Mill the jingjie into a fine power and add it to the inside content of the egg, mixing the 2 well with a chopstick. Continue to add the herb powder and mixing until the egg is full. Lay a small piece of wet paper (towel) over the hole and cook the egg in an oven until done. Eat the egg along with the jingjie, 1 a day for 3 days.
As typical of many Chinese reports, this one is short of precise details. For example, no specific amount of jingjie is specified. Nor are cooking time and temperature given. Still, it is not such a big problem. One will automatically have to stop adding the herb powder when one can’t add any more. And anyone who knows how to cook should be able to cook an egg in an oven.
Jingjie or Herba Schizonepetae (aboveground parts) is a common Chinese herb, related to catnip, belonging to the mint family. It was first described in the Shen Nong Ben Cao Jing (the Shennong Herbal) 2,000 years ago, and has since been widely used in formulas for treating headache, colds, flus and associated symptoms. The usual daily dose is 3-10 g.
(1) C.T. Liu, “Treatment of 21 Cases of Migraine with Egg and Jingjie (Nepeta tenuifolia Benth.),” Zhongguo Minjian Liaofa, 9(6): 38-39(2001);