Twelve Integrator Voices on a Theme: NCCIH's Past and Future Plans for Research on Botanical Medicines

Botanical plan described

Research on botanicals at the National Center for Complementary and Integrative Health (NCCIH) has engendered controversy from NCCIH's earliest days as NCCAM. One after another, year by year, another major herb was summarily dismissed via NCCIH-funded trials. To advocates, it seemed that a system born to serve private sector pharma was picking off public domain botanicals like a hunter shooting ducks on a pond.

Gutsy publication on botanical research

So when the

Eric Yarnell, MD

1. Bastyr Faculty Eric Yarnell, ND: "Go back to studying what actually happens in historic practice"

"The NCCIH approach so far has been to treat herbs as though they were drugs. This has failed miserably, as highlighted in Dr. Hopp's piece in HerbalGram on the negative, large double-blind randomized trials funded by NCCIH (as NCCAM) in the past. Rather than concluding herbs don't work, one could conclude that this approach to herbs doesn't work. Never in

	"Models for whole-practice or whole-system studies exist and have already proven themselves preliminarily, such as Lynne Shinto, ND, MPH, et al.'s trial on whole-system naturopathy for people with multiple sclerosis." - Eric Yarnell, ND

history were the extracts (generally highly refined, pseudo-pharmaceutical agents) studied used. Instead, go back to studying what actually happens in real traditional medicine. This almost always involves multiple therapies happening simultaneously, including the healing relationship with a practitioner who listens and cares, multiple herbs formulated to match the individual, dietary and lifestyle changes, and other interventions. Models for this type of research (whole-practice or whole-system studies) exist and have already proven themselves preliminarily, such as Lynne Shinto, ND, MPH, et al.'s trial on whole-system naturopathy for people with multiple sclerosis (J Altern Complement There 2008;14(5):489-96). Stop trying to squeeze drug-like herbal extracts into the pharmaceutical model and instead focus on studying how natural medicine is actually practiced."

Bevin Clare, MS, RHG, LDN

2. AHG President Bevin Clare, MS, RH, LDN: "The move to explore herbs in health enhancement is closer to tradition"

Clinical herbalist Bevin Clare, MS, RH, LDN is the president of the American Herbalists Guild, the nation's largest body of professional herbalists. a clinical herbalist, nutritionist, and is an associate professor at the Maryland University of Integrative Health. She is also adjunct faculty at MCPHS University (which houses the former NESA and former Massachusetts College of Pharmacy). Her BS is in Ethnobotany from Lesley University and MS in Infectious Disease at the London School of Hygiene and Tropical Medicine.

"The movement of NCCIH to explore herbal medicines and health enhancement could provide a model for understanding which is closer to their application in traditional and modern systems of herbalism as utilized by herbalists.

"If the target of NCCIH can understand  the specific foci of health which can be supported within a disease state model, we will end up with data which is both useful in a variety of related disease states as well as a more appropriate niche for botanicals used in integrative models."  - Bevin Clare, MS, RH, LDN

"Herbal medicines are most effectively used in situations where health enhancement and support of physiological systems is the goal. The chemical complexity and the co-evolutionary relationship they share with humans primes them for the subtle and dynamic support needed to enhance health. Compensatory medicine, on the other hand, is highly targeted, strong, and by its very nature biologically over-powering, precisely the kind of medicine herbal medicine in its natural state is not.

"This doesn't mean herbal medicines cannot be used for disease states. On the contrary, they hold immense possibility for people with chronic disease, but in these cases their effectiveness comes from the individualized approach of assessing the physiological systems which need support and applying botanicals in a way which meets the needs of the individual. For example, an individual suffering from depression may be approached with botanicals which can support refreshing sleep, a balanced gut / brain axis, support productive energy levels, and reduce systemic inflammation. The concept of using an herb to specifically compensate the imbalance which is causing depression is putting herbal medicine into a disease model which may be best served by the construct which is pharmaceutical medicine.

"If the target of NCCIH can be broadly conceptual enough to understand the specific foci of health which can be supported within a disease state model, such as in the support of quality of sleep in patients with depression, or the management of concurrent digestive concerns in patients undergoing chemotherapy, we will end up with data which is both useful in a variety of related disease states as well as a more appropriate niche for botanicals used in integrative models."

Michael Timms, PhD

3. Michael Timms, PhD: "Hopp's point is good in measuring wellness outcomes not just pathophysiology"

The academic director for herbal programs at Maryland University of Integrative Health (MUIH), Michael Timms, PhD, began in this field as a health food store owner. He subsequently pursued and earned a doctorate after which he was awarded, according to the MUIH site, "several National Institute of Standards and Technology/National Institutes of Health postdoctoral fellowships to design and produce botanical standard reference materials." He also had a role in developing the online medicinal plant database, HerbMed, that is now housed at American Botanical Council.

"In discussing methodological development, improved biological characterization of herbal products is needed for conducting trials that speak to potential efficacy. Dosing protocols need to be improved, by systematically mining both evidence base and traditional literature. A case in point, the Echinacea rhinovirus trial (Turner et al., 2005), which was well designed, used a maintenance dose as opposed to starting with a higher loading dose. The PI on the paper pointed out that funding limits prevented investigation of multiple dosing regimens.

	"Trial design that borrows from systems biology capable of mapping complex interactions (network pharmacology paradigm) is needed, not only in herbal research, but in areas of cancer and HIV treatments that use cocktails of compounds." - Michael Timms, PhD

"A more robust approach to the extraction process rationale, focused on clinical endpoints rather than pharmaceutical marker compounds, would be a good next step. Additionally, trial design that borrow from systems biology capable of mapping complex interactions (network pharmacology paradigm) is needed, not only in herbal research, but in areas of cancer and HIV treatments that use cocktails of compounds.

"Dr. Hopp makes an important point when he noted that the trials also need to measure wellness outcomes as much as pathophysiological changes. Beyond questionnaire generated data, addressing the need for effective Wellness 'biomarkers' would be a useful tact. My hope is that NCCIH would avoid funding animal trials for evidence for efficacy, since results of pharmaceutical investigations have not provided strong correlation for effective product development (Pippin, 2013).

"Finally, use of the FDA Investigational New Drug laws may end up being a barrier to research.

• Turner RB, Bauer R, Woelkart K, et al. An evaluation of Echinacea angustifolia in experimental rhinovirus infections. New England Journal of Medicine. 2005;353(4):341-348. Available at: www.ncbi.nlm.nih.gov/pubmed/16049208. Accessed July 6, 2015.
• Neurological, C., & Hormone, D. M. (2013). Animal Research in Medical Sciences and Animal Law, 51, 469-511.

Bill Reddy, LAc, DiplAc

4. Bill Reddy, LAc,DiplAc: "NCCIH is being myopic by primarily studying Western herbs"

"I believe NCCIH is being myopic by primarily studying Western herbs. The majority of the earth's population (1.36B Chinese and 1.25B Indians) use Traditional Chinese Medicine  (TCM) and Ayurvedic herbs, and their use is growing outside of those countries, especially in America and the EU.  There are currently over 28,000 board licensed TCM practitioners in the US with over 60 accredited schools teaching this ancient form of herbal medicine and acupuncture, and those numbers are on the rise.  The National Ayurvedic Medical Association has 595 current members in the US, representing a small fraction of the total number of practitioners across the nation.

"PubMed provided 10,505 articles (search dated Oct 2015) in response to a search query containing the key words 'Traditional Chinese Medicine.'  When I restricted the search to those papers written in English, the number dropped to 7,420.  Perusing the list of authors of the first 60 publications (in English), only one paper (Danish origin) contained non-Asian names.  Even though strategic objective #2 from the NCCAMs Third Strategic Plan 2011-2015 seeks to advance research on CAM natural products including 'Traditional Medicine Formulations,' not one study funded in 2014 (according to the RePORTER under FY2014 new and competing awards) evaluated any traditional Chinese medicine or Ayurvedic herbs.  There were two studies funded on the mechanisms of acupuncture.

"The only 'fly in the ointment' is that one size does not fit all in the Indian and Chinese medical systems and differential diagnosis (in Chinese Medicine) not only includes common signs and symptoms, but also the patient's 'constitution,' as well as tongue and pulse information to 'dial in' the proper herbal combination." - Bill Reddy, LAc, DiplAc

"There are over 13,000 medicinals in the Chinese Pharmacopoeia, however, quite a few common varieties are used to treat everyday illnesses: these herbs include cordyceps, chrysanthemum, hawthorn fruit, ganoderma/reishi mushroom, rehmannia, rhodiola, atragalus, white peony root, ginseng and licorice root - with several being adaptogens.  Phytopharmacologist researchers in China, Japan, Korea and other Eastern countries are far ahead of their Western counterparts in the 21^st century.

"My recommendation to NCCIH leadership is to perform a preliminary literature review on common Chinese and Ayurvedic herbs and find which ones have strong scientific support and conduct additional study of those medicines.  Cross-reference that list with the top health issues in the US to further prioritize the comparative effectiveness research.  The only 'fly in the ointment' is that one size does not fit all in the Indian and Chinese medical systems and differential diagnosis (in Chinese Medicine) not only includes common signs and symptoms, but also the patient's 'constitution,' as well as tongue and pulse information to 'dial in' the proper herbal combination.  Study design must be developed with well-seasoned Ayurvedic/TCM practitioners closely involved in the process to develop inclusion/exclusion criteria, etc."

"NCCIH researchers must look to the future, and the majority of Americans are shifting their focus to options beyond drugs and surgery."

Michael Levin

5. Michael Levin: "If not NIH, who will invest in clinical research that could drive down drug costs?"

"While Dr. Hopp did an outstanding job describing the background behind which NCCIH has redirected its research priorities away from botanical disease treatment, I fear the embedded chart may be misunderstood at best, misleading at worst. 

"In disclosing the St Johns Wort trial, for example, the fact is that this study (all other study limitations aside for the moment) was a double-blind, placebo controlled 8-week trial having  three treatment arms  that compared effectiveness of SJW or sertraline (Zoloft(tm)) in major depression of moderate severity against placebo. Neither SJW or Zoloft was found more effective than placebo, a fact not disclosed in the chart (nor in the title of the NIH press release!) leaving the casual reader to unfortunately conclude 'SJW doesn't work', thus providing yet another misleading soundbite for mainstream media and politicians to misuse.

"Yet, Sertraline remains on the US market as part of a drug class on which America spent $11-billion last year. Stunning.

	"The missed opportunity of doing tightly focused botanical research in areas where a) the herb has a high probability of safely/effectively providing symptomatic relief, 2) areas in which millions of people spend billions of dollars on drugs, is a failure in leadership. "Shouldn't we invest in way to provide safe and effective relief at a lower cost?" - Michael Levin

"Does SJW 'work'? The National Library of Medicine ranks SJW as 'likely effective for mild to moderate depression.' Noting the challenges of variable product quality and after reviewing 29 studies involving 5498 patients, the Cochrane Collaboration concurs with the NLM stating: 'Overall, the St John's wort extract were superior to placebo, similarly effective as standard antidepressants, and had fewer side effects than standard antidepressants.'

"While I appreciate the argument that NCCIH doesn't want to invest in areas covered by other NIH agencies, a quick review of the National Institute of Mental Health research priorities shows that more botanical research on St Johns Wort will not happen. Doing so is outside of their strategic research priorities. 

"If not NIH, who will invest in clinical research that could drive down drug costs? Certainly not Pharma! (Possibly a few enlightened PBMs might tackle this based on ROI, but that's a subject for a later date.)

"The missed opportunity of doing tightly focused botanical research in areas where a) the herb has a high probability of safely/effectively providing symptomatic relief  in 2) areas in which millions of people spend billions of dollars on drugs, is a failure in leadership. Shouldn't we invest in way to provide safe and effective relief at a lower cost? 

"As a taxpayer, I view this as an economic imperative. In addition to depression ($11 billion/year in spending, per IMS), other 'low hanging botanical  fruit' that could help millions of people includes those with sleep disorders ($5 billion in Rx spending, per IMS) and anxiety disorders (billions).

"While economic impact does not appear to be part of the NIH research priority charter, it's time we invest tax dollars on smart projects that could reduce healthcare costs, today!  I hope NCCIH reconsiders it mandate. Based upon the preponderance of global evidence, herbal medicine clearly offers such opportunities."

Sheila Kingsbury, ND, RH(AHG)

6. Sheila Kingsbury, ND, MS, RH(AHG): "I like the focus on pharmacognosy so we can tease out how the plants work"

The chair of botanical medicine at Bastyr University, Sheila Kingsbury, ND, MS, RH(AHG)

"I am pleased to see NCCIH recognizing where modern research falls short in terms of the study of botanicals and that they acknowledge that what has been plaguing this research is the variables of dose and preparation, as well as specific parts of the plant to be used. 

""I am pleased to see NCCIH recognizing  where modern research falls short in terms of the study of botanicals and that they acknowledge that what has been plaguing this research is the variables of dose and preparation, as well as specific parts of the plant to be used." - Sheila Kingsbury, ND, MS, RH(AHG)

"I also like that the new emphasis on doing studies with a focus more on the pharmacognosy of the plants so that we can really begin to tease out the information about how the plants work within the body.  Their emphasis on improving the research methodologies with botanicals is much needed and will likely reflect more useful results with far more impact. 

"This article doesn't really affect how I use the plants in my practice.  I have enough clinical experience and education to understand how the plants have been used traditionally as well as the evidence I've gained in just using them in practice to make me feel quite confident in their use.  I personally value the traditional information and find it highly useful for knowing how to work with the botanical medicines.  The research, to me, just helps me to confirm what we already know or to show mechanism.  So, this change in focus will be quite valuable to us who know how the plants work for treating conditions but lack enough explanation for HOW they work."

Tori Hudson, ND

7. Tori Hudson, ND: "This begs the question of synergy, herb and provider, herb and patient, with a whole approach"

Pioneering integrative clinician, author and internationally-recognized educator Tori Hudson, ND was also an early researcher in the rebirth of the naturopathic profession. She practices at A Woman’s Time , P.C., is program director for the Institute of Women’s Health and Integrative Medicine, and on the faculty at three naturopathic medical schools. Hudson is also director of research and product development at Vitanica. I had the opportunity to work closely with Hudson on a major 1991 North American naturopathic medical conference, entitled "Into the Light," that focused on in-office research.

"After a quick read of the NCCIH piece on the future of botanical research within this NIH entity, I noticed questions in my mind:

"In modern clinical naturopathic/alternative medical practice, these herbs are not used on their own.  They are used as a part of a whole approach including relationship with the patient, lifestyle changes, and other herbs/nutrients.  I think this begs the question of synergy - synergy between herb and provider; synergy between herb and patient; synergy between herb and other ingredients and influences." - Tori Hudson, ND

"1) Why did so many of these studies at conventional academic research institutions fail, and why have others, in other parts of the world, or studies in settings with more alternative oriented practitioners, succeed?  I do not know the answers to these questions, but obvious issues would arise around dosing, quality of the product used, and other aspects of study design.

"2)  I also am reminded of how these herbs, both historically, and in modern clinical naturopathic/alternative medical practice, are not used on their own.  They are used as a part of a whole approach including relationship with the patient, lifestyle changes, and other herbs/nutrients.  I think this begs the question of synergy - synergy between herb and provider; synergy between herb and patient; synergy between herb and other ingredients and influences. 

"Yes, a double-blind placebo controlled trial removes variables with a goal of separating out other influences in order to assess the true validity of the item being studied.  But, with due respect to very smart researchers and very honorable conventional academic research departments, perhaps instead we should be studying these plants in such a way that reflects their long treasured traditional history of use, and reflects how they are actually used in clinical practice, by practitioners who are familiar with and aligned with the medicine of plants."

James Snow, MA, RH(AHG)

8. MUIH's James Snow, MA, RH(AHG): "The results should still give pause to anyone looking for simple answers"

Maryland University of Integrative Health (MUIH) assistant provost for academic research James Snow, RH(AHG) also serves the multidisciplinary MUIH as interim academic director for Integrative Health Sciences. He has more than 25 years of experience merging modern scientific perspectives with traditional explanatory models of healing. He is also a passionate advocate of MUIH's commitment to the "healing presence."

"While the herbal formulations and dosages in the NCCIH-funded clinical studies may be vulnerable to criticism, the results should still give pause to anyone looking for simple answers on the shelf at the natural food store. These studies support the position that an herb-drug substitution model, or a 'one herb for one disease' model, has limited value in disease management. I applaud NCCIH's decision to shift their focus from funding further research along these lines. The question is where to go next?

"These studies support the position that an herb-drug substitution model, or a 'one herb for one disease' model, has limited value in disease management. "I applaud NCCIH's decision to shift their focus from funding further research along these lines. The question is where to go next?" - James Snow, MA, RH(AHG)

"NCCIH has chosen a path that now emphasizes exploration of mechanisms of action for herbal medicines. This certainly has value but it is an approach that moves research further away from patient-centered outcomes. Alternative avenues of inquiry include pragmatic trials designed to investigate whole systems of herbal medicine. Such trials can help answer the practical question of whether clinical herbal medicine, in its entirety, is an effective treatment option in routine care.

"Traditional herbal medicine incorporates individualized and compounded herbal formulae along with dietary and lifestyle changes.  This is entirely distinct from the generic herbal monotherapy utilized in previous NCCIH clinical studies. Pragmatic pilot studies, followed by large multicenter pragmatic trials, can investigate herbal medicine on its own terms and  maintain the focus on patient-centered outcomes. I would like to see NCCIH fund such studies in parallel with their current research agenda."

Bill Egloff

9. Crane Herbs' Bill Egloff: Two suggestions for research directions in herbs for NCCIH

The Crane Herb Company has recently been in the news as the firm selected by the Cleveland Clinic to fulfill at prescriptions to their patients at their Chinese Herbal Medicine Clinic. (See The Chinese Herb Strategy at the Cleveland Clinic: Insights from Jamie Starkey, LAc, Program Manager.) Crane's founder and CEO, Bill Egloff is a long-time Integrator reader with whom I have been in dialogue on multiple occasions. He responded to my call for responses with two brief notes on possible research ideas.

A.  Clinical Usage of Chinese Herbal medicine in the USA
Chinese Herbal medicine is being prescribed by licensed health practitioners in countries with national health insurance systems, like Switzerland, Germany, Taiwan and Japan. Research: Do these countries track the same data fields? What TCM herbal data should be tracked by state-licensed TCM practitioners? Data fields might include conditions, herb formula, dosage, side-effects, adverse events, effectiveness, treatment duration, cost to patient, etc.

B. Clinical Usage of Ma Huang
Ma Huang (Ephedra sinica Stapf) is prescribed safely and effectively by licensed health practitioners in Switzerland, Canada, Japan and Taiwan.  Ma Huang should be able to be prescribed by state-licensed practitioners in the USA, if they are trained in the traditional usage of Ma Huang and pass the NCCAOM Herbal Certification Exam. Research: Clinical usage data from these countries' national health insurance records would confirm if Ma Huang can be prescribed safely and effectively by licensed health practitioners. Relevant data would include the patient's condition, dosage, side-effects and adverse events. Example: Taiwan National Health Insurance shows that in 2013, Ma Huang was prescribed by doctors in over 300,000 formulas and ICD-9 codes show conditions for which it was prescribed.

Paul Bergner

10. Herbalist and Educator Paul Bergner: "They could have saved on those trials by reading previous literature"

Commentator Paul Bergner is director of the North American Institute of Medical Herbalism in Portland, Oregon. He supervised teaching clinics in medical herbalism and clinical nutrition in Boulder, CO from 1996 until 2013, and has published and edited the Medical Herbalism journal since 1989.  He has studied and practiced natural medicine, medical herbalism, and nutrition since 1973. He has authored seven books on medical herbalism, clinical nutrition, ethnobotany, and naturopathic medicine. I first got to know Bergner in the mid-1980s when we worked in close collaboration in the re-birth of the naturopathic profession, including creating the field's first cost-effectiveness document, and reached out to him here.

"Most of these trials were for uses that no herbalist would ever use them, at odds with the larger body of research, have significant under-dosing, and re-discover what is already well-known." - Paul Bergner

"Most of those trials were either:

1) For uses that no herbalist would ever use them. Ginkgo for hypertension? Are you kidding? How about taking an ACE inhibitor for scabies? That wouldn't work either.

2) At odds with the larger body of research, for instance Hypericum on meta-analysis is better than placebo even for major depression.

3) Have significant under-dosing compared to contemporary herbal practice (the Echinacea trials).

4) Rediscover what was already well-known; for instance in previous trials, Serenoa was never much better than placebo for BPH and doesn't actually work in a clinically-significant way even if there is a statistically-significant result.

Likewise Gingko may benefit a subclass of the elderly for non-dementia, non-Alzheimers memory loss, but not memory in general. And Allium has never lowered blood pressure by more than a small amount, a few points. They could have saved the money on those trials by just reading what was already established in the literature."

Beth Pimentel, ND, LM

11. Beth Pimentel, ND, LM: "Is herbs as 'complex mixtures' a step toward researching real-world prescribing"

The former dean at the University of Bridgeport College of Naturopathic Medicine, Beth Pimentel, ND, LM, is presently a consultant to health professions programs for issues related to accreditation and curriculum development. Pimentel has served in national leadership roles for the North American Board of Naturopathic Examiners, the Association of Accredited Naturopathic Medical Colleges and the interprofessional Academic Consortium for Complementary and Alternative Health Care. Pimentel offered her comments from a semi-sabbatical that has her on a boat, with her spouse and child, on the way to the Bahamas.  She is also a licensed midwife.

"Just for context - I'm not a researcher and I've been out of the loop for the past two years as I sail around the Bahamas.  Nonetheless, here are my thoughts on the botanical research at NCCIH.

	"The focus on improving research methodology and exploring the ways in which 'natural products, as complex mixtures or isolated ingredients, interact with biological systems' seems to be a good thing." - Beth Pimentel, ND, LM

"That NCCIH is changing its research agenda to focus on improving research methodology and exploring the ways in which 'natural products, as complex mixtures or isolated ingredients, interact with biological systems' seems to be a good thing.  Building a foundation of evidence for botanical medicines is important as this is a modality used across complementary and integrative health and medicine disciplines and professions. Perhaps this is just the first step in the evolution of NCCIH moving toward the study of real-world botanical prescribing that is performed on an individual basis in the context of the whole person.  Now that would be something exciting!"

Anonymous response

12. Anonymous Academically-Based Researcher: "Arrrggggghhh!"

One of the responses I received, from a long-time researcher associated with an institution that educates professionals into a doctoral level integrative health field, was the following two-part, short e-dialogue, not for attribution. The first e-reply:

"The first major research focus is on improved methodology across all aspects of natural products research. The second major focus is on exploration of the ways in which natural products, either as complex mixtures or as isolated ingredients, interact with biological systems.

"So if I'm reading [Hopp's] article correctly, NCCIH is going to focus botanical research on methodology and adverse effects?  (It says 'interaction with biological systems' but from what that author said, that's likely to translate into drug-botanical interactions in humans taking both; at least that's my cynical take on it.)  Hopefully I'm wrong. My main response to NCCIH is generally even briefer: 'Arrrggggghhh.' So I'm not sure any commentary by me would be helpful."

1. Appreciating the admission of poor methods in the early herb-for-disease trials.
   
2. Liking the interest in the potential of herbs with a health focus.
   
3. Intrigued by anticipated basic research that explores the complexity of botanicals. And, in an area strong by many,
   
4. Research on real world outcomes in clinical practices that include botanical preparations.

"The Director of the Center shall, as appropriate, study the integration of alternative treatment, diagnostic and prevention systems, modalities, and disciplines with the practice of conventional medicine as a complement to such medicine and into health care delivery systems in the United States." [Bolding added.]