Integrative Medicine: A Clinician's Journal

JUNE/JULY 2016 • VOL. 15 NO. 3

Integrative Medicine: A Clinician’s Journal

Rheum rhaponticum Extract: Postmarketing Data on Safety Surveillance • Neural Therapy in Patients With Bell’s Palsy • Chronic Rhinosinusitis and Irritable Bowel Syndrome: A Case Report • Presenters 2016: Christopher Hobbs, PhD, LAc, AHG • Interview with Datis Kharrazian, DHSc, DC, MS, MNeuroSci, CNS • Where Is Health Care Headed? • Three Myths About Dietary Supplements • Editorial: Is Mold Toxicity Really a Problem for Our Patients? Part 2—Nonrespiratory Conditions

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June/July 2016 • Vol. 15 No. 3

Integrative Medicine: A Clinician’s Journal www.imjournal.com

EDITORIALS 8

Is Mold Toxicity Really a Problem for Our Patients? Part 2—Nonrespiratory Conditions Joseph Pizzorno, ND, Editor in Chief; Ann Shippy, MD

16

Where Is Health Care Headed?

Jeffrey Bland, PhD, FACN, FACB, Associate Editor

64

The Case for Civility Bill Benda, MD, Associate Editor

COMMENTARY 20

Three Myths About Dietary Supplements … and How Knowing the Right Answers Is Good for Your Integrative Medicine Practice Loren Israelsen; Frank Lampe

26

Federal Strategies for Pain and Opioids Wildly Uneven on Value of Integrative Practitioners … plus more John Weeks

ORIGINAL RESEARCH 34

Rheum rhaponticum Extract (ERr 731): Postmarketing Data on Safety Surveillance and Consumer Complaints Jyh-Lurn Chang, PhD; Michael B. Montalto, PhD; Peter W. Heger; Eva Thiemann; Reinhard Rettenberger, PhD; Jürgen Wacker, MD, PhD

CASE STUDY 40

The Effectiveness of Neural Therapy in Patients With Bell’s Palsy Ferdi Yavuz, MD; Bayram Kelle, MD; Birol Balaban, MD

CASE REPORT 44

Chronic Rhinosinusitis and Irritable Bowel Syndrome: A Case Report Mikhail Kogan, MD; Carlos Cuellar Castillo, MS; Melissa S. Barber, MS

PRESENTERS 2016 30

Christopher Hobbs, PhD, LAc, AHG: Mushrooms for Nutrition and Wellness Interview by Craig Gustafson

VIEWPOINTS 56

Datis Kharrazian, DHSc, DC, MS, MNeuroSci, CNS: Finding Hope for Neurological Autoimmune Disease Interview by Craig Gustafson

EPTHECA 62

Conference Calendar

Table of Contents

Integrative Medicine • Vol. 15, No. 3 • June 2016

3

June/July 2016 • Vol. 15 No. 3

Integrative Medicine: A Clinician’s Journal www.imjournal.com

Editor in Chief Joseph Pizzorno, ND drpizzorno@innovisionhm.com IMCJ Associate Editors Sidney MacDonald Baker, MD

Jennifer C. Lovejoy, PhD, CNS

Autism Research Institute

Institute for Systems Biology

Bill Benda, MD, FAAEM

David S. Riley, MD

Senior Graduate Fellow, Program in Integrative Medicine, University of Arizona; St. Mary's Medical Center in West Palm Beach, FL

Academy of Integrative Health and Medicine; Integrative Medicine Institute; National College of Natural Medicine

Jeffrey Bland, PhD, FACN, FACB

Darcy Vavrek, ND, MS

Cofounder, Institute for Functional Medicine; Founder, Personalized Lifestyle Medicine Institute

University of Western States

Tori Hudson, ND

David Wickes, DC, FICC, Dipl ABCI

Medical Director, A Woman’s Time; Program Director, Institute of Women’s Health and Integrative Medicine; Research/Education Director, Vitanica

Canadian Memorial Chiropractic College

IMCJ Editorial Board Lise Alschuler, ND, FABNO ◆ Executive Director, TAP Integrative; Coprinciple, Thrivers; Clinician, Naturopathic Specialists Jeremy Appleton, ND ◆ Nature’s Way Brands

Douglas MacKay, ND ◆ Senior Vice President, Scientific & Regulatory Affairs, Council for Responsible Nutrition Antonio C. Martinez, II, JD ◆ Attorney at Law

Phillip Barr, MD ◆ Concierge Health Consultants

Robert Martinez, ND, DC, DABCO ◆ Private Practice, Kirkland, WA

Donald M. Blair, DDS, ND ◆ Bellevue, WA

David Matteson, MPH, MS, MPA, APR ◆ Early Edge Solutions, Nativis

O’Dane Brady, DC, MSc ◆ World Spine Care

Gerard E. Mullin, MD ◆ Division of Gastroenterology and Hepatology, Johns Hopkins Hospital Stephen P. Myers, ND, PhD, BMed, FACNEM ◆ Southern Cross University, Australia

Andrew W. Campbell, MD ◆ Editor in Chief, Alternative Therapies in Health and Medicine Alan R. Gaby, MD ◆ Concord, NH Steve Given, DAOM, LAc ◆ American College of Traditional Chinese Medicine Elizabeth A. Goldblatt, PhD, MPA/HA ◆ Academic Consortium of Complementary and Alternative Health Care (ACCAHC) Patrick Hanaway, MD ◆ Cleveland Clinic Mary L. Hardy, MD ◆ Stiles Integrative Oncology Program at UCLA; Wellness Works

Paula J. Nenn, MD, ABIHM, MRCP(UK) ◆ States of Jersey, Department of Medicine; University of Southampton David Perlmutter, MD, FACN, ABIHM ◆ Perlmutter Health Center Lara Pizzorno, MA (Div), MA (Lit), LMT ◆ Editor, Longevity Medicine Review; Integrative Medicine Advisors, LLC; Salugenecists, Inc Ronald G. Reichert, ND ◆ Boucher Institute of Naturopathic Medicine; Bioclinic Naturals Corey Resnick, ND ◆ Integrative Health & Nutrition; Integrative Therapeutics

Mark Hyman, MD ◆ Institute for Functional Medicine; The Center for Mind-Body Medicine; The UltraWellness Center Loren D. Israelsen, JD ◆ President, United Natural Products Alliance

Jacob Schor, ND, FABNO ◆ Denver Naturopathic Clinic; Fellow, American Board of Naturopathic Oncology; Associate Editor, The Natural Medicine Journal; Board Member and Past President, Oncology Association of Naturopathic Physicians Clyde B. Jensen, PhD ◆ University of Western States; Oregon Collaborative Vivek Shanbhag, ND, MD(Ayur) ◆ YogaAyurveda.org; Natural Medicine Clinic & for Integrative Medicine; Association of Health Sciences Colleges Academy; Adjunct Faculty, Bastyr University & MMI Ayurveda College and Universities Claire Johnson, DC, MSEd, DACBSP ◆ National University of Health Sciences Andrew David Shiller, MD ◆ Integrative Rehabilitation Medicine; The Valley Hospital, Ridgewood, NJ Herb Joiner-Bey, ND ◆ Barlean’s Organic Oils Pamela Snider, ND, PhND(Hon) ◆ Executive and Senior Editor, Foundations of Naturopathic Medicine Project; Associate Editor, National College of Natural Robert H. Lerman, MD, PhD ◆ Adjunct Associate Professor of Medicine, Boston Medicine; Adjunct Faculty, Bastyr University University School of Medicine DeAnn Liska, PhD ◆ Sr. Director Nutrition & Scientific Affairs, Biofortis Nutrition Nancy Sudak, MD, ABIHM ◆ Academy of Integrative Health & Medicine Research, a Merieux NutriSciences Company Chongyun Liu, OMD, LAc ◆ Bastyr University Kathie Madonna Swift, MS, RDN, LDN, FAND ◆ Saybrook University School of Mind Body Medicine; Dietitians in Integrative and Functional Medicine Rick Liva, ND, RPH ◆ Connecticut Center for Health; Vital Nutrients Melvyn R. Werbach, MD ◆ Tarzana, CA Michael R. Lyon, MD ◆ Diplomate of the American Board of Obesity Medicine; Adjunct Professor, University of British Columbia; Food, Nutrition and Health Research Director, Canadian Center for Functional Medicine; Medical Director, Medical Weight Management Centre

Jonathan V. Wright, MD ◆ Tahoma Clinic

Statement of Purpose Integrative Medicine: A Clinician’s Journal® provides clinicians with peer-reviewed, scientifically accurate, practical information about the integration of conventional and natural medicine. Integrative Medicine: A Clinician’s Journal is indexed in CINAHL. The views expressed in this journal are those of the authors and not necessarily those of the publisher or its advertisers. Integrative Medicine: A Clinician’s Journal® (ISSN 1546-993X) is published 6 times per year (in February, April, June, August, October, and December) by InnoVision Professional Media, Copyright ©2016. Cover image used under license from Shutterstock.com, 2016 All rights reserved. No part of this publication may be reproduced in any medium or photocopied without written permission from the publisher. Individual subscriptions to Integrative Medicine: A Clinician’s Journal must be prepaid in US dollars only and are available for $85 for one year. To order or for subscription address changes, write, fax, or call: Integrative Medicine: A Clinician’s Journal, PO Box 11292, St. Paul, MN 55111 • Toll Free: (877) 904-7951 • Phone: ( 651) 251-9684

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Integrative Medicine • Vol. 15, No. 3 • June 2016

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THE PATH AHEAD

Is Mold Toxicity Really a Problem for Our Patients? Part 2—Nonrespiratory Conditions Joseph Pizzorno, ND, Editor in Chief; Ann Shippy, MD

Abstract In my last editorial, I addressed the respiratory effects of mold exposure. The surprising research shows that as many as 50% of residential and work environments have water damage1 and that mold toxicity should be considered in all patients with any chronic respiratory condition. This is especially true in adult-onset asthma, two-thirds of which appears to be caused by toxins released from water-damaged buildings. The carcinogenic effects of food-borne mold contamination are also well documented. Less clear is the role of indoor mold exposure in water-damaged buildings and its relationship to nonrespiratory conditions. As we look at the research on mold toxicity and toxins in general, we propose that the medical community (by all its names) has focused too much on the “yellow canaries” and missed the big picture

National and International Organizations on Mold and Nonrespiratory Conditions According to the World Health Organization (WHO), “Although mycotoxins can induce a wide range of adverse health effects in both animals and human beings, the evidence that they play a role in health problems related to indoor air is extremely weak.”1 The US Centers for Disease Control and Prevention (CDC) issued a report in 2004 that asserts there is no conclusive evidence of nonrespiratory conditions being caused by mold or damp buildings. Review of the current recommendations according to its Web site shows no apparent change in its position.2 These statements appear highly conclusive but are in fact based on a very limited body of published research and are probably outdated. Research in this area has been limited, because it has not been possible to build cohorts of individuals exposed to mycotoxins and their controls and study them. This is due primarily to the serious limitations of the testing technology used to detect the presence of hidden indoor mold.

There are many different testing approaches all with unique limitations and all with many false negatives. In

8

Integrative Medicine • Vol. 15, No. 3 • June 2016

that toxins have now become a primary driver of disease in the general population, not only among those most susceptible. The mold toxicity conundrum illustrates this issue quite well. As summarized in this editorial, there clearly is a portion of the population, the size of which is currently unknown, who experience neurological and/or immunological damage from mold toxicity. In addition, a substantial portion of the population experiences chronic respiratory problems from mold exposure. This does not mean we should stop paying attention to our more affected patients. Rather, we need to realize that almost everyone is being affected by toxins to some degree: molds, metals, solvents, persistent organic pollutants, etc.

addition, human testing for mold toxin load via sampling tissue and body fluids is very limited. At the time of this publication, we can test for only 4 mycotoxin groups with 15 individual toxins. There are likely hundreds of mycotoxins, possibly even an order of magnitude more.

Another challenge with standard research is that statistical results in population groups inherently obfuscate individual susceptibility. This, of course, is where our medicine is so important for suffering patients who are outside those statistical norms. Clearly, we know that toxins affect individuals in different ways depending on their genetics, synergistic toxins present, and nutritional status. Studies that evaluate the most important variables of genetics, toxin exposure, and nutritional status and their complex effect on health need to be conducted.

Toxins Produced in Water-damaged Buildings The research is unequivocal that water-damaged buildings expose their occupants to a diverse range of toxins with many physiologically damaging effects. They are produced by chemical, microbial, and physical processes that break down building materials. Tables 1 and 2 list the

Pizzorno and Shippy—The Path Ahead

Table 1. Toxic Metabolites Produced by Bacteria Isolated From Water-damaged Materials and Indoor Air3 Metabolite

Organisms

Physiological Effects

Disease

Valinomycin

Streptomyces griseus

Mitochondrial poison

Unknown

Leptomycin B

Streptomyces species

Inhibition of inducible nitric oxide synthetase Unknown

Toxic peptide

Bacillus amyloliquefaciens

Depolarized transmembrane; decreased ATP and NADH cell death

Unknown

Mitochondrial toxin

Bacillus pumilus

Disruption of mitochondrial membrane

Unknown

Mitochondrial toxin

Nocardiopsis species

Disruption of mitochondrial membrane

Unknown

Cytostatic compounds

Coculture of Stachybotrys chartarum and Stachybotrys californicus

Cytotoxic compounds that are just as toxic as doxorubicin and AMD

Unknown

Abbreviations: ATP, adenosine triphosphate; NADH, nicotinamide adenine dinucleotide + hydrogen; AMD, actinomycin D.

Table 2. Mycotoxins Produced by Toxic Molds3 Metabolite

Organisms

Gliotoxin

Aspergillus fumigatus, Immune toxicity, immune terreus, flavus, niger; suppression, neurotoxicity Trichoderma virens; Penicillium spp; Candida albicans

Aflatoxin B1, kojic acid, aspergillic acid, nitropropionic acid

Aspergillus flavus

Liver pathology and cancer, immune Carcinogenesis toxicity, neurotoxicity

Fumigaclavines, fumitoxins, fumitremorgins, verruculogen, gliotoxin

Aspergillus fumigatus

Lung disease, neurotoxicity, tremors, Aspergillosis immune toxicity

Ochratoxin A

Physiological Effects

Disease

Immunosuppression

Urinary tract tumors

Aspergillus niger

Aspergillosis

Penicillium verrucosum

Lung disease

Ochratoxin A

Aspergillus ochraceus

Nephropathology

Invasive aspergillosis

BEN BEN

Urinary tract damage

Penicillic acid, xanthomegnin, viomellein, vioxanthin

Tumors

Sterigmatocystin, 5-methoxysterigmato cystin

Aspergillus versicolor

Chaetomiums

Chaetomium globosum Cytotoxicity

Unknown

Cell division

Unknown

Chaetoglobosum A and C Griseofulvin Dechlorogriseofulvins

Pizzorno and Shippy—The Path Ahead

Liver pathology and cancer

Memnoniella echinata Carcinogenesis?

Carcinogenesis

Unknown Reproductive toxin

Integrative Medicine • Vol. 15, No. 3 • June 2016

9

Table 2. (continued) Metabolite

Organisms

Physiological Effects

Disease

Trichodermin

Hypersensitivity?

Trichodermo

Protein synthesis inhibition

Mycophenolic acid

Penicillium brevicompactum

Cytotoxic, mutagen

Botryodiploidin

Penicillium expansum Immune toxicity, cytotoxic

Unknown Unknown

Patulin, citrinin, chaetoglobosin, roquefortine C Verrucosidins

Tremors

Penicillium plonicium

Cytotoxicity

Tremors

Penicillic acid, nephrotoxic glycopeptides Trichothecenes

Nephropathology Trichoderma species

Trichodermol, trichodermin, gliotoxin, viridin

Trichothecene toxicity

Unknown

Immunotoxicity

Immune impairment

Fumonisins

Fusarium verticillioides Neural tube defects in animals and (AKA Fusarium humans moniliforme)

CNS birth defects

Spirocyclic

Stachybotrys chartarum

Pulmonary bleeding

Respiratory bleeding

Drimanes, roridin

Protein synthesis inhibition

Satratoxins (F, G, H)

Neurotoxicity

Hydroxyroridin E

Cytotoxicity

Verrucarin J; trichodermin; dolabellanes; altrones B, C; stachybotrylactams

Immune toxicity

Abbreviations: BEN, Balkan endemic nephropathy; CNS, central nervous system. toxins released, organisms involved, physiological dysfunctions induced, and disease associations. Although we are focusing on molds in water-damaged buildings, Table 1 shows that bacterial growth also releases toxins.

As can be seen from the above, a wide diversity of physiological dysfunction can be caused by these toxins released in water-damaged buildings and many have associated diseases. In addition, food-borne mycotoxins have been shown to cause cancer, impaired child growth, neural tube defects, immunotoxicity, gastroenteritis, and renal disease.4 Add to this biochemical individuality, and most any chronic clinical condition could be caused by these toxins.

The challenge is that statistical, generic research makes documenting such effects in specific patients very difficult to prove.

Mycotoxins A tremendous amount of research has been published on the clinical effects mycotoxins: more than 40 000 hits in

10

Integrative Medicine • Vol. 15, No. 3 • June 2016

PubMed and still a huge 10 000 with limit humans. Although this is the area apparently of most interest in the integrative medicine community, outside respiratory effects of mycotoxins the research is disappointingly limited.

Andrew Campbell, MD, editor in chief of our sister publication Alternative Therapies in Health and Medicine, has written several excellent articles on mold toxicity. In a comprehensive review published in 2004, Campbell in collaboration with functional medicine laboratory expert Aristo Vojdani, PhD, and colleagues5 evaluated the research on the physiological effects of mold toxins. The research they reported included the symptoms of people living or working in water-damaged buildings. Particularly important is that they compared their symptoms with an “unexposed” control population. (I believe this is critical, as too often ignoring false positives overstates the significance of symptoms.) This is a conservative view, as the “controls” may have included individuals being exposed to hidden active mold, which is estimated to be as high as 50%. In Table 3, I reworked their data a bit to show

Pizzorno and Shippy—The Path Ahead

Table 3. Symptoms Caused by Mold Toxicity/Water-damaged Buildings5 Symptom

% in Exposed Population % in Controls

P Value

Memory problems

5.1

3.3

.0002

Spaciness

4.8

3.2

.0007

Excessive fatigue

5.8

4.3

.0001

Coughing

4.6

3.2

.001

Slurred speech

4.5

3.1

.002

Weak voice

4.1

2.8

.003

Watery eyes

4.6

3.4

.004

Lightheadedness

4.4

3.2

.006

Dizziness

4.3

3.1

.005

Weakness

4.2

3.0

.008

Headache

5.2

4.1

.005

Throat discomfort

4.5

3.4

.008

Sinus discomfort

4.7

3.6

.01

Coordination problems

4.0

2.9

.01

Nasal symptoms

5.1

4.1

.02

Bloating

4.2

3.2

.02

Visual changes

3.9

2.9

.02

Rash

3.9

2.9

.02

which symptoms have the best predictive value for suspicion of mold exposure. As can be seen, neurological symptoms are predominant.

Although damage from mold/damp buildings can affect all systems of the body, the two nonrespiratory systems with the strongest research are neurological and immunological. Authors comparing mycotoxins with pesticides have concluded that mycotoxins are more toxic than pesticides.6 In addition, fungal metabolites have synergistic genotoxic and other harmful effects.7

reported that fungal VOCs had a greater toxic effect than do formaldehyde, xylene, benzene, and toluene.10 mVOCs increase inflammation biomarkers such as myeloperoxidase, lysozyme, and eosinophil cationic protein, and they cause headache, nausea, and mucosal irritation.11 A recent study reported:

Microbial Volatile Organic Compounds In addition to mycotoxins, active mold produces microbial volatile organic compounds (mVOCs). This is currently a very active area of research. mVOCs are low molecular weight compounds that include numerous alcohols, esters, ethers, ketones, aldehydes, terpenoids, thiols, and their derivatives. Because these compounds are small and volatile, they can diffuse into the air and enter the body through the lungs and skin. Some researchers have suggested that mVOCs be thought of as mycotoxins and have proposed the term volatoxin.8 Research is showing that mVOCs are even more toxic than the chemicals traditionally thought of as being industrial toxins. For example, 1-Octen-3-ol has been shown to be more toxic to human embryonic stem cells than is toluene.9 Another study

The same study also stated that “these vast changes in membrane are known to contribute to the breakdown of normal cellular function and possibly lead to death.” mVOCs induce neurotoxicity in the Drosophila model even at very low concentrations inducing locomotor defects and changes in antigen-labeled dopaminergic neurons.13 Another Drosophila study showed that the mVOC 1-Octen-3-ol induces nitric oxide-mediated inflammatory response.14

Pizzorno and Shippy—The Path Ahead

The impact of fungal VOCs, 2-octenal and oct-1-en-3-ol on bone marrow stromal cells that are vital for the appropriate development and activation of the immune system showed increased membrane fluidity.12

Neurotoxicity Neurotoxicity is clearly associated with mycotoxins and other chemicals produced by mold. An interesting study looked at neurobehavioral and pulmonary impairment in 105 adults with indoor exposure to molds and 100 exposed to chemicals, comparing them with

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202 “unexposed” community referents.15 A big challenge, of course, is, as noted in past IMCJ editorials, we conclude finding a control group without toxin exposure is essentially impossible. Looking at several respiratory measures, they found 6.1% abnormalities in mold exposed and 7.1% in chemical exposed compared with 1.2% abnormalities in controls. This is consistent with the clearly demonstrable respiratory effects reported in the last editorial. Neurologically, they found statistically significant problems in both exposed groups: decreased balance, longer reaction times, increased blink reflex latency, increased color discrimination errors, decreased visual field, and reduced grip strength. They also found several measures of cognitive and memory performance measures abnormal, again in both exposed groups. We find interesting that they found little difference in virtually all measures between the mold and chemical exposed populations.

A study of 100 individuals exposed to mold in their home found multiple neurological deficits in 70% and abnormalities in T and B cells in more than 80% of the patients.16 A study of 95 employees working in a welldocumented water-damaged school building compared with 110 “unexposed” controls found statistically significant loss of visual contrast sensitivity (VCS), an apparently sensitive measure of neurodysfunction, as well as the usual respiratory problems.17 An important study suggests that individuals exposed to satratoxin (SH), a trichothecene, and microbial organisms results in a chronic immune response (inflammation and oxidative stress) leading to neural damage.18 Their results demonstrate that “regardless of whether the neurons were exposed to SH alone or under additive effects, the sensitivity of the neurons to these compounds is high and neurological system cell damage can occur from SH exposure.” In addition, these data demonstrate that constant activation of inflammatory and apoptotic pathways at low levels amplifies the devastation and leads to neurological cell damage from indirect events triggered by the presence of a trichothecene mycotoxin. And they concluded, “From this study and others, we show that neurological system cell damage from exposure to mycotoxins is a potential public health threat for occupants of water-damaged buildings.”

Immunotoxicity A number of animal studies have clearly shown moldinduced immunotoxicity. The research in humans is quite clear that chronic mold/damp building exposure increases production of multiple inflammatory measures and alters immune function mediators. These effects are not small, with the immune systems of those working in damp buildings reacting to exposure with 2- to 1000-fold increased production of a wide variety of these inflammatory/immune mediators.19

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While digging our way through the mold toxicity research, we came across a fascinating article that proposed multiple sclerosis is primarily a mold toxin disease.20 Their basic thesis is that gliotoxin, a heat-stable secondary metabolite produced by various species of Aspergillus and Candida, suppresses immune function, increases bloodbrain-barrier permeability, and is highly neurotoxic. As is well known, the incidence of multiple sclerosis (MS) increases with distance from the equator, which also correlates with mold exposure and decreased vitamin D—a critical nutrient for immune system modulation. Could MS be primarily due to the combination of mold exposure and vitamin D deficiency?

Another study of chronic fatigue syndrome (CFS) patients showed a high correlation in the presence of mycotoxins in the patient’s urine and having a diagnosis of CFS. Of the 102 CFS patients studied, 93% had 1 mycotoxin present. Almost 30% had 2 or more mycotoxins present.21 Further research is warranted to better understand this association.

Conclusion The research cited in this and the last editorial supports the conclusion that indoor mold metabolites have a harmful effect on human health. The nonrespiratory mold evidence, although limited, is quite compelling. We need further data/research. It is somewhat shocking that more research is not being done based on what is known about these environmental toxins and their potential effect, especially given the common occurrence of water damage in buildings.

As can be seen in Tables 1 and 2, the bacterial, mold, and building material breakdown products have definitively been documented in cell culture, animal models, and very limited human studies to cause diverse physiological dysfunctions. The challenge when applying this data to humans is obvious, ranging from differences between human and animal physiology, to dramatically varying dosages, sensitization, genetic polymorphisms, etc. Even so, the animal, Drosophila, and human cellular studies support similar conclusions to the very limited human findings thus far. Note that the Disease columns in Tables 1 and 2 are full of unknowns as the research simply has not been done or is inconclusive when considering population groups. And, as we all well know, real patients are very different from generic populations used for statistical analyses of significance. As can be seen in these tables, disrupting mitochondrial function, misbalancing nitric oxide synthesis, inflammatory mediators, neurotoxicity, cytotoxicity, immune suppression, carcinogenesis, and mutagenesis— the list is long and can show up in virtually any clinical manifestation in our patients depending on their specific exposure and unique biochemistry.

Because as many as 50% of buildings in North America show water damage, here are our recommendations for when to consider investigating the presence of mold toxins or hidden water damage in homes and/or workplaces:

Pizzorno and Shippy—The Path Ahead

1. Every patient with a chronic respiratory disease, especially asthma.

2. Every patient with a chronic disease, especially neurological or immunological, and chronic respiratory symptoms.

3. Any patient with a chronic disease, again especially neurological or immunological, who is not responding as expected and all other causes have been ruled out.

Let us be clear: We do not believe that every patient in one of the 3 categories above is affected by mold. We do believe that potential mold exposure should be considered. With the solid advances in technology for both medical and environmental testing during the last 10 years, we can now, as practitioners, actively begin to link medical symptoms with indoor mold exposure. For individual patients we can now use enzyme-linked immunosorbent assay (ELISA) testing to detect 15 mycotoxins both in the patient and in their environment and assess the relationship between the two. In addition, we can now detect and quantify the presence of 36 molds by qualitative polymerase chain reaction (QPCR) in human tissue and the environment.

Genetic testing can help us to identify those most susceptible to mold toxins and other environmental toxins.

Genetic single nucleotide polymorphisms (SNPs), proteomics, and other markers of cellular function of the immune, detoxification, mitochondrial, and methylation systems may help identify those most susceptible and those most affected, as well as potential treatment options.

In addition, assessing potential nutritional deficiencies and levels of other environmental toxins that may help identify those with increased individual susceptibility. As additional research is completed, it will be imperative to improve and expand these technologies. Given the complex nature of the interaction between the human genome and environmental toxins, this seems a likely problem to be solved, at least in part, with applying the science of bioinformatics. Such an approach will help us understand more fully the relationship (ie, severity and magnitude) of indoor mold exposure to human health.

In This Issue Thank you Ann Shippy, MD, for coauthoring the second part of this mold editorial with me. I was really struggling with the topic and she brought clarity. As a former IBM engineer, Dr Shippy left over a decade in engineering to adapt her skill-set to the world of medicine after recovering from an illness that allopathic medicine alone did not have solutions for. She attended the University of Texas Medical School and has a thriving functional medicine practice in Austin, Texas. She is board certified in internal medicine and functional medicine.

As part of our efforts to continually improve IMCJ, we are now also putting commentaries through our standard

Pizzorno and Shippy—The Path Ahead

peer-review process. I would to express my sincere appreciation to our contributing editors for being willing to subject themselves to this added rigor. As widely acknowledged and leading experts in their field, having others critique their work might be felt as disrespectful. I believe their receptivity is a powerful validation of their commitment to excellence and egoless advancement of this medicine that is so critical to restoring and improving health.

Associate Editor Jeffrey Bland, PhD, leads off this issue with an intriguing discussion of the intersection of personalization of health care, technology, and innovation.

I thought particularly compelling his quote from NEJM of how this will impact health care professionals and professions and the choices they can make. To paraphrase: ignore, regulate, or compete. We know the choices made by the conventional medicine political entities in the past.

Let’s not make the same mistakes.

Congratulations to John Weeks, the new editor in chief of Journal of Alternative and Complementary Medicine.

Good luck in your new endeavor my friend. In his review of the new federal strategies on opioid addiction, he chastises the Obama administration for total lack of consideration of nonpharmacological approaches and the non-MD healing arts experts. One of the first chapters written for the Textbook of Natural Medicine in 1985 was “Non-Pharmacological Control of Pain” by Richard Kitaeff, MA, ND, LAc. Come on people, the research has been there for more than 30 years and practiced for centuries!

Loren Israelsen and Frank Lampe take on the very challenging issue of the politics, regulatory environment, and marketplace dynamic that powerfully affect the quality of the natural health products we prescribe our patients. Long-time readers will remember that we have published more than 50 editorials and articles on the extremely important issue of product quality and safety. We practitioners must take a lead in recognizing and supporting the companies investing the resources to create truly great product and warn our patients about the unscrupulous who don’t.

Christopher Hobbs, PhD, LAc, through his interview by Managing Editor Craig Gustafson provides us useful guidance in the use of mushrooms for wellness and health promotion. He is a keynote lecture at the 14th Annual International Conference of the Association for the Advancement of Restorative Medicine. I will also be lecturing at this conference on how toxicity has become one of the primary causes of chronic disease.

Original research on postmarketing safety of Rheum rhaponticum is provided by Jyh-Lurn Chang, PhD; Michael B. Montalto, PhD; Peter W. Heger; Eva Thiemann; Reinhard Rettenberger, PhD; and Jürgen Wacker, MD, PhD. Assessing the efficacy AND safety of natural medicines is critical for the advancement of our medicine.

Ferdi Yavuz, MD; Bayram Kelle, MD; and Birol Balaban, MD, from Turkey provide us an informative case report of the use of neural therapy in patients with Bell’s

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palsy. I thought especially interesting the efficacy on a nonpharmacological approach after conventional treatments had failed. Great to see growing international interest in IMCJ. Mikhail Kogan, MD; Carlos Cuellar Castillo, MS; and Melissa S. Barber, MS, provide us a case report on a woman with comorbidities of chronic rhinosinusitis and irritable bowel syndrome. An excellent example of how the symptom-treatment model fails so many patients who then experience real cure by treating the actual causes of their illness. Great that innovative laboratories are providing us an ever growing range of tests to help us understand our unique patients.

When I first heard Datis Kharrazian, DHSc, DC, MS, MNeuroSci, CNS, lecture, my immediate thought was, “This fells like a Jeff Bland firehose lecture!” Such a treat. Another great interview by Craig. Full disclosure, I think his work so important I have accepted Datis’s invitation to join the board of his International Association of Functional Neurology and Rehabilitation. If you’ve not heard him lecture, you are in for quite a treat that will change how you think about patients with neurological disease.

Finally, Bill Benda, MD in BackTalk makes a very, very valid point: While easy to critique conventional medicine for being the third leading cause of death in the United States, this is totally unfair as dramatically more deaths were prevented by conventional medicine. The problem is not the conventional medicine model—where appropriately applied. The problem is use of symptom suppression instead of curative understanding of why patients are sick and how to restore health. Such a monolithic system is only possible when other perspectives have been actively suppressed. See my comment about Jeff ’s commentary above.

An optimal health care system collaboratively combines public health, life-saving conventional medicine, and the curative health restoration we advocate.

References 1. World Health Organizataion. WHO guidelines for indoor air quality: D a m p n e s s a n d m o u l d . h t t p : / / w w w. w h o . i n t / i n d o o r a i r / publications/7989289041683/en/. Published 2009. Accessed June 7, 2016.

2. US Centers for Disease Control and Prevention. Basic facts: Molds in the environment. http://www.cdc.gov/mold/faqs.htm#affect. Updated May 22, 2014. Accessed February 15, 2016.

3. Thrasher JD, Crawley S. The biocontaminants and complexity of damp indoor spaces: More than what meets the eyes. Toxicol Ind Health. 2009;25(910):583-615.

4. Wu F, Groopman JD, Pestka JJ. Public health impacts of foodborne mycotoxins. Annu Rev Food Sci Technol. 2014;5:351-372 5. Campbell AW, Thrasher JD, Gray MR, Vojdani A. Mold and mycotoxins: Effects on the neurological and immune systems in humans. Adv Appl Microbiol. 2004;55:375-406.

6. Paterson RR, Lima N. Toxicology of mycotoxins. EXS. 2010;100:31-63.

7. Juil K, Seong-Hwan P, Hun Do K, Kim D, Moon Y. Interference with mutagenic aflatoxin B1-induced checkpoints through antagonistic action of ochratoxin A in intestinal cancer cells: A molecular explanation on potential risk of crosstalk between carcinogens. Oncotarget. April 2016. doi:10.18632/ oncotarget.8914. [Epub ahead of print] 8. Bennett JW, Inamdar AA. Are some fungal volatile organic compounds (VOCs) mycotoxins? Toxins (Basel). 2015;7(9):3785-3804.

9. Inamdar AA, Moore JC, Cohen RI, Bennett JW. A model to evaluate the cytotoxicity of the fungal volatile organic compound 1-octen-3-ol in human embryonic stem cells. Mycopathologia. 2012;173(1):13-20.

10. Inamdar AA, Zaman T, Morath SU, Pu DC, Bennett JW. Drosophila melanogaster as a model to characterize fungal volatile organic compounds.

Environ Toxicol. 2014;29(7):829-836.

11. Robert Wålindera, Lena Ernstgårdb, Dan Norbäcka, et al. Acute effects of 1-octen-3-ol, a microbial volatile organic compound (MVOC)—An experimental study. Toxicol Lett. 2008;181(3):141-147.

12. Hokeness K, Kratch J, Nadolny C, et al. The effects of fungal volatile organic compounds on bone marrow stromal cells. Can J Microbiol. 2014;60(1):1-4.

13. Inamdar AA, Masurekar P, Bennett JW. Neurotoxicity of fungal volatile organic compounds in Drosophila melanogaster. Toxicol Sci. 2010;117(2):418-426.

14. Inamdar AA, Bennett JW. A common fungal volatile organic compound induces a nitric oxide mediated inflammatory response in Drosophila melanogaster. Sci Rep. February 2014;4:3833.

15. Kilburn KH. Neurobehavioral and pulmonary impairment in 105 adults with indoor exposure to molds compared to 100 exposed to chemicals. Toxicol Ind Health. 2009;25(9-10):681-692.

16. Rea WJ, Didriksen N, Simon TR, et al. Effects of toxic exposure to molds and mycotoxins in building-related illnesses. Arch Environ Health.

2003;58(7):399-405.

17. Thomas G, Burton NC, Mueller C, et al. Comparison of work-related symptoms and visual contrast sensitivity between employees at a severely water-damaged school and a school without significant water damage. Am J Ind Med. 2012;55(9):844-854.

18. Karunasena E, Larrañaga MD, Simoni JS, Douglas DR, Straus DC. Buildingassociated neurological damage modeled in human cells: A mechanism of neurotoxic effects by exposure to mycotoxins in the indoor environment.

Mycopathologia. 2010;170(6):377-390.

19. Rosenblum Lichtenstein JH, Hsu YH, Gavin IM, et al. Environmental mold and mycotoxin exposures elicit specific cytokine and chemokine responses.

PLoS One. 2015;10(5):e0126926.

20. Purzycki CB, Shain DH. Fungal toxins and multiple sclerosis: A compelling connection. Brain Res Bull. 2010;82(1-2):4-6.

21. Brewer JH, Thrasher JD, Straus DC, et al. Detection of mycotoxins in patients with chronic fatigue syndrome. Toxins (Basel). 2013;5(4):605-617.

Joseph Pizzorno, ND, Editor in Chief drpizzorno@innovisionhm.com http://twitter.com/drpizzorno

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Pizzorno and Shippy—The Path Ahead

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CREATING SYNTHESIS

Where Is Health Care Headed?

Jeffrey Bland, PhD, FACN, FACB, Associate Editor

Abstract Looking at the trends, developments, and discoveries points us toward the future, but it is only when we consider these in the context of our understanding about the origins of disease that we can truly gain a clearer view of where health care is headed. This is the view that moves us from a focus on the diagnosis and treatment of a disease to an understanding of the origin

Jeffrey Bland, PhD, FACN, FACB, is the president and founder of the Personalized Lifestyle Medicine Institute in Seattle, Washington. He has been an internationally recognized leader in nutrition medicine for more than 25 years.

Dr Bland is the cofounder of the Institute for Functional Medicine (IFM) and is chairman emeritus of IFM’s Board of Directors. He is the author of the 2014 book The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life.

O

n December 7, 2015, former President Jimmy Carter announced via a press release that his brain cancer, for which he had been given a “grim prognosis” just months before, had disappeared. This positive and remarkable turn of events resulted from Carter receiving a new cancer immunotherapy drug—one that unleashed his immune system to successfully attack and win the battle with his metastatic melanoma. Carter’s treatment involved the application of the recently approved immune-oncology drug pembrolizumab (Keytruda, Merck Oncology, Kenilworth, NJ, USA), a programmed cell death 1 (PD-1) immune checkpoint inhibitor.1 The PD-1 receptor is an inhibitory T-cell receptor. Its function is to act as a braking mechanism on the cellmediated immune system. As such, the excessive expression and inhibitory activity of the PD-1 receptor in cancer can result in the cancer cell defending itself against an individual’s own immune system. Pembrolizumab, as a PD-1 inhibitor, blocks the activity of the PD-1 receptor, which allows the immune system to recognize and attack the tumor cell. In a recent editorial in the New England Journal of Medicine, Antoni Ribas, a principal investigator in clinical studies using PD-1 inhibitors in cancer therapy, describes the future progression of investigation this way: “The next frontier in the treatment of cancer requires meeting the goal of inducing a high frequency of longlasting tumor response on the basis of selectable markers

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of the alteration in function in the individual. This change in both perspective and understanding of the origin of disease is what will lead us to a systems approach to health care that delivers personalized and precision care that is based on the inherent rehabilitative power that resides within the genome.

in order to personalize therapies.”2 Inhibition of PD-1 meets this objective for a number of cancers and paves the way for the development of new immunotherapies.

The development of personalized therapies marks the start of a new era in innovation in health care delivery and medicine that focuses on the activation of an individual’s own native recuperative abilities locked into their genes.

These messages are deep within all genetic structures, but they may be silenced due to epigenetic or environmental factors that prevent their expression. In January 2016, the Journal of the American Medical Association (JAMA) announced the launch of a year-long series of articles that will focus on innovations in health care delivery. The JAMA editorial team—Drs Bauchner, Berwick, and Fontanarosa— state that major innovations are needed in self-care, teamwork within the health care system, patient safety, and learning systems.3 With the emergence of precision medicine concepts born out of the genomic revolution, future innovations must also occur in the development of drugs, devices, delivery of services, doctor-patient communication, and education.

Underscoring the tremendous interest in this topic, perspectives on innovation and future directions are now routinely published in many of the top medical journals. In the March 3, 2016, issue of the New England Journal of Medicine, 2 authors—Detsky and Garber—make the case that seemingly unrelated fields—such as health care and the transportation industry—can, in fact, share common ground when considering the influence of disruptive technology. The authors offer Uber, an innovative car service that has found success both with customers and independent operators all over the world, as an example that health care should take note of. Why? Because factors such as unreliable service, inconvenience, uncomfortable surroundings, and high prices all aggregated with the development of the smart phone and digital applications to give rise to Uber as an alternative to the traditional taxi cab business. Many of these issues also represent concerns and criticisms that have been expressed

Bland—Creating Synthesis

about our current health care system. The parallels exist, and authors do not mince words: Uber’s message for health care is clear. Providers have three choices: ignore innovators and hope for the best; call for increasing regulation to make it harder for innovators to enter the market; or compete on quality and efficiency, disruptive though that might be.4

Companies that deal in data—and the consumers who provide the data to be analyzed—are very relevant to transitions that are taking place in health care. One of the disruptive concepts that is expected to drive the future of health care is an increasing interest in patient-driven health information and the transportable electronic health record (EHR) owned and managed by the individual. This was nicely described in another 2016 New England Journal of Medicine article, this one authored by Drs Mandl and Kohane, who remind us we saw the beginning of this trend as early as 2006 when Google and Microsoft independently launched Google Health and Microsoft HealthVault. The concept has continued to evolve with technology, and in 2015 Apple released HealthKit, which allows users to interface with their smart devices and create an electronic health data repository.5 How will disruption affect interventions—specifically prescription drugs and surgeries—that are integral to the health care model both today and in the future? In a 2015 New England Journal of Medicine article, researchers Peter J. Neumann and Joshua T. Cohen describe the development of frameworks for assessing the value of drugs and other interventions. Leading institutions and professional societies, including the American College of Cardiology, the American Society of Clinical Oncology, the Institute for Clinical and Economic Review, the Memorial Sloan Kettering Cancer Center, and the National Comprehensive Cancer Network, are already working on this challenge of creating assessment frameworks. This article is accompanied by a useful table showing some of the factors being used to examine various interventions—things such as quality of clinical data, magnitude of treatment effects, likelihood of severe adverse events, and cost effectiveness.6 This concept will result in a new approach to evaluating the cost-benefit of various therapies and move toward a “pay for performance” model. As these metrics emerge in the next few years, the value of early intervention and personalized lifestyle medicine programs will become more highly valued for their cost effectiveness.

The care model is changing, and at the same time we are also witnessing the dawn of the age of precision predictive analytics that will provide for a greatly expanded understanding of an individual’s functional health status.

Unlike approaches that used retrospective data to identify high-risk individuals (such as the Framingham risk model), predictive analytics are intended to determine real-time risk of a clinical event. Innovations in this field, which include biometrics, information from wearable devices, noninvasive functional physiological assessment

Bland—Creating Synthesis

tools, and cloud-based bioinformatic systems, are expected to be applied across the health care spectrum—in acute care, postdischarge care, chronic disease management, and scientific wellness promotion programs.7 Can our current health care system handle all of the changes that are coming? The present system is focused on pathology, and so it is very possible that it cannot adequately incorporate innovations that are meant to address one of our major health care challenges: complex chronic disease. The solution to these diseases may reside in a new system of thinking—one that emerges out of the increasing understanding of the immune system and how to unleash its native therapeutic and restorative capabilities, as we have seen pioneered in the field of immune oncology.

In 2015, innovative research into PD-1 immunotherapy was widely acknowledged with prestigious awards. The 2015 Lasker-DeBakey Clinical Research Award was given to Dr James Allison for his work on immune checkpoint blockade in cancer therapy.8 The 2015 Albert Lasker Basic Medical Research Award was presented to Dr Stephen Elledge and Dr Evelyn Witkin for discovery of the DNA damage response and its relationship to health and disease.9 These discoveries—and the work that continues from this research—demonstrate the importance of developing a better understanding of the functional capabilities of the individual from a systems perspective. They help us understand that the cellular microenvironment of the individual with a specific disease is very important. The cellular microenvironment depends on both inherent genetic expression patterns and expression patterns induced by the interaction of the individual with their lifestyle and environment. These modifiable factors are now recognized to have a considerable influence on the host immune system function and the resistance to DNA damage that is associated with the etiology of most age-related chronic diseases.10,11,12 As we see amazing new discoveries in the basic biological and clinical science emerge, so too is significant investment capital being applied to the development of personalized precision health care. Dr Lee Hood is the cofounder of the prestigious Institute for Systems Biology in Seattle and is also cofounder of Arivale, a company focused on the development of the delivery of personalized scientific wellness. On March 13, 2016, Dr Hood announced an affiliation with Providence Health and Services that will bring personalized medicine to one of the largest health systems in the United States. This partnership represents an example of how innovation is transforming health care from a reactive to a proactive mode.

Dr Hood was quoted as saying: [The Providence Team] is leading the way in driving the paradigm shift that is taking place in health care today. …

This, combined with Providence’s vast network of hospitals, outstanding clinicians, and the rich collection of data from the more than 3.3 million patients they serve across five states will help to accelerate discovery of powerful insights into scientific wellness.13

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Human Longevity, Inc, which is headed by Human Genome Project pioneer Dr Craig Venter, has recently raised $220 million in investment capital for their company’s development of precision medicine activities. These activities will include a clinical health center called Health Nucleus, which will aim to provide a complete practical picture of a person’s functional health status.14 Also recently announced is the expansion of the Center for Functional Medicine at the Cleveland Clinic. The Center for Functional Medicine opened in late 2014 under the leadership of Dr Mark Hyman and Dr Patrick Hanaway and has grown much faster than anticipated; the center now has a waiting list of more than 1100 individuals.15 The success of these companies and partnerships indicates that we are witnessing the emergence of innovative disruptive technologies that will help transform the future of health care to be more patient activated, personalized, and precise in its delivery.

Trying to forecast where health care is going is a daunting task. Predicting the future, of course, comes with inherent uncertainty. However, there are many early signs of the form and function of the future of health care if you know where to look. I believe the examples to watch and trends to follow are immune oncology; personalization through the use of smart devices; cloud-based health data collection and analysis; the recognition of the influence that lifestyle, diet, and the environment have on genetic and epigenetic regulation of health and disease; and the understanding that within our genes reside the information necessary to provide for an improved disease-free health span if it can be “unleashed.”

Consider this final example. Hypertension is a major global health issue that is associated with the etiology of many chronic diseases. Approximately 80 million US adults have hypertension and it remains a leading risk factor for stroke and cardiovascular disease. In 2009–2010, 48% of treated hypertensive patients in the United States were taking more than 1 drug, and blood pressure remained uncontrolled in 40% of those receiving drug treatment. In 2011, the National Research Council introduced an innovative approach to this problem using precision personalized medicine, and this effort was highlighted in a recent article published in the JAMA titled “Ushering Hypertension Into a New Era of Precision Medicine.” As this article states, hypertension is not a homogeneous disorder. In functional medicine, we would say this: Hypertension occurs as a result of many different functional alterations in epigenetic expression patterns.

An integrated approach to better understanding the cause of hypertension in an individual is focused on epigenetic profiling that will identify epigenetic mechanisms that are sustained across generations, RNA profiling to evaluate the influence of epigenetic changes on gene expression, and the integration of whole DNA sequencing variation, epigenetic changes, and gene expression into understanding the actionable areas for personalization of precision therapies that will combine lifestyle, diet, environmental,

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and pharmacological components. Circling back to the JAMA article, there is alignment with the functional medicine perspective: Precision medicine that incorporates epigenetic analysis is a potentially powerful approach for evaluating the influence of environmental and lifestyle modifications on the heritability of hypertension and for personalizing patient care. … Clinical translation will require convergence, coordination, and integration among multidisciplinary teams with expertise in laboratory, clinical and population-based research, as well as computational and modeling methods.16

Looking at these trends, developments, and discoveries points us toward the future, but it is only when we consider these in the context of our understanding about the origins of disease that we can truly gain a clearer view of where health care is headed. This is the view that moves us from a focus on the diagnosis and treatment of a disease to an understanding of the origin of the alteration in function in the individual. This change in both perspective and understanding of the origin of disease is what will lead us to a systems approach to health care that delivers personalized and precision care that is based on the inherent rehabilitative power that resides within the genome.

References 1. Brodsky AN. Former President Jimmy Carter declared cancer-free, thanks to immunotherapy. Cancer Research Institute Web site. http://www. cancerresearch.org/news-publications/our-blog/december-2015/formerpresident-jimmy-carter-declared-cancer-free-thanks-to-immunotherapy.

Published December 7, 2015. Accessed May 27, 2016.

2. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366(26):2517-2519.

3. Bauchner H, Berwick D, Fontanarosa PB. Innovations in health care delivery and the future of medicine. JAMA. 2016;315(1):30-31.

4. Detsky AS, Garber AM. Uber’s message for health care. N Engl J Med. 2016;374(9):806-809.

5. Mandl KD, Kohane IS. Time for a patient-driven health information economy? N Engl J Med. 2016;374(3):205-208.

6. Neumann PJ, Cohen JT. Measuring the value of prescription drugs. N Engl J Med. 2015;373(27):2595-2597.

7. Parikh RB, Kakad M, Bates DW. Integrating predictive analytics into highvalue care: The dawn of precision delivery. JAMA. 2016;315(7):651-652.

8. Allison JP. Immune checkpoint blockade in cancer therapy. The 2015 LaskerDeBakey Clinical Medical Research Award. JAMA. 2015;314(11):1113-1114.

9. Elledge SJ. The DNA damage response—self-awareness for DNA: The 2015 Albert Lasker Basic Medical Research Award. JAMA. 2015;314(11):1111-1112.

10. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: From mechanisms to therapy. Nat Med. 2015;21(12):1424-1435.

11. Van Deursen JM. The role of senescent cells in ageing. Nature.

2014;509(7501):439-446.

12. Li CJ, Elsasser TH, Li RW. Epigenetic regulation of genomes: Nutrientspecific modulation of genetic networks in bovine cells. Dev Biol (Basel).

2008;132:391-398.

13. Institute for Systems Biology. Providence Health & Services and Institute for Systems Biology affiliate to catalyze scientific wellness. Institute for Systems Biology Web site. https://www.systemsbiology.org/news/2016/03/14/providencehealth-services-and-institute-for-systems-biology-affiliate-to-catalyze-scientificwellness/. Published March 14, 2016. Accessed May 27, 2016.

14. Fikes BJ. La Jolla’s human longevity raises more than $220 million. The San Diego Union Tribune. http://www.sandiegouniontribune.com/news/2016/apr/04/ human-longevity-220-million. Published April 4, 2016. Accessed May 27, 2016.

15. Goldman E. Facing huge demand, Cleveland Clinic doubles its functional medicine center. Holistic Primary Care Web site. https://holisticprimarycare. net/topics/topics-a-g/functional-medicine/1772-facing-huge-demandcleveland-clinic-doubles-its-functional-medicine-center.html. Published February 18, 2016. Accessed May 27, 2016.

16. Kotchen TA, Cowley AW Jr, Liang M. Ushering hypertension into a new era of precision medicine. JAMA. 2016;315(4):343-344.

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COMMENTARY

Three Myths About Dietary Supplements … and How Knowing the Right Answers Is Good for Your Integrative Medicine Practice Loren Israelsen; Frank Lampe

Abstract The use of safe and beneficial dietary supplements remains an important part of your patients’ healthy lifestyle—and supplements are likely an important part of your integrative medicine practice. Although issues surrounding potency, ingredient identification, adulteration, and the enforcement of existing laws are legitimate concerns for medical professionals and consumers, the responsible industry is actively working to raise quality standards for its products through a number of self-regulatory measures. These include education about and adoption of additional quality assurance initiatives, such as GMPs for botanical ingredients; better supply-chain management; adoption

Loren Israelsen is president, and Frank Lampe is vice president, of Communications & Industry Relations for the United Natural Products Alliance (UNPA), an international trade association representing many leading natural products, dietary supplement, functional food, scientific and technology, and related service companies that share a commitment to provide consumers with natural health products of superior quality, benefit, and reliability. For more information, visit http://www.unpa.com.

D

ietary supplements have been in the news a lot for the last couple of years, and for the most part, the news has not been positive. Accusations of fraudulent and unsafe products and repeated cries that the industry is unregulated, promulgated by a number of mostly reputable media and scientific sources, permeate the headlines.

Yet the industry, valued at $37 billion in 2015,1 enjoys solid, sustainable growth as more and more consumers continue to take charge of their own health and well-being, aided by an expanding body of research showing the benefits of a healthy diet, exercise, and proper dietary intake.

Questions, based on the perception that the US Food and Drug Administration (FDA), the agency responsible for the regulation of dietary supplements, isn’t doing its job, abound in these negative reports. In response, a number of states’ attorneys general have chosen to pursue enforcement actions of their own

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of improved identification and testing methodologies; an industry-wide product registry; the use of accredited third-party certifications and seals; and initiatives to promote widespread membership in the industry’s trade associations, which is a reliable indicator of a company’s support of and adherence to strict quality guidelines. Also, industry support of appropriate enforcement actions against problem players and products from the US Food and Drug Administration (FDA), the Federal Trade Commission (FTC), and states’ attorneys general continues in an effort to rid the market of unsafe and mislabeled products.

against the industry. In February of 2015, the New York attorney general, Eric Schneiderman, opened a scientifically incompetent investigation against 8 botanical products sold at 4 leading retailers,2 claiming that the products, most of which were extracts of botanicals, didn’t contain what was on the label and were adulterated with a number of other substances, including substances known to cause allergic reactions.

Schneiderman’s methodology of choice was DNA barcode testing, part of a suite of emerging DNA technologies that is revolutionizing all areas of species identification, including anthropology, genealogy, forensics, medicine, and law enforcement. It is not inconceivable to imagine that in the not-too-distant future, all plant and animal life on Earth will be sampled and catalogued, creating an unparalleled database representing the essence of matter. But as with many emerging technologies, the viability of its application, in this case for botanical extracts and finished dietary supplement products, is a work in progress. Schneiderman’s use of DNA barcode testing on botanical extracts exposed its limitations as well as problems with its quantitative— and not qualitative—results.

At issue for the use of DNA testing for botanical extracts are a lack of validated reference standards; problems with low quality or fractured DNA (an expected result from the extraction process); the inability to identify plant parts; and potential cross-contamination in the laboratory. In

Israelsen—Dietary Supplement Myths

March of 2015, four of the industry’s trade associations commissioned a widely distributed white paper3 that discussed “the capabilities and limitations of DNA barcoding for botanical dietary supplement authentication to inform assessments of the applicability and accuracy of DNA test results,” provided guidance on how to perform DNA barcoding properly, and offered a critique of the methodology used by the New York attorney general.

Sadly, the flaws inherent in Attorney General Schneiderman’s methodology didn’t seem to concern him, his staff, or a number of mainstream media outlets, specifically the New York Times,4 which led a credibility assault on the dietary supplement industry. But once the 24-hour news cycle had ended, few of these media chose to question the testing methodology or the inaccurate findings of Schneiderman’s “investigation.” The attorney general’s investigation was discredited in articles in Forbes5 and the New Yorker.6 More than a year later, however, there has been no closure for 3 of the 4 retailers implicated and the products implicated remain off the shelves of those stores as the case remains “under investigation.”

In light of all of the negative press—much of it unwarranted and inaccurate—American consumers and many patients of integrative medical professionals may be questioning the integrity and safety of the supplement brands they see on store shelves—and on the shelves of medical dispensaries. In response, we present the following 3 myths about dietary supplements and the facts behind those myths, which, we hope, will lead to measured and thoughtful discussions about a highly complex and important topic.

Myth 1: Dietary Supplements Are Unregulated Contrary to what consumers are likely to read in mainstream media, dietary supplements are subject to a host of regulations as promulgated by the FDA under the Code of Federal Regulations, Title 21, of the Food, Drug and Cosmetic Act7 and as amended by the passage of the Dietary Supplement Health and Education Act8 (DSHEA) in 1994, which created a new regulatory framework for the safety and labeling of dietary supplements as a category of foods—and not drugs— that are “intended to supplement the diet.”

The DSHEA was passed by unanimous consent of US Congress, and for the first time it created a legal definition for dietary supplements as a separate class of products and created the structure that determined how the FDA regulates the industry.

This regulatory structure includes: 1. The labeling of dietary supplements.

2. Good manufacturing practices (GMPs).

3. Premarket notification for new dietary ingredients.

4. Control of/approval over structure/function claims.

5. Manufacturing facility and equipment inspection, including specific record-keeping requirements.

6. Enforcement of all of the above, including the issuance of warning letters and injunctions, to

Israelsen—Dietary Supplement Myths

remove from the market illegal products and to sanction dietary supplements companies and facilities that are out of compliance with the law.

7. Creation of the Office of Dietary Supplements within the National Institutes of Health.

Upon signing the DSHEA into law, President Bill Clinton said: After several years of intense efforts, manufacturers, experts in nutrition, and legislators, acting in a conscientious alliance with consumers at the grassroots level, have moved successfully to bring common sense to the treatment of dietary supplements under regulation and law.

When observers look at a supposed lack of supplement regulation, it’s instructive to note that it took legislation from Congress, at the urging of the dietary supplement industry, to force the FDA to create GMP regulations, more than 10 years after the DSHEA was passed into law.

And contrary to most media perceptions, the supplement industry has repeatedly worked to support regulations, as seen by its support for the passage of the Dietary Supplement and Nonprescription Drug Consumer Protection Act9 in 2006 that created the serious adverse event reporting system now in use.

In addition, dietary ingredients are further regulated under the Food Safety Modernization Act (FSMA),10 which was signed into law by President Barack Obama in January 2011.

A point of criticism about the DSHEA is that it distinguishes between “old” and “new” dietary ingredients.

As with many other categories of products, including foods and medical devices, when a new law is passed, consideration has to be made for existing products on the market—also called “grandfathering.” In many cases, a presumption of safety is made based on long history of use and no evidence of adverse events—and this was the case for dietary ingredients sold in the marketplace prior to October 1994.

Under the DSHEA, new ingredients are treated differently and do require a premarket safety notification to the FDA. This process is referred to as a New Dietary Ingredient Notification. In this way, both existing market realities and recognition that new dietary ingredients should be treated differently were addressed in the law. The FDA has the power to remove products from the marketplace when it finds them to be unsafe and has done so when needed.

In addition, the ingredients contained in most supplements are not patentable, which greatly reduces the economic incentives needed to conduct the premarket testing that all patentable drugs, with their promise of tremendous profits, are required to undergo. Yet this testing has not stemmed the number of deaths each year from prescription drugs, including those from prescription drug overdoses, estimated at 28 000 in 2014 alone, according to a Centers for Disease Control and Prevention study.11 Of course, no new law is perfect, and the DSHEA is no exception. Since its passage 22 years ago, it has held up

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remarkably well, with no amendments, yet viable areas of concern have emerged. These issues are currently being addressed by industry, although it’s also accurate to say that the actions by New York Attorney General Schneiderman have been a motivator for some of these changes.

Issues of note are as follows: 1. Manufacturer and product registry: Currently, under provisions of the Bioterrorism Act of 2002 and the FSMA, all food companies—including dietary supplement manufacturers and ingredient suppliers— must register with the FDA. Thus, the FDA has the largest and most complete database of companies doing business in this marketplace. But the agency does not share this information, making it difficult for consumers and the media to research companies and products. A supplement label database that is available to consumers, compiled by the National Institutes of Health,12 has partially resolved this issue, but it is voluntary and incomplete. As this article went to press, 4 of the industry trade associations are collaboratively working to either join an existing database or create a new one that would likely require participation as a condition of membership.

2. Third-party certification of GMPs: Although the FDA regularly inspects manufacturing facilities for GMPs, among other requirements, its resources to inspect the majority of facilities in the United States and worldwide is limited. Wide adaption of credible third-party certification, as offered by NSF International, USP, UL, and others, will lead to better quality supplements as well as greater confidence in the products by medical practitioners and consumers.

3. Unlike its provisions for dietary supplements, the DSHEA did not provide for GMPs for botanicals.

The FDA could have created subset GMPs but did not, leaving industry botanical ingredients suppliers on their own to create suitable manufacturing practices. In addition, when the FDA finally published Section 111, the GMPs for dietary supplements, it chose to exclude dietary ingredients, because of the objections of the industry. The consequence of these decisions was that the industry faced disconnection between GMPs for finished dietary supplement products and ingredients, creating a “hole” in the regulation of the botanicals and supplement supply chain. However, both of these issues have largely been resolved through the passage of the FSMA, which addresses and mandates stringent “farm-to-shelf ” supply chain controls, documentation, and management for both food and supplement ingredients, including botanicals. An effort begun in 2015 by the industry to create botanical “GMPs,” with a focus on agricultural and harvesting best practices, is ongoing.

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Regarding enforcement of the industry, when critics argue that the law does not provide enough oversight of the industry, even the FDA has stated that it has adequate regulatory authority in place for it to properly regulate the dietary supplement industry.13 The FDA’s biggest impediment to more robust enforcement measures has been a lack of resources—and Congress has repeatedly chosen to not increase budgets for the FDA to enforce the DSHEA. But it’s important to note that responsible supplement companies support and encourage robust enforcement measures by the FDA, the Federal Trade Commission (FTC), and the Department of Justice against noncompliant products, including those companies targeted at a joint Department of Justice press conference14 in November 2015.

The elevation of the FDA’s Division of Dietary Supplements to an Office15 in December 2015, which industry publicly supported, is indicative that the agency will seek additional resources and is engaged and intent on actively regulating the industry.

Myth 2: Dietary Supplements Are Not Safe More than 68% of US adults consume dietary supplements16 to support their health and well-being.

With extremely few adverse events as reported by both government and industry data, supplements are actually one of the safer product categories on the market.

Notwithstanding, reputable scientific journals have repeated the myth that supplements are broadly unsafe, ostensibly because of a lack of the premarket approval that is required for drugs. As stated earlier, supplements largely derived from foods or that include food use should not be required to adhere to the same strict standards as a drug or pharmaceutical with clear physiological effect that is often a synthetically created chemical and that has no clear history of safe use in the marketplace.

As an example of this bias within the scientific community, a peer-reviewed study in the New England Journal of Medicine17 in October 2015, which received plenty of media attention, estimated that 23 000 emergency room (ER) visits, characterized by the study authors as “adverse events” between 2004 and 2013, were the result of issues with dietary supplements. But the article failed to mention that the study included an unknown number of over-the-counter drugs, topical creams, and other confounding factors.

Speaking at an educational briefing held in December 2015 that was sponsored by the bipartisan Congressional Dietary Supplement Caucus18 in Washington, DC, Rick Kingston, PharmD, a clinical professor at the University of Minnesota, College of Pharmacy, and an adjunct professor at the National Center for Natural Product Research at the University of Mississippi, noted that the study had many additional shortfalls, including the fact that “not all emergency room visits are created equal in terms of level of severity or seriousness.” Kingston observed that “in

Israelsen—Dietary Supplement Myths

almost 90 percent of the heart-related ER visits, the patients were discharged from the ER and sent home.”

Kingston pointed out that more than 20% of ER visits cited in the article involved “unsupervised ingestion by children, and although a concern, supplement ingestions by children often require no treatment and result in no adverse effects despite the child being evaluated in an emergency department.” He further noted that among older adults, pill-induced swallowing problems led to more than one-third of the ER visits, which is something that the industry can help evaluate and address. Another 10% of the overall visits were from excessive doses.

When looking at total emergency room visits per year, dietary supplements, even at the inflated estimate of 23 000 within a 10-year period, represent 0.017% of all visits. By comparison, pharmaceutical drugs—as prescribed by medical doctors—resulted in 731 000 ER visits per year.

Despite a proven safety record and widespread use by consumers, the responsible industry is burdened by repeated claims that a number of the products do not contain the amounts of ingredients listed on the labels (or contain too much of the ingredient) or are adulterated with lesser quality and less expensive ingredients—or worse, that they are adulterated with undeclared active pharmaceutical ingredients (see Myth 3, later in this article). Reports from independent testing firms, such as consumerlab.com, have shown that label claims about potency don’t always reflect what’s in the bottle.

The certification programs discussed earlier in this article— and the certification seals from reputable certifiers on the labels of supplement products, help ensure that the products do indeed meet label claims. Until the FDA, which routinely tests supplement products, has the resources to broaden its testing, consumers and medical practitioners are encouraged to purchase products with legitimate certification labels.

A second issue is economic adulteration. This occurs when a manufacturer or an ingredient supplier purposefully substitutes a less-expensive ingredient for an active one.

This practice is not exclusive to dietary supplements, of course, as it has been going on in commerce for thousands of years and is the source for the well-known phrase caveat emptor, Latin for “buyer beware.” In dietary supplements, such substitutions include inert materials, such as maltodextrin, for example, to bulk up weight, or the use of a different, lower-cost ingredient or even a different species of the listed plant that can pass commonly used identification tests. Examples include the adulteration of ginkgo with rutin/quercetin from buckwheat, coenzyme Q10 with idebenone, and saw palmetto with palm oil.19 The issue is widespread enough that the American Botanical Council (ABC), in partnership with the American Herbal Pharmacopeia (AHP) and the National Center for Natural Products Research (NCNPR) at the University of Mississippi and with wide financial support from industry, has created the ABC-AHP-NCNPR Botanical Adulterant Program,20 to educate stakeholders about the issue. The intention of the program

Israelsen—Dietary Supplement Myths

… is to confirm the extent of adulteration in the United States and global markets, determine which official or unofficial analytical methods are currently available to help detect the presence (or absence) of a suspected or known adulterant, and to provide comment and guidance on the relative strengths and/or weaknesses of differing analytical methods.

To date, the program has issued 5 adulteration reports and 3 laboratory guidance documents to help stem the accidental or purposeful adulteration of botanical ingredients.

The industry is also in the process of expanding transparency about its ingredients through a number of initiatives designed to improve supply-chain integrity. Some of these initiatives are part of the FSMA discussed elsewhere in this article and include adoption of increased facility inspections; heightened, targeted ingredient testing; and the use of innovative track-and-trace systems that record in real time the source, location, and status of all dietary ingredients.

Myth 3: Products With Unapproved Drugs Are Dietary Supplements It must be repeated that the large majority of supplement companies are responsible, follow the law, and produce high-quality products that serve consumer needs.

Yet it’s a common misperception that is repeated over and over again in media (as well as by regulators) that products containing undeclared or adulterated active pharmaceutical ingredients (APIs) are dangerous “dietary supplements.”

In fact, these products—even though they are labeled as dietary supplements—are legally classified as unapproved new drugs,21 or more commonly, “illegal, tainted products being sold as dietary supplements.”23 The distinction is crucial as these products are the ones most often responsible for negative press as well as serious safety concerns for consumers, because these products are often spiked with APIs that have been withdrawn from the market or that may be present at doses far beyond recommended levels.

Weight loss, sports nutrition, and sexual enhancement products are the leading categories where such adulteration is most likely to take place. The old adage, “If it sounds too good to be true, it probably is,” applies here, because “dietary supplements” offering fast or drug-like results are, in fact, most often mislabeled drugs and should be avoided by consumers.

The DSHEA was passed prior to the wide use of and could not foresee the widespread sales channel that developed for supplements on the Internet, which created opportunities for an almost anonymous selling environment, making enforcement much more challenging. Nor did the DSHEA see the explosion of overseas ingredient sourcing, particularly from China.

Previously, most products were sold via various retail and practitioner channels and by multilevel marketing associates with ingredients sold to the brand holders or contract manufacturers by a relatively small handful of suppliers and importers. With the staggering growth of the industry since 1994, the demand for ingredients has mushroomed as has the supply chain, leading to dishonest

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supply sources and creating consumer fraud and deception.

Although the task of identifying and removing problem products ultimately falls on the shoulders of an underresourced FDA and the self-regulatory efforts of the industry, the issue of adulterated products has caught the attention of a handful of states’ attorneys general, as mentioned previously. In addition to its support for resources for the FDA, the responsible industry has expanded its outreach to the attorneys general and their staffs in key states in a concerted effort to educate them about the value of quality supplementation as part of a healthy lifestyle and the economic effect of a mature and “clean” industry, inform them about the regulatory provisions already in place at the national level, provide them with information and resources, and help them shift their focus toward noncompliant companies and unsafe products.

In addition, the industry is working to take action against the deceptive, false, and misleading advertising claims of products by noncompliant companies through 2 efforts: a joint effort created by the Council for Responsible Nutrition Foundation and the National Advertising Division23 and a separate effort sponsored by the Natural Products Foundation’s “Truth in Advertising” program,24 which in 2013, reviewed 275 advertising cases and mailed 150 warning letters to companies responsible for marketing dietary supplements with illegal drug and disease claims.

Conclusion The use of safe and beneficial dietary supplements remains an important part of your patients’ healthy lifestyle—and supplements are likely an important part of your integrative medicine practice. Although issues surrounding potency, ingredient identification, adulteration, and the enforcement of existing laws are legitimate concerns for medical professionals and consumers, the responsible industry is actively working to raise quality standards for its products through a number of self-regulatory measures.

These include education about and adoption of additional quality assurance initiatives, such as GMPs for botanical ingredients; better supply-chain management; adoption of improved identification and testing methodologies; an industry-wide product registry; the use of accredited thirdparty certifications and seals; and initiatives to promote widespread membership in the industry’s trade associations, which is a reliable indicator of a company’s support of and adherence to strict quality guidelines. Also, industry support of appropriate enforcement actions against problem players and products from the FDA, the FTC, and states’ attorneys general continues in an effort to rid the market of unsafe and mislabeled products.

References 1. Bradley J. NBJ: ‘The US supplement industry is $37 billion, not $12 billion.’

Nutraingredients USA Web site. http://www.nutraingredients-usa.com/ Markets/NBJ-The-US-supplement-industry-is-37-billion-not-12-billion.

Published June 1, 2015. Accessed June 7, 2016.

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2. New York State Office of the Attorney General. A.G. Schneiderman asks major retailers to halt sales of certain herbal supplements as DNA tests fail to detect plant materials listed on majority of products tested. http://www.ag.ny.gov/ press-release/ag-schneiderman-asks-major-retailers-halt-sales-certain-herbalsupplements-dna-tests.Published February 3, 2015. Accessed June 8, 2016.

3. Harbaugh D, Mishler B, Neal-Kababick J, Brown P. The capabilities and limitations of dna barcoding of botanical dietary supplements. United Natural Product Alliance Web site. https://unpa.com/assets/news_resource/ asset/76/The_Capabilities_and_Limitations_of_DNA_Testing_FINAL_310-2015.pdf. Published March 2015. Accessed June 8, 2016.

4. O’Connor A. New York attorney general targets supplements at major retailers.

New York Times Web site. http://well.blogs.nytimes.com/2015/02/03/new-yorkattorney-general-targets-supplements-at-major-retailers/?hp&action=click&pgt ype=Homepage&module=a-lede-package-region&region=top-news&WT. nav=top-news&_r=1. Published February 3, 2015. Accessed June 8, 2016.

5. Morrell A. Did The NY AG flub its testing in herbal supplement smackdown?

Forbes Web site. http://www.forbes.com/sites/alexmorrell/2015/03/14/didthe-ny-ag-flub-its-testing-in-herbal-supplement-smackdown/. Published March 14, 2015. Accessed June 8, 2016.

6. Twilley N. How not to test a dietary supplement. New Yorker Web site. http:// www.newyorker.com/tech/elements/dna-barcoding-new-york-dietarysupplement. Published February 10, 2015. Accessed June 8, 2016.

7. US Food and Drug Administration. CFR – Code of Federal Regulations Title 21.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch. cfm?cfrpart=111. Updated August 21, 2015. Accessed June 8, 2016.

8. National Institutes of Health. Dietary Supplement Health and Education Act of 1994. https://ods.od.nih.gov/About/DSHEA_Wording.aspx. Published October 25, 1994. Accessed June 8, 2016.

9. US Food and Drug Administration. Dietary Supplement and Nonprescription Drug Consumer Protection Act. http://www.fda.gov/RegulatoryInformation/ Legislation/SignificantAmendmentstotheFDCAct/ucm148035.htm.

Published December 22, 2006. Accessed June 8, 2016.

10. US Food and Drug Administration. FDA Food Safety Modernization Act. http://www.fda.gov/Food/GuidanceRegulation/FSMA/. Updated February 25, 2016. Accessed June 8, 2016.

11. Centers for Disease Control and Prevention. Injury prevention & control: Opioid overdose. http://www.cdc.gov/drugoverdose/data/. Updated March 14, 2016. Accessed June 8, 2016.

12. National Institutes of Health. National Institutes of Health Office of Dietary Supplements dietary supplement label database. http://www.dsld.nlm.nih. gov/dsld/. Updated December 2015. Accessed June 8, 2016.

13. US Food and Drug Administration. The regulation of dietary supplements: A review of consumer safeguards. http://www.fda.gov/newsevents/testimony/ ucm112576.htm. Updated July 22, 2009. Accessed June 8, 2016.

14. US Department of Justice. Justice Department and federal partners announce enforcement actions of dietary supplement cases. https://www.justice.gov/opa/ pr/justice-department-and-federal-partners-announce-enforcement-actionsdietary-supplement-cases. Updated January 22, 2016. Accessed June 8, 2016.

15. US Food and Drug Administration. FDA creates the Office of Dietary Supplement Programs and announces new nutrition office leadership. http:// www.fda.gov/Food/NewsEvents/ConstituentUpdates/ucm478303.htm Published December 21, 2015. Accessed June 8, 2016.

16. Council for Responsible Nutrition. The CRN consumer survey on dietary supplements: 2014. http://www.crnusa.org/CRNconsumersurvey/2014/.

Published October 30, 2014. Accessed June 8, 2016.

17. Geller A, Shehab N, Weidle N, et al. Emergency department visits for adverse events related to dietary supplements. N Engl J Med. 2015; 373(16):1531-1540.

18. Council for Responsible Nutrition. Product safety expert debunks research questioning the safety of dietary supplements at congressional briefing. http:// www.crnusa.org/CRNPR15-DSC-ProductSafety121115.html. Published December 11, 2015. Accessed June 8, 2016.

19. Obermeyer W. economically motivated adulteration in the dietary supplement marketplace (PowerPoint). US Food and Drug Administration Web site. www. fda.gov/downloads/newsevents/meetingsconferencesworkshops/ucm163645. ppt. Published June 1, 2009. Accessed June 8, 2016.

20. American Botanical Council. The ABC-AHP-NCNPR Botanical Adulterant Program. http://cms.herbalgram.org/BAP/index.html?ts=1459182280&signa ture=4201a716a30689d1246c5f684d1be80b. Accessed June 8, 2016.

21. Hamburg M. Letter to manufacturers of dietary supplements. US Food and Drug Administration Web site. http://www.fda.gov/downloads/Drugs/ResourcesForYou/ Consumers/BuyingUsingMedicineSafely/MedicationHealthFraud/UCM236985. pdf. Published December 15, 2010. Acccessed June 8, 2016.

22. American Herbal Products Association. FDA enforces against tainted products masquerading as supplements. KeepSupplementsClean Web site. http://www. keepsupplementsclean.org/. Published 2011. Accessed June 8, 2016.

23. Council for Responsible Nutrition. Industry self-regulation program. http:// www.crnusa.org/NAD/. Published 2006. Accessed June 8, 2016.

24. Natural Products Foundation. Truth in advertising expands education outreach. http://www.naturalproductsfoundation.org/index.php?src=news&srctype=detail& category=News&refno=75. Published December 11, 2013. Accessed June 8, 2016.

Israelsen—Dietary Supplement Myths

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COMMENTARY

Federal Strategies for Pain and Opioids Wildly Uneven on Value of Integrative Practitioners … plus more John Weeks

This column is offered in collaboration with The Integrator Blog News & Reports (http://theintegratorblog.com), a leadership-oriented news, networking, and organizing journal for the integrative medicine community. For more information on these and other stories, enter keywords from the articles in the site’s search function.

Federal Strategies for Pain and Opioids Wildly Uneven on Value of Integrative Practitioners The first months of 2016 witnessed a cascade of federal strategies, guidance, and new directions relative to mounting discomfort both with pain and the means of treatment. In a series of 3 recent articles, I analyzed the extent that nonpharmacologic complementary and integrative practices, and practitioners were viewed as part of the solution.1-3 Here is a quick breakdown. The Fact Sheet on President Barack Obama’s $1.1-billion opioid strategy is devoid of any reference to nonpharmacologic approaches.4 The final Guideline for Prescribing Opioids for Chronic Pain from the US Centers for Disease Control and Prevention (CDC) features, as step 1: “Nonpharmacologic therapy and non-opioid pharmacologic therapy are preferred for chronic pain.”5 The featured options, however, are limited to exercise; aquatic, aerobic, psychological, and cognitive behavioral therapy; and bio-psycho-social interventions. There is no mention of any other integrative practices or practitioners.

The National Pain Strategy from the US Department of Health and Human Services (HHS) issued on March 18, 2016, 3 days after the CDC guideline, shows greater inclusion. My analysis found 15 separate mentions of complementary or integrative practices in the 55-page document. (This compares to 66 for “opioids.”)

Most notably, in 4 of the 16 objectives in the strategy, complementary or integrative health practitioners were directly included as key collaborators. They were indirectly referenced as potential partners in others.

One notable finding in the series of analyses is that the sponsoring federal agencies did not choose to seek advice from a very wide net of professions. With one exception, none of the advisory bodies included chiropractors, integrative medical doctors, naturopathic doctors, acupuncturists, or other professionals from these fields. The one exception was Maryland integrative academic and researcher Brian Berman, MD. He was on one of the 6 working groups for the National Pain Strategy. Berman was the sole expert in integrative pain among the 80 professionals who shaped the strategy’s objectives through working group activity.

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Comment: When the Joint Commission, the major hospital accreditor, issued a “Clarification of the Pain Management Standard”6 in November of 2014, it seemed that the era of apartheid in pain treatment was over.

Elevated were what they called “chiropractic therapy, acupuncture therapy, massage therapy” and other nonpharmacologic approaches. They appeared on par with pharma. Notably, that position came out of a process that began with submissions to a Joint Commission task force of research from members of the integrative health community.7 The failure of the CDC and HHS to properly convene inclusive interprofessional teams appears to have significantly limited the value of integrative elements. It is a shame, given the depth of the crisis, that policy leaders are not yet welcoming all of the tools to the tool box and professions to the table as the US body politic staggers, drug-addled, toward solutions.

Chiropractic, Naturopathic, and Acupuncture Associations Step Into the Opioid Debate National organizations representing integrative practice professionals are stepping into the nation’s debate about pain and opioid strategies. In separate activities, the American Chiropractic Association (ACA), the American Association of Naturopathic Physicians (AANP), and the American Society of Acupuncturists (ASA) kicked off new initiatives to insert themselves in the emerging dialogue.8 The AANP sent a message, via media release, to the American Medical Association’s (AMA’s) president Steven Stack, MD. In a commentary, Stack had recently wondered aloud to his fellow medical doctors: “When was the last time we looked at the research on opioid alternatives?” The AANP offered itself and members as the AMA’s educator partners.

The ACA promoted a “conservative” course on pain treatment through a resolution from its House of Delegates. The key positions included investigation of nonpharmacologic interventions for pain treatment, promotion of evidence-based nonpharmacologic therapies, interprofessional education, and “public health campaigns to raise awareness of drug-free treatment options for pain syndromes.”9 The American Society of Acupuncturists, in a joint statement with the Acupuncture Now Foundation, filed a 10-page document with the CDC during the public comment period on the guidance, detailing the science behind acupuncture for pain care. It concluded, “Considering the magnitude of the opioid crisis, nonopioid alternative approaches to the management of

Weeks—Industry Insights

ShortTakes X Chanda Hinton-Leichtle and the Coloradobased Chanda Plan Foundation are in the process of creating the nation’s first integrative patient-centered medical home that focuses on people with long-term disabilities. The remarkable Hinton-Leichtle herself has quadriplegia, due to a childhood accident.

X The teaching clinic at Bastyr University clinic, led by naturopathic physicians, ranked high in regional comparison of all primary care centers for the third year in a row. The survey came from a third-party payer group.10 X The Veterans Health Administration (VHA) is exploring its first functional medicine practice via Henri Roca, MD, the former clinical leader at the Yale integrative medicine program. Roca’s VHA practice is in Arkansas.

X Speaking of the VHA, Ben Kligler, MD, MPH, the former chair of the Academic Consortium for Integrative Medicine and Health, will be the first director of the VA’s Integrative Health Coordinating Council.11 Kligler will leave 16 years at Continuum Center for Health and Healing in New York City.

X David O’Bryon, JD, the executive director of the Association of Chiropractic Colleges and the chair of the Academic Collaborative for Integrative Health, was granted a Special Award of Honor from the American Chiropractic Association.

X The American Association of Naturopathic Physicians has published its 2025 Strategic Plan and announced that is available online.12 X Mainstream medical reform leader Don Berwick, MD, MPP, used a commentary in JAMA to urge the medical industry to enter a “new Moral Era.”13 The announcement provoked a look at the “shadow” in medicine’s prior

chronic pain that are shown to be safer, while of equal or superior clinical effectiveness to opioids, should not merely be categorized as a ‘possible option’. The research presented below demonstrates these positions and we urge policy makers to carefully consider this information and contact us with and questions.”

Comment: Experts in nonpharmacologic approaches need to be active in the nation’s work on pain and opioids. This is evident in the poor representation of such approaches and practitioners in the CDC’s guidelines and in much of the National Pain Strategy. In what we likely an overly hopeful media release following the CDC’s guideline, the ACA sent a message encouraging “patients and healthcare providers

Weeks—Industry Insights

movements toward patient-centered care, toward evidence-based medicine, and toward value-based medicine.14 What is medicine if not focused on patients, evidence, value, and morals?

X National College of Natural Medicine in Portland, Oregon, announced formation of the AgeWise Institute to “promote healthy aging at every age through community-based programs, education and research.”15 X The National Center for Integrative Primary Health Care has published competencies for integrative medicine in primary care. The Health Resources and Services Administration-based initiative is based at the University of Arizona Center for Integrative Medicine.16 X A project styled the “Integrative Wisdom Series” backed by Integrative Therapeutics is publishing short clips from leaders of the naturopathic medical field, including from the editor of this publication.17 X The Maryland University of Integrative Health has signed a Memorandum of Understanding with the conservative Johns Hopkins School of Medicine to begin providing integrative services for Hopkins patients. The first venue will be Hopkins’ Howard County Health Center.18 X The National Certification Board for Therapeutic Massage and Bodywork has a new partnership with Central Carolina Technical College (CCTC) through which the certifying body is introducing the profession’s first Specialty Certificate in Massage Therapy for Integrative Healthcare.19 X The American Herbal Products Association is promoting Health Savings Accounts as a tool that is useful to some people choosing nonconventional practitioners and products.20

to first consider exhausting conservative forms of pain management before initiating higher-risk options such as opioids.”21 This is perspective on which all 3 professions, and the integrative medical doctors, agree. Might there be value in a sustained campaign from all of these, working together to educate policy leaders and clinicians? A reasonable question is whether the optimal inclusion of integrative practices in the nation’s pain strategy can happen without the power that might come from such collaboration on this core principle. There is good news in that a collaboration of integrative health organizations, the Integrative Health Policy Consortium, has already been active on the issue.22 Can it step up its game?

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Functional Medicine Leader Mark Hyman, MD, Hits the Trifecta The last half of February held a remarkable trio of events in the life of the current president of the Institute for Functional Medicine, author, clinician, and sometimes political actor Mark Hyman, MD. The least of these was that he was honored on February 25, 2016, in front of 1000 fellow practitioners with the Leadership Award from Integrative Healthcare Symposium in New York City. Only days prior, the 3-time best-selling author released his new book, Eat Fat, Get Thin, which is, at this writing, number 2 on a New York Times bestseller list.23 A few days earlier, word came out that the Cleveland Clinic, where Hyman had forged a tie to create a historic Center for Functional Medicine, planned to double the allotted space to 17 000 prime square feet in the heart of the hospital.24 Comment: My general bias is away from a “great man theory” of history. From time to time, one needs to stop and honor just what a single individual has accomplished.

I would say Hyman hit an integrative health trifecta here.

Thanks for the good work, Dr Hyman.

References 1. Weeks J. Chronicle of health creation: Are integrative health and medicine part of the national pain strategy? Huffington Post. http://www. huffingtonpost.com/john-weeks/chronicle-of-health-creat_b_9548062.html.

Updated March 29, 2016. Accessed May 26, 2016.

2. Weeks J. The uneven entrance of nonpharmacologic approaches as tools in the opioid crisis. Altarum Institute Web site. http://altarum.org/healthpolicy-blog/the-uneven-entrance-of-nonpharmacologic-approaches-astools-in-the-opioid-crisis. Published March 29, 2016. Accessed May 26, 2016.

3. Weeks J. Open letter to Barack Obama on your $1.1 billion opioid initiative: The imperative for integrative medicine. Huffington Post. http://www. huffingtonpost.com/john-weeks/open-letter-to-barack-oba_2_b_9152892. html. Updated February 5, 2016. Accessed May 26, 2016.

4. WhiteHouse.Gov. Fact sheet: President Obama proposes $1.1 billion in new funding to address the prescription opioid abuse and heroin use epidemic. https://www.whitehouse.gov/the-press-office/2016/02/02/president-obamaproposes-11-billion-new-funding-address-prescription. Published February 2, 2016. Accessed May 26, 2016.

5. Centers for Disease Control and Prevention. CDC guideline for prescribing opioids for chronic pain — United States, 2016. http://www. cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm. Updated March 18, 2016.

Accessed May 26, 2016.

6. The Joint Commission. Clarification of the pain management standard. http://www.jointcommission.org/clarification_of_the_pain_management__ standard/. Published November 5, 2014. Accessed May 26, 2016.

7. Weeks J. Chronicles of health creation: Joint Commission issues new pain standards in response to integrative medicine team. Huffington Post. http:// www.huffingtonpost.com/john-weeks/integrative-medicine-and-_b_6213662. html. Updated January 31, 2015. Accessed May 26, 2016.

8. Weeks J. Addressing opioid abuse and non-opioid pain management.

Integrative Practitioner Web site. http://www.integrativepractitioner.com/ whats-new/industry-insights/addressing-opioid-abuse-and-non-opioidpain-management/. Published Marcy 8, 2016. Accessed May 26, 2016.

9. American Chiropractic Association. Chiropractic’s role in opioid crisis, senior health among top policies approved at 53rd ACA annual meeting. http://www.acatoday.org/News-Publications/News/News-Releases/ Chiropractics-Role-in-Opioid-Crisis-Senior-Health-Among-Top-PoliciesApproved-at-53rd-ACA-Annual-Meeting. Published March 2, 2016.

Accessed May 26, 2016.

10. Bastyr Center for Natural Health. News and events. http://www.bastyrcenter. org/about/news/2016/03/patients-love-their-experience-bastyr-center.

Updated Thursday, March 17, 2016. Accessed May 26, 2016.

11. Weeks J. Ben Kligler leads Veterans Affairs integrative health strategy.

Integrative Practitioner Web site. http://www.integrativepractitioner.com/ whats-new/industry-insights/ben-kligler-leads-veterans-affairs-integrativehealth-strategy/. Published March 29, 2016. Accessed May 26, 2016.

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12. American Association of Naturopathic Physicians. Vision and goals. http:// www.naturopathic.org/content.asp?contentid=19. Accessed May 26, 2016.

13. B e r w i ck DM . E r a 3 for m e d i c i n e and h e a lt h c are. JA M A .

2016;315(13):1329-1330.

14. Weeks J. chronicle of health creation: The shadow in Berwick’s sall for a ‘Moral Era’ for medicine. Huffington Post. http://www.huffingtonpost.com/ john-weeks/chronicle-of-health-creation-the-shadow-in-berwicks-call-for-amoral-era-for-medicine_b_9396516.html. Updated March 17, 2016.

Accessed May 29, 2016.

15. Agewise Institute. National College of Natural Medicine. http:// agewiseinstitute.com/. Accessed May 26, 2016.

16. Weeks J. Integrative health competencies for primary care professionals.

Integrative Practitioner Web site. http://www.integrativepractitioner.com/ whats-new/industry-insights/integrative-health-competencies-for-primarycare-professionals/. Published March 15, 2016. Accessed May 26, 2016.

17. Integrative Wisdom. Videos. http://integrativewisdom.net/videos/?utm_ content=view-all-videos. Accessed May 26, 2016.

18. Maryland University of Integrative Health. MUIH and Howard County General Hospital sign affiliation agreement. http://muih.edu/muih-andhoward-county-general-hospital-sign-affiliation-agreement. Published February 25, 2016. Accessed May 26, 2016.

19. Campaign Archive. NCBTMB & CCTC announce specialty certificate. http:// us5.campaign-archive2.com/?u=aacfda5bc8992a6b00f2e4ba7&id=141e28b05 7&e=cf9ef319af. Accessed May 26, 2016.

20. American Herbal Products Association. Letter the Honorable Orrin G. Hatch, Chairman. http://ahpa.org/Portals/0/PDFs/Advocacy/Hatch_Health_Savings_ Act_Letter.pdf. Published February 22, 2016. Accessed May 26, 2016.

21. American Chiropractic Association. Chiropractic physicians applaud CDC guideline on opioid prescribing; encourage conservative options first for pain. http://www.acatoday.org/News-Publications/News/News-Releases/ Chiropractic-Physicians-Applaud-CDC-Guideline-on-Opioid-PrescribingEncourage-Conservative-Options-First-for-Pain. Published March 18, 2016.

Accessed May 26, 2016.

22. Integrative Health Policy Consortium. Comments on proposed 2016 Guidelines for Prescribing Opioids for Chronic Pain. http://www.ihpc.org/ wp-content/uploads/IHPC_Comments-CDC_Pain2016.pdf. Published January 13, 2016. Accessed May 26, 2016.

23. New York Times. Advice, how-to & miscellaneous. http://www.nytimes.com/ best-sellers-books/2016-04-03/advice-how-to-and-miscellaneous/list.html.

Accessed May 26, 2016.

24. Goldman E. Facing huge demand, Cleveland Clinic doubles its Functional Medicine Center holistic primary care. Holistic Primary Care Web site. https://holisticprimarycare.net/topics/topics-a-g/functional-medicine/1772facing-huge-demand-cleveland-clinic-doubles-its-functional-medicinecenter.html. Published February 18, 2016. Accessed May 26, 2016.

Weeks—Industry Insights

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PRESENTERS 2016

Christopher Hobbs, PhD, LAc, AHG: Mushrooms for Nutrition and Wellness Interview by Craig Gustafson Facilitated by the Association for the Advancement of Restorative Medicine (AARM) 14th Annual International Conference, to be held in Hilton Head, South Carolina, from September 15 to 18, 2016.

Christopher Hobbs, Phd, LAc, AHG, will present on the clinical use of mushrooms and herbs to treat infection at the 14th Annual International Conference of the Association for the Advancement of Restorative Medicine, September 15 to 18, 2016, in Hilton Head, South Carolina. He is a fourthgeneration, internationally renowned herbalist, licensed acupuncturist, herbal clinician, research scientist, consultant to the dietary supplement industry, expert witness, botanist, and mycologist with more than 35 years of experience.

The author or coauthor of more than 20 books, Christopher lectures on herbal medicine worldwide. He has taught at universities and medical schools such as Stanford Medical School; University of California, Santa Cruz; Bastyr University and the National School of Naturopathic Medicine; and most recently for 7 years at the University of California, Berkeley, as a graduate student instructor and lecturer. He earned his PhD at UC Berkeley, with research and publication in evolutionary biology, biogeography, phylogenetics, plant chemistry, and ethnobotany.

For more information about the conference, visit http://www.restorativemedicine.org/.

Integrative Medicine a Clinician’s Journal (IMCJ): Mushrooms are often considered to be filler when it comes to nutritional profiles. Could you talk a little bit about the nutritional profile of mushrooms and how they can contribute to functional diets?

Dr Hobbs: When most people think of mushrooms and nutrition, they think of button mushrooms from the store, Agaricus bisporus. They are often used just as a little flavorful dressing or garnish on a salad, though I think that’s changed quite a bit over the last number of years. People are starting to eat more shiitake mushrooms, which have been cultivated for a long time, maybe 800 years. The number-1 cultivated mushroom in the world is Agaricus bisporus, the button mushroom, but second is shiitake. If you go to into a Chinese restaurant, the Chinese black mushrooms that you get are shiitake. However, they do not really taste like fresh shiitake that have been cooked. The ones that you generally find in Chinese restaurants have been dried and might have been around for a while, and then they are reconstituted and cooked in different dishes.

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Mushrooms are really out there and are widely available.

They are served everywhere now, but they do not really get the credit they deserve for being such a nutritional powerhouse. Oyster mushrooms are also quite popular and can be found in a lot of markets. They come in different colors: pink and yellow, even blue, and then white or offwhite, like you would find in the woods. They grow all over the world. Oyster mushrooms are the most digestible of all mushrooms. Some species of oyster mushrooms contain up to around 30% useful protein, and by that I mean the protein is very absorbable and has the full complement of amino acids that we need. Shiitake mushrooms are not quite as digestible as oyster mushrooms, but they still contain quite a bit of protein, up to about 25% of usable protein. Besides the protein, there are a lot of trace minerals in mushrooms.

Mushrooms are also a great source of phosphorus, potassium, zinc, copper, magnesium, and other minerals.

Besides minerals, mushrooms contain a lot of B vitamins. By the way, many mushrooms, including shiitake, especially after being exposed to the sun, contain quite a bit of vitamin D. It is in the form of ergosterol in mushrooms, and when they are exposed to the sun, they actually transform that compound into vitamin D2— ergocalciferol—that can be used by people. Mushrooms are also a very good source of digestible and indigestible fiber—we all need more fiber; there is no doubt about that.

They are also low calorie. Mushrooms are not sweet, so they are an ideal diet food, with a high nutritional profile, lots of protein, high fiber, and low fat. I think when people really take a second look at what mushrooms can offer in the diet on a regular basis, people will start eating more mushrooms.

It is really fun to go out in the woods and hunt wild mushrooms as well, like porcini and oyster mushrooms. Of course, you have to be really careful about what you are picking, because there are some lethal mushrooms out there like the death cap. Go on mushroom walks and make sure you get a good guide or two. Hunting wild mushrooms can provide a lot of health benefits, besides the nutritional benefits, for instance walking in the forest, getting the fresh air, moving your body—all very uplifting and healthful.

IMCJ: When it comes to vegan and vegetarian diets, sourcing B12 is a concern. Are there particular varieties of mushrooms that have higher B12?

Hobbs—Presenters

Dr Hobbs: Again, oyster mushrooms. The form of B12 in mushrooms is not as usable as the vitamin sourced from meat, but it is still somewhat useful. I would say 25% of what is found in mushrooms can be utilized by the body. It is a good source if you are eating mushrooms regularly, especially for vegetarians. As far as which other ones contain the most B vitamins, I think shiitake has a pretty good complement, as well as oyster mushrooms. Porcini also has some B vitamins— not quite as usable but still a good source.

IMCJ: Is cooking necessary to unlock some of the nutrients, or are we able to access them from the raw state?

Dr Hobbs: As a good general rule, always cook mushrooms.

There are some exceptions. I eat a few things out in the woods, like witch’s butter, which is pretty tender. I eat that in the raw form, but not excessive amounts of it. Most mushrooms should be cooked. The reason why is because they contain a tremendous amount of fiber that is mostly indigestible by us, including chitin, which is an amino polymer, and lots of heteropolysaccharides, which are bound up with chitin and also other polymers in the cell wall. Heating it, steaming it, or cooking it even lightly can break down some of those insoluble fibers and allow better access to the nutritional aspects—the minerals and the vitamins—along with the beta glucans, which are essential to the immunomodulating activity of fungi.

One paper that was published recently—and this is really quite an interesting study by a group who—did an ex vivo study where they fed people mushrooms, drew blood, and then challenged the blood that had leukocytes and other immune cells in it with a virus or bacteria. They found that, when the mushrooms were cooked and not just dried or eaten raw, the immune system had more activity against pathogens. It is clear from the literature that it is very important to cook mushrooms for the strongest immunomodulatory activity, and also to get more nutrients out of them.

If you eat raw or undercooked mushrooms, even shiitake, they can be quite nauseating to some people. I have experienced that a number of times eating meals with mushrooms when they were not cooked properly, especially if you’re eating more than one species at a time.

You can get pretty green after eating a plate of mushrooms if they are not well cooked.

IMCJ: How would a clinician go about using mushrooms for immune support?

Dr Hobbs: There is a lot to it, that’s for sure. There are so many species being used today. We ask: Is one species any better than another? What are the most popular ones? How much is the proper dose? Also, there are commercial products, leading to questions and interesting discussions about what the best commercial products are. Is the mycelium better, or the fruiting body? Because products are made from

Hobbs—Presenters

the fruiting body or the mycelium. I think, first of all, if a practitioner is going to be interested in using mushrooms for immunomodulation, supporting immune function, and preventing different illnesses, or even as an adjunct part of a treatment program, then first you have to know what the best products are, how to use them, what the proper dose is, and so forth. That is a really important discussion that is going on in the dietary supplement industry, and among practitioners.

I have found misunderstandings about these questions.

I think we can all realize that mushrooms have come on the scene as a therapeutic option these days. I just had a conversation with a major mushroom supplier who said that some major food companies now are starting to get interested in the immunomodulatory effect of mushrooms—how they can add that into their food product lines. I am talking about major food manufacturers.

It really is starting to get into the mainstream, now.

As far as use in the clinical setting, again, the practitioner has to make sure to use enough. Research clearly shows that there is a threshold you have to reach before they become active. Too little is not going to be active, and with too much—if you’re giving too high a concentration—that also could be problematic. Some research shows too much of these immunomodulatory compounds in your body could have a mildly suppressive effect. There is a sweet spot where you want to achieve the proper dose, not too much or too little.

As far as the form goes, I just finished an article for HerbalGram that is going to be coming out in the next issue and discusses commercial medicinal mushroom products. So stay tuned for that. There are a lot of factors.

The main active compounds in mushrooms are polymers, beta glucans, which are part of the cell wall. We actually have ancient receptor sites for them in our gut. Believe it or not, 60% of our immune tissue is in our gut. When we ingest mushrooms, these compounds—these higher molecular weight compounds, again beta glucans—are complexed with proteins, chitin, and other molecules. Our bodies can recognize those. We have specific binding sites that can actually recognize these compounds and say, “Hey, there’s some fungi in our body and that could be a problem, and so, mount an immune response.” That is one of the main mechanisms by which they work. It is a very ancient pathway of recognition.

IMCJ: When it comes to mushrooms’ effects on cancer, are there multiple mechanisms in play based on the type of cancer and the type of mushroom, or do they all work in a similar way?

Dr Hobbs: In each mushroom species, the branching pattern of the beta glucans is different. For instance, they might be different sizes. They are also in different tertiary forms as well. Each mushroom species really is unique.

The big questions would be: Which mushroom is the most potent, and which one provides the greatest benefits? Of

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course, according to traditional medicine, some varieties have been utilized for a long time, such as reishi and shiitake, and of course, turkey tails. Each one is quite different. I was mentioning the tertiary structure. The beta glucans in the mushroom cell wall form a helix, so they are coils. Research shows that if they are in the coiled form rather than the straight form, or if they are in pieces because of too much heating, then they are less effective. They are less stimulatory.

Does the species affect it differently? Does it stimulate different vector cells like macrophages, or other leukocytes?

Yes, that is the case, so I think if you really look deeply into the literature, you can see that turkey tails may be a stronger stimulant of certain different cytokines, whereas reishi might have other effects. However, all mushrooms have beta glucans, and all mushrooms have immunomodulatory activity, and that includes button mushrooms, porcini, and maitake. Even these edibles have the same type of immunestimulatory compounds in them as the major medicinal species like reishi and shiitake. The types of polymers in the major medicinal species may have especially potent effects versus edible mushrooms that haven’t particularly been noted for their medicinal effects, but that has not been adequately studied.

There is an extensive literature if you want to really dig deeply, and you can see that each species has certain effects that have been noted. Some cytokines are more stimulated than others. Yes, it is quite complicated. At this point, we need more human studies. There are quite a few human studies that have been performed, but only on a few species.

We need more, and some of the existing studies are not up to modern standards. Probably 50 species have been extensively studied for their immunomodulatory effects.

IMCJ: Clinically, how do mushrooms work for providing adjunctive cancer therapy?

Dr Hobbs: Turkey tails, Trametes versicolor, which is the most widely researched mushroom, certainly has the most clinical trials of any of the mushroom species, especially considering oral application only, not IV administration.

The best of the clinical trials, and the best results that they have achieved, show one group of people using chemotherapy by itself and the other, chemotherapy plus turkey-tail extract. The 5-year survival rate in the group of people taking the mushroom plus the chemotherapy was reported to be up to one-third higher than the group that was not taking any of the mushroom products, only chemotherapy. That is pretty significant. Not only that, but it was shown that, in the mushroom group, nausea was less, energy was better, and just general mood and quality of life were better. As adjuncts to modern, or, I might say modern medical treatments like chemotherapy, mushrooms can offer incredible support for reducing symptoms and improving quality of life.

IMCJ: Do they have any effect on cachexia?

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Dr Hobbs: Now that is an interesting question. I do think there are several studies with turkey tails on reducing that rapid weight loss that often occurs, especially as cancer progresses. I do not recall exact papers, but I seem to recall that there was an effect. I do not think it is a huge effect, however. That is very difficult to reverse , obviously, once it begins.

IMCJ: How about mitigating complications, such as infections and pneumonia that plague people who are going through the chemotherapy and radiation?

Dr Hobbs: Chemotherapy and radiation are so immunosuppressive. There is a lot of research that shows the single most-important factor for a good outcome in cancer, in general, is a strong immune status. It is unfortunate that the major treatment, chemotherapy, is very, very strongly immunosuppressive. It hardly makes sense. Fortunately, in adding mushroom medicine extracts like turkey tails to the mix, you can counteract that immunosuppression to a certain extent. That is a key feature of using medicinal mushrooms with conventional treatments. You can counteract immunosuppression, at least to a degree that can still provide a real benefit to the patient.

IMCJ: Is the clinical potential for mushrooms defined at this point, or is that something that is still evolving?

Dr Hobbs: It is rapidly evolving, definitely. We need more clinical trials to really show which species may be better than another, and what format to use. As one example, I do not recommend tinctures of medicinal mushrooms for immunomodulation because that interferes with the activity, and actually the tertiary structure of the glucans. Foremost among the problems with tinctures for immunotherapy is that the fungal beta glucans are not soluble in alcohol!

Mushrooms also have small molecular weight compounds in them, like triterpenes. Those have other effects, for instance, on the nervous system. Reishi is well known for insomnia and other things that may be attributable to the triterpenes. Those are soluble in alcohol, but the fungal beta glucans are very specific to mushrooms, and those are what we are talking about. It has to be a dried, powdered extract, in my opinion.

There are so many products out there on the market that are getting more and more popular, especially in the last few years. Many practitioners are prescribing them.

Many people are going into the store and buying them.

You see these 4-color boxes in the health-food store showing lion’s mane or showing turkey tails. They are very attractive, and they have labeling and implied claims like immunomodulation, reducing infections, and so forth. So many people are taking them and really without much knowledge about what the effects might be. One thing that I always want to point out in my talks on medicinal mushrooms is: Don’t get your expectations too high. They

Hobbs—Presenters

are not magic bullets. They are not going to—just by themselves—cure cancer or a viral syndrome.

They really are adjunct treatments to support immune function, but they really should go along with all the other things that we know. In other words, an integrated approach, such as diet and exercise and meditation, as well as stretching and mindfulness—all the things that a good practitioner would recommend for a total program for health in viral syndromes and any syndrome or disease involving the immune system.

On the other hand, I do not want to be discouraging, because I think they are incredibly helpful. I prescribed them in my clinical practice and have taken them myself for years and years, and I have seen a real benefit in energy and mood. As you know, if there is immunosuppression, that affects a lot of different processes in the body.

Remember that the immune system, the hormonal system, and the nervous system are all integrated.

If you have immunosuppression, that is going to affect the nervous system function, the mood, and hormonal balance. By addressing immunosuppression, or by using immunemodulators such as medicinal mushrooms, you can get a lot of benefit. On the other hand, I do not want people to get the idea that this one medicine is going to resolve all their issues, because it really isn’t. It is used along with all these other things and it can be incredibly helpful, and it should be in everybody’s clinical practice as one valuable medicine in the medicine chest—not by itself, particularly.

IMCJ: What more will people learn by attending your lecture at AARM? Dr Hobbs: Well, of course, I will address how to choose the best products and what criteria are most important— that is, absolutely key to success with medicinal mushrooms. I will discuss how to actually make mushroom extracts that can be highly effective. This is getting the raw mushrooms, ordering a pound of dried shiitake mushrooms, and making your own right in the kitchen with a blender, a pot, and a dehydrator. I will also discuss what type of fillers are used in commercial products and what type to use if you’re making them at home.

I will also talk about how to choose the best commercial product. Also, proper dose will be discussed, and I will review the clinical trials. I am going to carefully review what clinical data that we have. Then we will talk about the biological effects. How do they work? What are the cellular stimulating mechanisms involved in immunomodulations after ingesting these fungal beta glucans? It is quite a fascinating story.

I will talk about mushroom nutrition. More specifically, I have got some really fascinating charts showing mushroom nutrition, such as what levels of minerals, vitamins, and so forth are in them. It is going to be a carefully considered view of the whole range of medicinal mushrooms.

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ORIGINAL RESEARCH

Rheum rhaponticum Extract (ERr 731): Postmarketing Data on Safety Surveillance and Consumer Complaints Jyh-Lurn Chang, PhD; Michael B. Montalto, PhD; Peter W. Heger; Eva Thiemann; Reinhard Rettenberger, PhD; Jürgen Wacker, MD, PhD

Abstract Context: Postmarketing surveillance data for a commercially available extract of Rheum rhaponticum (ERr 731) have not been published since the beginning of the reporting in 1993 in Germany about adverse events (AEs) that were believed to be associated with it. The extract is derived from the plant’s roots and is indicated for menopausal relief. In Germany, the extract has been marketed as Phytoestrol N and other related products— Phyto-Strol, Phyto-Strol Loges, and Phyto-Strol compact and as femi-loges. In the United States and Canada and in South Africa, the product had been marketed as Estrovera.

Objective: The study’s objective was to summarize the AE reports from Germany from 1993 to June 2014 and also to assess consumers’ complaints in North America and South Africa from the date of the extract’s launch to June 2014.

Design: AE reports recorded by 2 German holders of marketing authorizations, Chemisch-Pharmazeutische Fabrik Göppingen, for Phytoestrol N, and Dr. Loges + Co. GmbH, for femi-loges, were collected and analyzed.

Consumers’ complaints in North America and South

Jyh-Lurn Chang, PhD, is the manager for medical affairs; and Michael B. Montalto, PhD, is the senior director of medical affairs at Metagenics, Inc, in Gig Harbor, Washington. Peter W. Heger is a director at Health Research Services GmbH in Ubstadt-Weiher, Germany.

Eva Thiemann is the qualified person for pharmacovigilance (QPPV) at Dr. Loges + Co. GmbH in Winsen (Luhe), Germany. Reinhard Rettenberger is a director at Chemisch-Pharmazeutische Fabrik Göppingen, Carl Müller, Apotheker, GmbH & Co KG, in Göppingen, Germany. Jürgen Wacker, MD, PhD, is medical director and head of the Department of Obstetrics and Gynecology Bruchsal, Teaching Hospital of the University of Heidelberg in Heidelberg, Germany.

Corresponding author: Eva Thiemann E-mail address: thiemann@loges.de

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Africa that had been captured by the US distributor of Estrovera were also collected and analyzed.

Results: From 1993 to June 2014, approximately 140 million daily doses of the extract were placed on the German market, and 124 AE reports were recorded.

The most common of those AEs were hypersensitivity, with 74 reactions, and gastrointestinal symptoms, with 47 reactions. From January 2009 to June 2014, approximately 13 million tablets of the supplement were sold in North America, and 79 complaints from consumers associated with a physical response to it had been recorded. The main complaints were gastrointestinal symptoms, with 23 cases, and failure to work as suggested, with 22 cases. From the date of the product’s launch in South Africa in February 2011 to June 2014, no consumer complaints have been reported.

Conclusions: The records related to postmarketing surveillance and consumers’ complaints suggest that the extract of R rhaponticum is generally safe for consumption.

A

n extract from the roots of Rheum rhaponticum has been used in Germany since the 1950s as an herbal medicine for the treatment of menopausal symptoms. The composition of the extract has been described previously.1,2 The extract has been marketed as an alternative for women considering a nonhormonal approach to managing menopausal symptoms. A standardized version of the extract, ERr 731, was commercially registered in Germany in July 1993 as Phytoestrol N (Chemisch-Pharmazeutische Fabrik Göppingen, Carl Müller, Apotheker, GmbH & Co KG, Göppingen, Germany). ERr 731 was also launched in Germany in 2011 with the name femi-loges (Dr. Loges + Co. GmbH, Winsen [Luhe], Germany). It was introduced as the dietary supplement Estrovera (Metagenics, Aliso Viejo, CA, USA) in 2009 in the United States, in 2012 in Canada, and in 2011 in South Africa. Experimental studies had demonstrated that both the extract and its individual

Chang—ERr 731 Postmarketing Surveillance Data

constituents—rhaponticin and desoxyrhaponticin, with small amounts of aglycones rhapontigenin and desoxyrhapontigenin—have exhibited selective estrogen receptor (ER)-β agonistic activity as well as a lack of ER-α affinity in endometrial and breast tissues.2-5 Safety data from experimental and clinical studies have been published previously. In ovariectomized rats, feeding ERr 731 in doses from 0.1 mg per kg of body weight per day, which is the equivalent of the therapeutic dose in humans, to 100 mg per kg of body weight per day for 72 hours, neither stimulated an uterotrophic response nor modulated the expression of genes associated with proliferation.4 Similarly, uterotrophic effects were not detected when ovariectomized rats were fed ERr 731 for 90 days at up to 1 g per kg of body weight per day, demonstrating its endometrial safety.5 Heger et al’s1 12-week, placebo-controlled, randomized trial with perimenopausal women (N = 109) reported no differences between the extract and a placebo in the gynecological findings (eg, endometrial biopsies and bleeding) and in the laboratory safety parameters. The trial also found that no adverse events (AEs) had been classified as being related to the extract. A second 12-week, placebo-controlled, randomized trial in perimenopausal women (N = 112) reported a similar safety profile and found that no serious AEs had occurred.6 Hasper et al’s7 long-term, observational clinical study that consisted of 81 women who had participated in Heger et al’s1 study, and who received ERr 731 for 96 weeks in the new study, found no changes in gynecological findings or laboratory safety parameters and no AEs that were related to use of the ERr 731. In a 6-month, open-label clinical evaluation conducted at 70 German gynecological practices with 252 menopausal women who were taking ERr 731, only 1 AE was documented. The gynecologist, however, assessed it as not being causally related to the extract.8 In a casecontrol study that examined the use of herbal preparations to alleviate climacteric symptoms and reduce the risk of postmenopausal breast cancer, neither use of Pulsatilla nor of R rhaponticum was associated with an increased risk.9 As per regulations in Germany, marketing authorization holders (MAHs) regularly submit postmarket safety reports on medicinal products, called periodic safety update reports (PSURs), to the Federal Institute for Drugs and Medical Devices (BfArM). Before PSURs are submitted, the cases are recorded in databases and assessed by the MAHs. The MAHs are also obliged to collect and document independently each AE report occurring with their products, whether or not those events have been reported by health care professionals or consumers.

Since the official registration of Phytoestrol N in the German market in 1993, when AE report collection began, no postmarketing surveillance data had been published. The current study’s primary objective was to summarize and assess AE reports associated with ERr 731 sold as Phytoestrol N, Phyto-Strol, Phyto-Strol Loges,

Chang—ERr 731 Postmarketing Surveillance Data

Phyto-Strol compact, and femi-loges that had been recorded in Germany.

In both the United States and Canada in North America, and in South Africa, health authorities do not require submission of AE reports by health care professionals and consumers for events that are suspected to be associated with dietary supplements. However, after health care professionals or consumers have reported suspected AEs to a product’s manufacturer, that company is required to send the report to regulatory authorities.10,11 Consumers’ complaints from North America and South Africa that have been related to the extract sold as Estrovera have been actively recorded by its distributor since the product’s launch. Therefore, information on consumers’ complaints from those regions that was related to any physical response postconsumption has been included in the current study.

Methods Procedures The PSURs for Phytoestrol N and other related products—Phyto-Strol, Phyto-Strol Loges, and PhytoStrol compact—were obtained from one MAH, ChemischPharmazeutische Fabrik Göppingen, Carl Müller, Apotheker, GmbH & Co. KG (Göppingen, Germany), and the information on the suspected AEs was analyzed. A second MAH, Dr. Loges + Co. GmbH (Winsen [Luhe], Germany), had also authorized the extract and launched a product in January 2011 with the name femi-loges.

Suspected AE cases that had been collected by that MAH were also obtained for analysis.

As the minimum information, each collected AE report provided the age or age group of the person experiencing the AE, a description of the reaction, and information on the outcome as well as an assessment of the individual case report.

Records for consumers’ complaints related to the extract in North America and South Africa were captured by the distributor when consumers directly used the tollfree product hotline or Web site or when a health care practitioner who had received a user’s complaint informed them. Each record provided a brief description of the complaint. Complaints regarding the quality of the product, such as a broken seal, a defective bottle cap, shipping damage, missing tablets, or smell were excluded as being unrelated to consumption. Only complaints related to a physical response that had occurred after ingestion of the product were relevant and included in the current study.

Outcome Measures The research team used the pharmacovigilance guideline E2A from the International Council for Harmonization (ICH) and the guideline from the World Health Organization’s Collaborating Center for International Drug Monitoring to define a suspected AE.12,13 ICH’s guideline E2B (R3) was used to define what constituted a serious AE.14

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The physical reactions were classified as expected (ie, they were mentioned on the Summary of Product Characteristics [SmPC] in the product’s package) or unexpected (ie, they not mentioned in the SmPC). Further, an event more specific or more severe than described in the SmPC was considered “unexpected.” For example, if acute renal failure was a labeled adverse drug reaction, a subsequent new report of interstitial nephritis or hepatitis with a first report of fulminant hepatitis would be considered unexpected.

The classification of the category of an adverse reaction was evaluated based on the nature of the AE and all other relevant information (eg, medical investigations, patient checkups).

For example, “hypersensitivity reactions of the skin (rash, pruritus, swelling)” is labelled in the SmPC; thus, a reaction reporting rash or pruritus was considered as “hypersensitivity reaction” with the symptoms of rash or pruritus or both. The decision whether a reaction was serious or not was based on the criteria for “seriousness” defined in the ICH guideline E2B (R3). A reaction is considered as serious when the following criteria apply: The reaction (1) results in death, (2) is life-threatening, (3) requires inpatient hospitalization or prolongation of existing hospitalization, (4) results in persistent or significant disability/incapacity, (5) is a congenital anomaly/birth defect, and (6) other medically important condition. The terms life threatening and other medically important condition are defined in the ICH E2A guideline. Because the R rhaponticum extract ERr 731 has a positive risk-benefit profile and the number of reports is very low, at most 2 persons were involved in the evaluation of the case reports. All cases were evaluated and classified by the qualified person for pharmacovigilance.

Results In Germany, 4 PSURs involving 55 AEs for products using ERr 731 had been submitted by ChemischPharmazeutische Fabrik Göppingen to BfArM, covering the period from July 1993 to May 2013. The 69 AE reports recorded by Dr. Loges + Co. GmbH covered the period from January 2011 to June 2014. Therefore, from July 1993 to June 2014, 124 AEs had been reported. Sales data from both MAHs, based on a standard daily dose of 1 entericcoated tablet, indicated that approximately 140 million daily doses of the marketed products were placed on the market during the period. On average, 6.7 million doses of products using the extract were sold annually, and 5.9 AE reports per year were recorded.

The 124 reports included 215 responses in various organ systems. In some cases, the patient mentioned several responses (Table 1). Eighty-four reactions were classified as expected and were seen as hypersensitivity reactions or intolerance to the extract. The unexpected reactions were either typical menopausal symptoms (eg, headache, intermediate bleeding, hot flashes, sweating, malaise, and other symptoms in the chest) or were gastrointestinal symptoms (eg, nausea, abdominal pain, diarrhea, and indigestion).

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The rest were individual cases or randomly occurring reactions that had occurred while taking the marketed products. In most cases, possible alternative causes were present, such as other medications, underlying disease, or diet. The cause attributed to the product was confounded so much in those cases as to be considered unlikely. In many reports, the causality could not be assessed due to a lack of information. All but one case, in which significantly elevated liver enzymes were reported, were classified as not serious according to ICH’s Guideline E2B (R3).14 From January 2009 to June 2014, approximately 13 million tablets of supplements using the extract had been sold in North America, and 79 complaints postconsumption had been recorded. On average, 2.4 million doses of the extract were sold annually, and 14.6 complaints from consumers per year were documented. The main reasons for complaints were gastrointestinal symptoms, in 23 cases; issues with the product not working as suggested, in 22 cases; headache, in 9 cases; and hypersensitivity or rash, in 8 cases (Table 2). One serious case was identified, in which the occurrence of endometrial cancer during the use of the extract had been reported. However, for all cases, insufficient information was available to evaluate whether the complaints were related to the extract’s use.

From February 2011 to June 2014, approximately 120 000 tablets of supplements using the extract had been sold in South Africa, and no consumer complaints had been recorded.

Discussion As part of complementary and alternative medicine, natural herbal products traditionally have been highly popular in many developing countries. Their use has been growing rapidly in developed countries, including in Germany15 where the herbal medicinal product using ERr 731 required a prescription and were sold only through pharmacies until 2005. It became a nonprescription herbal medicine available only in pharmacies after December 2005 due to its efficacy and to the safety it had demonstrated in clinical trials. The extract is contraindicated for individuals with any known or suspected estrogen-dependent cancer, as stated in the package’s insert.1,6,7 The current investigation of the extract’s postmarketing surveillance data found that 5.9 AEs were reported for every 6.7 million doses sold per year in Germany. In North America, 14.6 complaints were documented for every 2.4 million doses sold annually. Those data suggest that the extract was safe for most users.

Hypersensitivity or rash, gastrointestinal symptoms, and symptoms of the nervous system, mainly headache, were the more frequent events in both Germany and North America. A major difference existed regarding complaints about the product not working as suggested, with those complaints representing 27.8% of all cases in North America but only 0.9% in Germany. The current

Chang—ERr 731 Postmarketing Surveillance Data

Table 1. Number of Reports of AEs from the R rhaponticum Extract, ERr 731, Recorded in Germany Between July 1993 and June 2014 Organ System (Reactions) No. of Reactions (%) Hypersensitivity or rash: Rash, itching, skin irritation, etc 74 (34.4%) Gastrointestinal symptoms: Diarrhea, nausea, cramps, abdominal pain, bloating, etc 47 (21.9%) Symptoms in nervous system: Headache, confusion, drowsiness, change in taste, etc 23 (10.7%) General symptoms and administration-site conditions: Edema, hot flushes, sweating, 21 (9.8%) chills, weakness, etc Investigations: Increased pulse rate, changes in blood pressure, weight gain, increased liver 13 (6.0%) values, etc Psychiatric symptoms: Sleep disorders, depression, restlessness, anxiety, self-doubt 8 (3.7%) Reproductive system and breast symptoms: Chest pain/discomfort, swollen breasts, spotting, etc 8 (3.7%) Metabolism-related symptoms: Water accumulation, loss of appetite 6 (2.8%) Respiratory symptoms: Allergic cold, impaired respiration 4 (1.9%) Eye symptoms: Itching, swelling, watering eyes 3 (1.4%) Heart symptoms: Palpitations, circulatory disorder 3 (1.4%) No effect 2 (0.9%) Ear and labyrinth symptoms: Tinnitus 1 (0.5%) Vascular symptoms: Thrombosis 1 (0.5%) Musculoskeletal: Connective tissue and bone symptoms—muscle and joint stiffness 1 (0.5%) Total 215 (100%) Abbreviation: AEs, adverse events.

Table 2. Consumers’ Complaints Related to Physical Responses in North America Between January 2009 and June 2014 Type of Complaint Gastrointestinal symptoms: Diarrhea, nausea, cramps, abdominal pain, bloating Failure to work as suggested

Cases (%) 23 (29.1%) 22 (27.8%)

Symptoms of the nervous system: Headache, bad taste in mouth Hypersensitivity/rash: Rash, itching, skin irritation Reproductive system and breast symptoms: Bleeding, pelvic congestion, vaginal rash Heart symptoms: Heart or chest palpitation Unexplained Metabolism related symptoms: Swelling in extremities Neoplasms; benign, malignant, and unspecified: Endometrial cancer Respiratory symptoms: Shortness of breath Hair loss Total

9 (11.4%) 8 (10.1%) 7 (8.9%) 4 (5.1%) 2 (2.5%) 1 (1.3%) 1 (1.3%) 1 (1.3%) 1 (1.3%) 79 (100%)

research team concluded that the nature of the databases contributed to that discrepancy. The German data came from reports specifically about AEs, whereas the North American data represented complaints for any reason upon consumption. For instance, one consumer reported that the product was not working as suggested even though she had used the product for only a short period.

That example illustrates one of the complicated issues that postmarketing surveillance faces when different reporting methods are used for the same herbal compound.

For the common gastrointestinal symptoms, many users suspected that lactose intolerance might have attributed to

Chang—ERr 731 Postmarketing Surveillance Data

their symptoms. However, the extract contained only 0.046 g/tablet of lactose, and research has suggested that even those with diagnosed lactose intolerance are able to tolerate foods containing 6 g of lactose.16 Therefore, it remains unclear whether lactose intolerance was the cause.

Another explanation, especially for symptoms regarding the stomach, could be the time of ingestion. The tablets with the extract have an enteric coating because the active ingredients can irritate the stomach lining. That protection is pH dependent and works only when no food is in the stomach.

The serious case recorded in Germany involved a hospital stay due to a sharp increase in liver enzymes, with

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serious toxic parenchymal damage to the liver of the patient. The product was discontinued. Viral hepatitis, autoimmune hepatitis, and alcohol abuse were excluded as potential causes. No other information on the patient was provided to the MAH by the reporting physician. Therefore, the causality for the case was not assessable. A literature search in MEDLINE was performed for comparable cases associated with the extract, R rhaponticum, or its individual components, but no liver toxicity cases were identified. One publication by Raal et al17 reported that extracts of R rhaponticum had exerted hepatoprotective effects in mice that were similar to those of transresveratrol, based on inhibition of the oxidation of the polyunsaturated fatty acids in the liver.

The serious case reported in North America involved a 53-year-old woman who was diagnosed with endometrial cancer after taking the extract for less than 1 year. Age is one of the main risk factors for endometrial cancer. That risk increases among those older than 50 years.18 Other risk factors include genetic predisposition, overweight, a high-fat diet, nulliparity, early menarche, or estrogen therapy that was unopposed by progesterone therapy.18 For the case in the current study, the degree to which other risk factors influenced the diagnosis was not known. The benefit/risk ratio of the extract has been continuously monitored, and no comparable cases have been found, neither from spontaneous reporting nor from the scientific literature so far. Given the selective ER-β agonistic activity and the lack of ER-α affinity of the extract in endometrial and breast tissues, a relationship between the development of endometrial cancer and the intake of the extract in the current case seems unlikely. Presumably, other factors have contributed to that reported AE. Spontaneous reporting captures postmarketing safety information that is more diverse than that generated from a clinical trial, which tests a relatively small group of selected participants in a more controlled environment for a fixed duration. However, unlike in clinical trials where all AEs are recorded, underreporting is a well-known limitation of spontaneous reporting.19 Many consumers believe that natural health products such as the extract of R rhaponticum are natural and do not involve risks, thereby failing to identify and report any adverse reactions that occur. Some health care providers consider AE reporting to be burdensome, especially if the symptoms are not serious; lack the awareness or knowledge as to how or where to report; or do not have the resources even to identify suspected AEs. Further, incomplete data gathering makes it difficult to assess causality.20 Missing information on treatment duration in many AE reports also precluded the assessment of the long-term safety of the extract. Often the symptoms that are reported as AEs were ones that are typical for menopause (eg, headache, sleep disturbance, or breast pain) or had nothing to do with either the extract or

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menopause. The latter were mostly due to an increased awareness of and attentiveness to body changes during the transitional period of menopause.

Another limitation was that the prevalence or incidence rates of AEs could not be precisely calculated because the prescription data and the number of women using the extract had not been reported in Germany. Nevertheless, because very few surveillances of postmarketing safety related to consumption of herbal supplements are published in peer-reviewed literature, the current research team believed that it was valuable as an alternative safety indicator to publish the number of AE reports related to the extract in relationship to the amount sold. Without ongoing postmarketing monitoring, health officials and consumers would not be able to identify any signal that warrants a safety re-evaluation of a marketed natural health product.

That monitoring is especially important for the extract of R rhaponticum, a product that is intended to be used by perimenopausal and postmenopausal women, many with chronic health conditions who may consume natural products for an extended period for relief of menopausal symptoms.

Conclusions Approximately 140 million daily doses of products using the extract of R rhaponticum, ERr 731, were placed on the German market from July 1993 to June 2014, and within that period, 124 predominantly nonserious AE reports were documented. Approximately 13 million tablets of supplements using the extract had been sold in North America and South Africa from the product’s launch up to June 2014, and 79 complaints from consumers, including 1 serious AE, had been recorded. Thus, the incidence of AEs can be considered to be very low.

However, the limitation of underreporting cannot be overlooked and, thus, data should be interpreted with caution. The current study’s analysis of data from postmarketing surveillance and consumers’ complaints have suggested that dietary supplements incorporating the extract of R rhaponticum are safe for consumption.

Author Disclosure Statement J. Chang and M. B. Montalto are employees of Metagenics, Inc, the distributor of ERr 731 in North America and South Africa. P. W. Heger is director of Health Research Services, a Contract Research Organization providing special services for ERr 731. E. Thiemann is the Qualified Person for Pharmacovigilance of Dr. Loges + Co. GmbH, the marketing authorization holder of femi-loges in Germany. R. Rettenberger is director of Chemisch-Pharmazeutische Fabrik Göppingen, the manufacturer of ERr 731. J. Wacker declares no conflict of interest.

References 1. Heger M, Ventskovskiy BM, Borzenko I, et al. Efficacy and safety of a special extract of Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric complaints: A 12-week randomized, double-blind, placebocontrolled trial. Menopause. 2006;13(5):744-759.

2. Wober J, Moller F, Richter T, et al. Activation of estrogen receptor-beta by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds. J Steroid Biochem Mol Biol. 2007;107(3-5):191-201.

Chang—ERr 731 Postmarketing Surveillance Data

3. Moller F, Zierau O, Jandausch A, et al. Subtype-specific activation of estrogen receptors by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds in U2OS human osteosarcoma cells.

Phytomedicine. 2007;14(11):716-726.

4. Papke A, Kretzschmar G, Zierau O, Kaszkin-Bettag M, Vollmer G. Effects of the special extract ERr 731 from Rheum rhaponticum on estrogen-regulated targets in the uterotrophy model of ovariectomized rats. J Steroid Biochem Mol Biol. 2009;117(4-5):176-184.

5. Keiler AM, Papke A, Kretzschmar G, Zierau O, Vollmer G. Long-term effects of the rhapontic rhubarb extract ERr 731(R) on estrogen-regulated targets in the uterus and on the bone in ovariectomized rats. J Steroid Biochem Mol Biol.

2012;128(1-2):62-68.

6. Kaszkin-Bettag M, Ventskovskiy BM, Solskyy S, et al. Confirmation of the efficacy of ERr 731 in perimenopausal women with menopausal symptoms.

Altern Ther Health Med. 2009;15(1):24-34.

7. Hasper I, Ventskovskiy BM, Rettenberger R, et al. Long-term efficacy and safety of the special extract ERr 731 of Rheum rhaponticum in perimenopausal women with menopausal symptoms. Menopause. 2009;16:(1)117-131.

8. Kaszkin-Bettag M, Beck S, Richardson A, Heger PW, Beer AM. Efficacy of the special extract ERr 731 from rhapontic rhubarb for menopausal complaints: A 6-month open observational study. Altern Ther Health Med. 2008;14(6):32-38.

9. Obi N, Chang-Claude J, Berger J, et al. The use of herbal preparations to alleviate climacteric disorders and risk of postmenopausal breast cancer in a German case-control study. Cancer Epidemiol Biomarkers Prev. 2009;18(8):2207-2213.

10. US Food and Drug Administration. Dietary supplements: Adverse event reporting. http://www.fda.gov/Food/DietarySupplements/ ReportAdverseEvent/default.htm. Accessed April 20, 2016.

11. Health Canada. Adverse reaction and medical device problem reporting. http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/index-eng.php.

Accessed April 20, 2016.

12. International Council for Harmonisation. ICH Guidelines E2A; Clinical safety data management: Definitions and standards for expedited reporting. http:// www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html.

Accessed June 2, 2016.

13. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf. 1994;10(2):93-102.

14. International Council for Harmonisation. ICH Guidelines E2B(R3); Clinical safety data management: data elements for transmission of individual case safety reports. http://www.ich.org/products/guidelines/efficacy/article/ efficacy-guidelines.html. Accessed June 2, 2016.

15. Pal SK, Shukla Y. Herbal medicine: Current status and the future. Asian Pac J Cancer Prev. 2003;4(4):281-288.

16. Hertzler SR, Huynh BC, Savaiano DA. How much lactose is low lactose? J Am Diet Assoc. 1996;96(3):243-246.

17. Raal A, Pokk P, Arend A, et al. Trans-resveratrol alone and hydroxystilbenes of rhubarb (Rheum rhaponticum L.) root reduce liver damage induced by chronic ethanol administration: A comparative study in mice. Phytother Res. 2009;23(4):525-532.

18. Cramer DW. The epidemiology of endometrial and ovarian cancer. Hematol Oncol Clin North Am. 2012;26(1):1-12.

19. Lopez-Gonzalez E, Herdeiro MT, Figueiras A. Determinants of underreporting of adverse drug reactions: A systematic review. Drug Saf. 2009;32(1):19-31.

20. Lindquist M. Data quality management in pharmacovigilance. Drug Saf. 2004;27(12):857-870.

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CASE STUDY

The Effectiveness of Neural Therapy in Patients With Bell’s Palsy Ferdi Yavuz, MD; Bayram Kelle, MD; Birol Balaban, MD

Abstract This report describes the case of a 42-y-old man with a type of facial nerve palsy of the lower motor neurons (LMNs) on the right side, who was treated with neural therapy. After exposure to cold weather, the patient had

Ferdi Yavuz, MD, is specialist of physical medicine and rehabilitation at the Clinic of Physical Therapy and Rehabilitation, Fizyocare Medical Center, in Ankara, Turkey. Bayram Kelle, MD, is an assistant professor in the Department of Physical Therapy and Rehabilitation, Faculty of Medicine, Cukurova University, in Adana, Turkey. Birol Balaban, MD, is a professor in the Clinic of Physical Therapy and Rehabilitation, Fizyocare Medical Center, and in the Department of Physical Therapy and Rehabilitation, Faculty of Health Sciences, European University of Lefke, in Lefke-Mersin, Turkey.

Corresponding author: Ferdi Yavuz, MD E-mail address: ferdiyavuz@yahoo.com

T

his report describes the case of a 42-year-old man with a type of facial nerve palsy of the lower motor neurons (LMNs) on the right side, who was treated with neural therapy. After exposure to cold weather, the patient had suddenly developed difficulty in closing his right eye and a deviation to the left in the angle of his mouth. He had no previous medical illness and had no history of trauma, smoking, alcohol intake, or blood transfusion.

Examination of his other cranial nerves showed that they were normal, and he had no cerebellar signs.

Magnetic resonance imaging (MRI) of the brain was completed and did not reveal any obvious abnormality.

Serological tests for various infectious agents, including

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suddenly developed difficulty in closing his right eye and a deviation to the left in the angle of his mouth. He had no previous medical illness and had no history of trauma, smoking, alcohol intake, or blood transfusion.

antibody tests for the syphilis antibody, Lyme (borreliosis) immunoglobulin M (IgM), and Epstein-Barr virus capsid antigen IgM, were all negative. After a differential diagnosis had ruled out any secondary causes of facial nerve palsy (Table 1),1 the patient was diagnosed with Bell’s palsy by a neurologist.

Treatment with steroids and antiviral drugs had been prescribed within 72 hours of the onset of the patient’s Bell’s palsy. He had taken the drugs for 21 days without any improvement. After the medical treatment, he was referred to physiotherapy. Physiotherapy with exercise and electrostimulation for a total of 21 sessions for a period of 4 consecutive weeks provided no clinical improvement.

Six weeks after the onset of the Bell’s palsy, the patient was diagnosed with the LMN type of facial nerve palsy on the right side (Figure 1). His facial nerve function was measured as a having a House-Brackmann score of grade 4, which reflects a moderate-to-severe dysfunction (Table 2).2 Six sessions with neural therapy were performed at the authors’ outpatient clinic, with sessions 3 times per week for 1 week and then 1 time per week for 3 weeks. All of the 6 sessions took place, therefore, within a period of 4 weeks. No adverse events or side effects occurred.

During each neural-therapy session, subcutaneous injections were performed using a 5-mL syringe with a 25-gauge, 1-inch (2.5-cm) needle. The deep autonomic ganglia injection in each session used a 5-mL syringe with a 27-gauge, 2-inch (5-cm) needle. The injections were performed on the affected hemi face.

The subcutaneous injections were carried out along the 5 branches of the facial nerve. The deep ganglia injections were carried out for the autonomic ganglia of

Yavuz—Neural Therapy in Bell’s Palsy

Table 1. Causes of Secondary, Unilateral Facial Nerve Palsy Types of Causes Examples Metabolic Disease

x Diabetes x Preeclampsia

Stroke

x Ipsilateral pontine infarction x Pontine tegmental hemorrhage

Infection

x Hansen’s disease (leprosy) x Otitis media x Mastoiditis x Herpes simplex infection x Varicella zoster infection x Ramsey–Hunt syndrome x Influenza viruses x Borreliosis x Cryptococcosis x Neurocysticercosis x Toxocariasis x Tuberculous meningitis x Parotitis and parotid abscess x Malignant external otitis x Syphilis

Surgery

x Removal of cerebellopontine angle tumors

Trauma

x Head trauma (crush injury) x Birth injury

Tumor

x Facial nerve neurinoma x Cerebellopontine angle tumors (neurinoma) x Pons tumor x Tumors of the petrosal bone x Tumors of the middle ear x Leucemia x Tumors of the parotid gland x Lymphoma

Immune System Disorder

x Guillain–Barré syndrome x Miller–Fisher syndrome x Systemic lupus erythematodes x Myasthenia gravis

Drugs

x Interferon x Linezolid

Other Causes

x Moebius syndrome x Melkersson–Rosenthal syndrome x Sarcoidosis x Histiocytosis X x Autism x Asperger’s syndrome x Parkinson syndrome

Yavuz—Neural Therapy in Bell’s Palsy

Figure 1. Examination of Facial Nerve Function Before Neural Therapy A

B

Note: Figure 1A shows inability to lift his right eyelid and Figure 1B shows drooping corner of mouth and loss of nasolabial fold on his right side.

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41

Table 2. House-Brackmann Scores HBS Grade 1

x Normal, symmetrical function in all areas

2

x Slight weakness on close inspection x Complete eye closure with minimal effort x Slight asymmetry of smile with maximal effort x Slight synkinesis, absent contracture or spasm

3

x Obvious weakness but not disfigurement x Inability to lift eyebrow x Complete and strong eye closure x Asymmetrical mouth movement with maximal effort x Obvious but not disfiguring synkinesis x Mass movement, spasms

4

x Obvious disfiguring weakness x Inability to lift brow x Incomplete eye closure x Asymmetry of mouth with maximal effort x Severe synkinesis x Mass movement, spasms

5

x Motion barely perceptible x Incomplete eye closure x Slight movement at corner of mouth x Synkinesis x Contracture x Usually absence of spasm

6

x No movement x Loss of tone x No synkinesis x Contracture x Spasm

Abbreviation: HBS, House-Brackmann score.

oticum and pterygopalatinum. A total of 10 mL of a solution consisting of 0.4% lidocaine was used for each subcutaneous injection, and 2 to 3 mL of a solution consisting of 1% procaine was used for the infiltration of the autonomic ganglia. After the 6 neural therapy sessions, the patient’s House-Brackmann score was grade 1, which describes a normal, symmetrical function in all areas (Figure 2). Since the treatments occurred, the patient has been asymptomatic, and no recurrence has been noted during his follow-up visits.

A unilateral, peripheral, facial nerve palsy may have a detectable cause (ie, may be a secondary facial nerve palsy) or may be idiopathic (ie, primary, without an

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Figure 2. Examination of Facial Nerve Function After Neural Therapy A

B

Note: Figure 2A shows the patient can lift his right eyelid and Figure 2B shows the patient can move his mouth symmetrically. There is no sign with drooping corner of mouth and loss of nasolabial fold.

obvious cause, such as Bell’s palsy).3-5 Secondary facial nerve palsy can be due to various causes (Table 1) and is generally less prevalent than Bell’s palsy at 25% versus 75%,6 respectively. Bell’s palsy was first described by Friedreich7 in 1974 and is a diagnosis of exclusion.8 In the treatment of Bell’s palsy, many therapies consist of corticosteroids, antiviral agents, exercise physiotherapy, electrostimulation, and surgical decompression.

Corticosteroids and antivirals are strongly recommended in the guideline for patients with Bell’s palsy. No recommendations have been made regarding offering exercise physiotherapy for acute facial nerve palsy of any severity. However, exercise physiotherapy is weakly

Yavuz—Neural Therapy in Bell’s Palsy

recommended for patients with persistent facial muscle weakness.9 The use of electrostimulation is also weakly recommended for patients with Bell’s palsy of any severity.9 Facial nerve palsy can take up to 1 year to improve.10 Patients with incomplete palsy have a better prognosis than patients with complete palsy.11 Without treatment, the prognosis for complete Bell’s palsy is generally fair, but approximately 20% to 30% of the patients are left with varying degrees of permanent disability.5,8,12 Approximately 80% to 85% of patients recover spontaneously and completely within 3 months, whereas 15% to 20% experience some kind of permanent nerve damage.12 Neural therapy is an injection treatment that is designed to repair the dysfunction of the autonomic nervous system and shows its effects by correcting the electrical condition of cells and nerves. Thus, the bioelectric disturbance at a specific site or nerve ganglion can be restored to normality. In neural therapy, local anesthetics, usually procaine or lidocaine, are used. Neural therapy involves the injection of local anesthetics into peripheral nerves, autonomic ganglia, scar tissues, endocrine glands, acupuncture points, trigger points, and other tissues.13 Some clinical trials and case reports have shown that neural therapy could be an effective treatment for relieving pain and improving functional loss or disability for patients with various disorders.14-16 However, the effectiveness of neural therapy is still in question.17,18 Conclusion The authors believe that this case review is the first description of the effectiveness of neural therapy for patients with Bell’s palsy. In the current case, the neural therapy was used as an alternative treatment, which worked very well for the patient’s recovery from Bell’s palsy.

Yavuz—Neural Therapy in Bell’s Palsy

Author Disclosure Statement The authors declare that they have no conflicts of interest.

References 1. Finsterer J. Management of peripheral facial nerve palsy. Eur Arch Otorhinolaryngol. 2008, 265(7):743-752.

2. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck Surg. 1985;93(2):146-147.

3. Kawiak W, Dudkowska A, Adach B. Diagnostic difficulties in etiology of the lesion of peripheral neuron of the facial nerve during the growth of sialoma.

Ann Univ Mariae Curie Sklodowska. 1993;48:125-128.

4. Peitersen E. Bell’s palsy: The spontaneous course of 2,500 peripheral facial nerve palsies of different etiologies. Acta Otolaryngol Suppl. 2002;549:4-30.

5. Shaw M, Nazir F, Bone I. Bell’s palsy: A study of the treatment advice given by neurologists. J Neurol Neurosurg Psychiatry. 2005;76(2):293-294.

6. Peitersen E. Bell’s palsy: The spontaneous course of 2,500 peripheral facial nerve palsies of different etiologies. Acta Otolaryngol Suppl. 2002;549:4-30.

7. Wolf SR. Idiopathic facial paralysis. HNO. 1998;46(9):786-798.

8. Axelsson S, Lindberg S, Stjernquist-Desatnik A. Outcome of treatment with valacyclovir and prednisone in patients with Bell’s palsy. Ann Otol Rhinol Laryngol. 2003;112(3):197-201.

9. de Almeida JR, Guyatt GH, Sud S, et al. Management of Bell palsy: Clinical practice guideline. CMAJ. 2014;186(12):917-922.

10. Atzema C, Goldman RD. Should we use steroids to treat children with Bell’s palsy? Can Family Physician. March 2006;52:313-314.

11. Adour KK, Wingerd J. Idiopathic facial paralysis (Bell’s palsy): Factors affecting severity and outcome in 446 patients. Neurology. 1974;24(12):1112-1116.

12. Slavkin HC. The significance of a human smile: Observations on Bell’s palsy.

JADA. 1999;130(2):269-272.

13. Nazlıkul H. In: Nazlıkul H, ed. Nöralterapi Teknikleri ve Bozucu Alan Terapisi.

Nöralterapi, Turkey: Nobel Tıp Kitabevleri; 2010.

14. Weinschenk S, Brocker K, Hotz L, Strowitzki T, Joos S; HUNTER (Heidelberg University Neural Therapy Education and Research) Group. Successful therapy of vulvodynia with local anesthetics: A case report. Forsch Komplementmed.

2013;20(2):138-143.

15. Hui F, Boyle E, Vayda E, Glazier RH. A randomized controlled trial of a multifaceted integrated complementary-alternative therapy for chronic herpes zoster-related pain. Altern Med Rev.2012;17(1):57-68.

16. Atalay NS, Sahin F, Atalay A, Akkaya N. Comparison of efficacy of neural therapy and physical therapy in chronic low back pain. Afr J Tradit Complement Altern Med. 2013;10(3):431-435.

17. Brobyn TL, Brobyn TL, Chung MK, LaRiccia PJ. Neural therapy: An overlooked game changer for patients suffering chronic pain?. J Pain Relief.

2015;4:184.

18. Weinschenk S. Neural therapy—A review of the therapeutic use of local anesthetics. Acupunct Related Ther. 2012;1:5-9.

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CASE REPORT

Chronic Rhinosinusitis and Irritable Bowel Syndrome: A Case Report Mikhail Kogan, MD; Carlos Cuellar Castillo, MS; Melissa S. Barber, MS

Abstract Introduction: Chronic rhinosinusitis (CRS) and irritable bowel syndrome (IBS) can be comorbidities that are difficult to treat. In this patient, an evidenceinformed treatment pathway guided by laboratory biomarkers was used to address both conditions.

Case Presentation: A 69-y-old female patient presented with a 50-y history of sinusitis that was worse in the winter, postnasal drip, frequent sore throats, gastrointestinal complaints, headaches, and yeast

Mikhail Kogan, MD, is medical director at George Washington University, G. W. Center for Integrative Medicine, in Washington, DC. Carlos Cuellar Castillo, MS, is a graduate of the physiology master of science program and complementary and alternative medicine at Georgetown University, in Washington, DC. Melissa S. Barber, MS, is at Helfgott Research Institute, National University of Natural Medicine, in Portland, Oregon.

Corresponding author: Mikhail Kogan, MD E-mail address: mkogan@gwcim.com

C

hronic rhinosinusitis (CRS) and irritable bowel syndrome (IBS) are common in the United States and microbiome alterations are associated with both conditions.1–4 CRS affects approximately 1 in 8 adults in the United States and is often associated with seasonal exacerbations.5 IBS affects approximately 1 in 10 adults in North America and can be associated with pancreatic insufficiency and food sensitivities—two conditions often untreated in primary care.6,7,8 The 2014 “American College of Gastroenterology Monograph on the Management of Irritable Bowel Syndrome and Chronic Idiopathic Constipation” discussed the prevalence and treatments of IBS and the absence of reliable laboratory biomarkers.9 This case demonstrated the use of laboratory biomarkers for pancreatic insufficiency and food sensitivities for treatment of both

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Integrative Medicine • Vol. 15, No. 3 • June 2016

infections. Two sinus surgeries (in years 2000 and 2002) and multiple courses of antibiotics had not resolved her sinus symptoms. In addition to CRS and IBS, this patient was noted to have intestinal overgrowth of Candida albicans, multiple food sensitivities, and leaky gut syndrome.

Conclusion: Antifungal medication and dietary changes in the course of 8 mo resulted in the resolution of her CRS and IBS.

CRS and IBS. A timeline of the patient’s medical history and course of care is described in Table 1.

Patient Information A 69-year-old female patient with a 50-year history of gastrointestinal (GI) and sinus symptoms (worse in the winter) was self-referred to the George Washington Center for Integrative Medicine in February 2011. Ten years earlier, in 2000 and 2002, she had sinus surgery that did not relieve her symptoms.

She also experienced frequent fatigue, disturbed sleep, headaches, sore throats, runny nose, and chronic cough, and she had a history of recurrent vaginal and intestinal symptoms consistent with overgrowth of Candida albicans several times per year. Her diet consisted of freshly prepared foods with some sensitivity to cheese and yogurt (which she avoided). Despite osteoarthritis in both knees, she walked 3.5 miles (5.6 km) daily and regularly played tennis. The patient was retired, lived at home with her dog, and had 2 adult children; she reported no known toxic exposures at home.

She had previously been diagnosed with ovarian cancer with surgery in 2007 and chemotherapy in 2008, which exacerbated her CRS and IBS symptoms. Patient medications at her initial visit included azithromycin for CRS and vitamin D3 supplementation. She had begun taking a selfprescribed dietary supplement—broccoli seed extract (OncoPLEX ES from Xymogen, Orlando, FL, USA).

Kogan—Chronic Rhinosinusitis and IBS

Table 1. Timeline of Patient’s Medical History and Course of Care Relevant Medical History 50-y history of CRS and multiple GI symptoms consistent with IBS. Previous treatments included antibiotics and 2 unsuccessful sinus surgeries (in years 2000 and 2002). Other health problems included food sensitivities, chronic vaginal and intestinal yeast overgrowth, osteoarthritis, and ovarian cancer (surgery in 2007 and chemotherapy in 2008).

Patient Visits

Chief Complaints

Sinusitis/postnasal drip Visit 1: Multiple GI 02/2011 symptoms Osteoarthritis

Sinusitis/postnasal drip Visit 2: Multiple GI 03/2011 symptoms Osteoarthritis Improving sinusitis/postnasal Visit 3: drip 04/2011 Improving GI symptoms Osteoarthritis

Resolving sinusitis Visit 4: Resolving GI 07/2011 symptoms Osteoarthritis

Visit 5: 09/2011 2-y Followup: 03/2013

CRS and GI symptoms resolved Osteoarthritis Sinus and IBS symptoms flare with increased sugar in diet Osteoarthritis

Laboratory Biomarkers CDSA 2.0: C albicans: 2+ Low pancreatic elastase and β-glucuronidase IgG FAA: Multiple food sensitivities

—

Diagnostic Significance

CRS IBS Intestinal overgrowth of C albicans Multiple food sensitivities Leaky gut syndrome (increased intestinal permeability) Chronic yeast infection

—

CDSA 2.0 C albicans: 0 Normal pancreatic elastase and β-glucuronidase levels IgG FAA: Few food sensitivities —

—

Recommendations and Interventions Continue azithromycin, vitamin D3, OncoPLEX ES Begin fish oil, Zyflamend, BCQ, Mushroom Mix, raw garlic, nasal lavage Stop OncoPLEX ES, Zyflamend, BCQ, Mushroom Mix, raw garlic Continue fish oil, nasal lavage, azithromycin, vitamin D3 Begin nystatin; GI Revive; probiotics; yeast-free, antiinflammatory diet Stop azithromycin Continue nystatin; GI Revive; probiotics; yeast-free, antiinflammatory diet; fish oil; nasal lavage; vitamin D3 Begin Zyflamend

Resolved CRS, overgrowth of C albicans, Stop nystatin, GI revive, leaky gut Zyflamend syndrome, Continue probiotics; yeast-free, yeast infection anti-inflammatory diet; fish oil; Few food nasal lavage; vitamin D3 sensitivities Resolving IBS

—

Continue probiotics; yeast-free, anti-inflammatory diet; fish oil; nasal lavage; vitamin D3

CRS and GI symptoms under Resume (continue) yeast-free, good control with anti-inflammatory diet attention to diet

Abbreviations: CRS, chronic rhinosinusitis; GI, gastrointestinal; IBS, irritable bowel syndrome; CDSA, comprehensive digestive stool analysis; IgG, immunoglobulin G; FAA, F-actin antibody.

Kogan—Chronic Rhinosinusitis and IBS

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Figure 1. IgG Food Antibody Assessment, February 2011 and July 2011 High

Reactivity

Moderate

Low 02/22/2011 07/04/2011

Very Low

None Detected 0

20

40 60 Number of Reactive Foods

80

100

Abbreviation: IgG, immunoglobulin G.

Clinical Findings Her physical exam was remarkable for boggy turbinates and postnasal drip.

Diagnostic Assessment Comprehensive Digestive Stool Analysis (CDSA) 2.0 (Genova Diagnostics, Asheville, NC, USA) revealed potentially pathogenic levels of C albicans and low levels of pancreatic elastase 1 and β-glucuronidase, supporting a diagnosis of dysbiosis (Appendix 1). An IgG Food Antibody Assessment (Genova Diagnostics) revealed moderate to high reactivity to several different foods, indicative of multiple immunoglobulin G (IgG) food sensitivities. Her symptoms were suggestive of leaky gut syndrome (Figure 1; Appendix 1). Her vitamin D level was 28.4 ng/mL (low). She was diagnosed with CRS, IBS, overgrowth of C albicans, multiple food sensitivities, and leaky gut syndrome.

Therapeutic Interventions and Follow-up This patient had 5 visits in 8 months and received therapeutic interventions—antifungal medication, nutritional, and dietary supplements—guided by laboratory testing (Table 1 and Table 2).

At the third visit (April 2011), the patient was much improved and grains, fruit, and dairy were gradually reintroduced. In June 2011, a repeat stool test showed resolution of C albicans overgrowth and improved pancreatic elastase 1 levels (increase from 121 mg/g to 273 mg/g) and β-glucuronidase levels (increase from 367 U/g to 1475 U/g) (Appendix 1) and the nystatin was discontinued in July 2011. Repeat IgG F-actin antibody

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(FAA) results (Figure 1) revealed a nearly 4-fold decrease in the number of highly reactive foods and a 30-fold increase in nonreactive foods—suggestive of normalized intestinal permeability. At her fourth and fifth visits, the patient continued to improve and noted resolution of her CRS and IBS symptoms as well as an increase in energy. In September of 2011, she was instructed to continue with the yeast-free, anti-inflammatory diet, nasal lavage, probiotics, fish oil, and vitamin D3 (Table 1).

The patient was seen in March 2013 after noting relapse of some of her CRS and IBS symptoms, which she attributed to increased sugar consumption and dietary indiscretions. She was counseled to continue on the yeastfree, anti-inflammatory diet as much as possible—to which she adhered.

Patient Perspective I am a very active person and enjoy playing tennis and gardening. My symptoms prior to coming to George Washington (GW) Center for Integrative Medicine prevented me from participating in the leisure activities that I enjoy. The quality of my sleep and my overall quality of life were not good. After coming to the GW Center for Integrative Medicine all of my symptoms improved and I experienced a drastic improvement in my quality of life.

I did not follow an “Elimination Diet” per se, but rather was instructed to follow a diet with foods to avoid based on my testing. I experienced a relapse of my sinus symptoms when I deviated too much from the diet, but am now able to control the symptoms by adjusting my diet accordingly.

Kogan—Chronic Rhinosinusitis and IBS

Table 2. Prescribed Interventions in Course of Care Intervention

Information

Rationale

Antifungal Medication Nystatin

1 million units, PO, BID, ×4 mo

CRS, IBS, chronic yeast infections

Dietary Supplements Fish oil supplement

1 teaspoon (4.93 mL) Improve gut function and (Liquid 3:1, EPA:DHA – Genestra) (liquid), PO, QD reduce inflammation

Rosmarinus officinalis, Curcuma longa, Zingiber officinale, 2 capsules, PO, QD, Ocimum sanctum, Camellia sasanqua, Polygonum ×1 mo californicum, Coptis chinensis, Berberis vulgaris, Origanum vulgare, Scutellaria baicalensis (Zyflamend – New Chapter)

CRS, pain

Boswellia serrata, Bromelain, C longa, quercetin 1–3 capsules, PO, (BCQ – Vital Nutrients) BID, ×1 mo

IBS, pain

Mushroom Mix

IBS, leaky gut syndrome

2 capsules, PO, BID, (My Community – Host Defense) ×1 mo

7.5 g in water, PO, L-Glutamine, N-acetyl glucosamine, citrus pectin, QD, ×4 mo Glycyrrhiza glabra, Aloe barbadensis, Ulmus pumila, mucin, Althea officinalis, Matricaria chamomilla, Abelmoschus esculentus, Uncaria tomentosa, methylsulfonylmethane, quercetin, prune powder, zinc (GI-Revive – Designs for Health)

IBS, leaky gut syndrome

Probiotic: Saccharomyces boulardii lyo 1 capsule, PO, BID, (FloraMyces – Designs for Health) ×6 mo 1 capsule, PO, BID, Probiotic: Lactobacillus acidophilus (CUL-60 and CUL×6 mo 21), Bifidobacterium bifidum (CUL-20), Bifidobacterium animalis subsp. lactis (CUL-34), FOS (HMF Forte – Genestra)

IBS, leaky gut syndrome

Probiotic: Lactobacillus reuteri, Lactobacillus acidophilus, 1 capsule, PO, BID, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus ×2 mo salivarius, Lactobacillus brevis, Lactobacillus plantarum, Streptococcus tigurinus, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium bifidum (Therabiotic Complete – Klaire Labs) Lifestyle Nasal lavage (Neti Pot)

BID

CRS

Yeast-free, anti-inflammatory diet (See Appendix 2)

Avoid sugar 2–4 wk; grains, fruit, dairy gradually reintroduced

IBS, CRS

Abbreviations: PO, by mouth; BID, twice per day; CRS, chronic rhinosinusitis; IBS, irritable bowel syndrome; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; QD, every day; FOS, fructooligosaccharides.

Kogan—Chronic Rhinosinusitis and IBS

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Discussion and Limitations CRS- and IBS-related symptoms are commonly reported complaints by patients.5,6 A recent case-controlled study of 133 subjects found a statistically significant association between CRS and IBS (odds ratio [OR] = 17.8; 95% confidence interval [CI] = 4.9 to 64.2; P < .001).2 When CRS has been present for 50 years, it is difficult to treat— particularly in a patient with a history of unsuccessful sinus surgeries and antibiotic use. Smith et al10 estimated direct and indirect costs for CRS in the United States at more than $20 billion in 2014. In addition to sinus surgery and antibiotics, the medical management of CRS commonly includes steroids and nasal lavage with saline.11 More than 1 in 5 antibiotic prescriptions are for treating acute and chronic rhinosinusitis.12 Antibiotics often provide little benefit, contribute to the occurrence of adverse events, alter the microbiome, and contribute to antibiotic resistance.13,14 Dietary supplements and nutritional recommendations have some evidence in treating CRS15—long-chain polyunsaturated fatty acids (LCPUFAs) may be helpful to patients with CRS that are refractory to treatment with antibiotics.16,17 Such LCPUFAs include docosahexaenoic acid (DHA) and arachidonic acid (ARA), found in fish oil or DHA/ARA-enriched foods.

IBS is both prevalent and costly with the annual cost burden of IBS estimated at more than $20 billion.6 IBS may be associated with exocrine pancreatic insufficiency and overgrowth of C albicans.7,18 Although Candida is part of a normal gut microbiome, increased levels may be associated with inflammation of the GI tract.18 Food sensitivities associated with food-specific IgG antibodies and IBS have been shown to have a response to elimination diets.19 Dietary changes, such as a low FODMAP diet or an IBS-specific diet, have also been shown to reduce IBS symptoms and food sensitivities and to improve nutritional status.20,21 A multistrain probiotic has been shown to improve the symptom severity of IBS and quality of life scores after 8 weeks in patients with IBS.19 A single case using an individualized approach with multiple interventions may have limited applicability to a broader population of patients. This patient’s IBS was diagnosed based on the patient’s self-reported symptoms without using the Rome criteria or a validated IBS quality of life scale. However, this case demonstrates that specific laboratory biomarkers can guide individualized treatment.

In this case, addressing biomarker imbalance associated with pancreatic insufficiency and food sensitivities may have led to the resolution of CRS and IBS in this patient.

Conclusion This case reports presents a cost-effective, successful treatment of a patient with chronic CRS and IBS using laboratory biomarkers to guide treatment that included dietary recommendations, antifungal medication, and nutritional supplements. Structured stool and IgG testing reduced the overall cost of diagnosis and guided

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management of this patient. The testing linked laboratory biomarker abnormalities with therapeutic interventions and outcomes, strengthening the association of specific laboratory biomarkers abnormalities and the diagnosis of IBS and CRS. This case offers testable hypotheses for future research to evaluate the effect of structured stool testing and IgG antibody testing to guide therapeutic interventions and improve patient outcomes.

Acknowledgements This case report was prepared according to the CARE guidelines. Genova Diagnostics provided an unrestricted medical writing grant to assist with the preparation of this manuscript.

Author Disclosure Statement Written consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review.

References 1. Lam K, Schleimer R, Kern RC. The etiology and pathogenesis of chronic rhinosinusitis: A review of current hypotheses. Curr Allergy Asthma Rep. 2015;15(7):41.

2. Darweesh M. PWE-240 Relationship between irritable bowel syndrome and chronic rhinosinusitis: A case control study. Gut. 2015;64(Suppl 1):A317.2-A318.

3. Salonen A, De Vos WM, Palva A. Gastrointestinal microbiota in irritable bowel syndrome: Present state and perspectives. Microbiology.

2010;156(11):3205-3215.

4. Carroll IM, Ringel-Kulka T, Siddle JP, Ringel Y. Alterations in composition and diversity of the intestinal microbiota in patients with diarrheapredominant irritable bowel syndrome. Neurogastroenterol Motil.

2012;24(6):521-530.

5. Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for U.S. adults: National health interview survey, 2012. Vital Health Stat 10. February 2014;260:1-161.

6. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(Suppl 1):S1-S35.

7. Leeds JS, Hopper AD, Sidhu R, et al. Some patients with irritable bowel syndrome may have exocrine pancreatic insufficiency. Clin Gastroenterol Hepatol. 2010;8(5):433-438.

8. Yang C, Li Y. The therapeutic effects of eliminating allergic foods according to food-specific IgG antibodies in irritable bowel syndrome. Zhonghua nei ke za zhi. 2007;46(8):641-643.

9. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology Monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(S1):S2-S26.

10. Smith KA, Orlandi RR, Rudmik L. Cost of adult chronic rhinosinusitis: A systematic review. Laryngoscope. 2015;125(7):1547-1556.

11. Hamilos DL. Chronic rhinosinusitis: Epidemiology and medical management. J Allergy Clin Immunol. 2011;128(4):693-707.

12. Anon JB, Jacobs MR, Poole MD, et al. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg.

2004;130(Suppl 1):1-45.

13. Small CB, Bachert C, Lund VJ, Moscatello A, Nayak AS, Berger WE. Judicious antibiotic use and intranasal corticosteroids in acute rhinosinusitis.

Am J Med. 2007;120(4):289-294.

14. Piromchai P, Thanaviratananich S, Laopaiboon M. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 1996.

15. Taw MB, Nguyen CT, Wang MB. Complementary and integrative treatments: Rhinosinusitis. Otolaryngol Clin North Am. 2013;46(3):345-366.

16. Birch EE, Khoury JC, Berseth CL, et al. The impact of early nutrition on incidence of allergic manifestations and common respiratory illnesses in children. J Pediatr. 2010;156(6):902-906.

17. Linday LA, Dolitsky JN, Shindledecker RD. Nutritional supplements as adjunctive therapy for children with chronic/recurrent sinusitis: Pilot research. Int J Pediatr Otorhinolaryngol. 2004;68(6):785-793.

18. Kumamoto CA. Inflammation and gastrointestinal Candida colonization.

Curr Opin Microbiol. 2011;14(4):386-391.

19. Williams E, Stimpson J, Wang D, et al. Clinical trial: Multistrain probiotic preparation significantly reduces symptoms of irritable bowel syndrome in a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2008;29:97-103.

20. Bohn L, Storsrud S, Liljebo T, et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: A randomized controlled trial. Gastroenterology. 2015;149(6):1399-1407.

21. Yoon SR, Lee JH, Lee JH, et al. Low-FODMAP formula improves diarrhea and nutritional status in hospitalized patients receiving enteral nutrition: A randomized, multicenter, double-blind clinical trial. Nutr J. 2015;14(1):116.

Kogan—Chronic Rhinosinusitis and IBS

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Appendix 1. CDSA 2.0 Results Prior to Treatment in February of 2011 and During Treatment in July of 2011

Analyte Pancreatic elastase 1 Putrefactive SCFAs Analyte Eosinophil protein X Calprotectin Analyte Beneficial SCFASs (total) n-butyrate pH β-glucuronidase Secondary Bile Acids LCA DCA LCA/DCA ratio Beneficial Bacteria Lactobacillus species Escherichia coli Bifidobacterium Additional Bacteria α-haemolytic Streptococcus–NP γ-haemolytic Streptococcus–NP Mycology Candida albicans–potential pathogen Parasite Cryptosporidium Giardia lamblia Entamoeba histolytica/dispar Additional Tests Helicobacter pylori stool antigen Shiga toxin Escherichia coli Campylobacter Clostridium difficile Occult blood Analyte Chymotrypsin Fecal Fat Distribution Triglycerides Cholesterol LCFA Phospholipids Fecal fat (total) Metabolic Products Acetate % Propionate % n-butyrate %

Digestion/Absorption 02/25/2011 121 3.0 Gut Immunology 02/25/2011 <1.2 <16 Metabolic 02/25/2011 44.8 6.5 7.2 367 1.76 2.50 0.70 Microbiology 02/25/2011 3+ NG 2+ 02/25/2011 4+ 4+ 02/25/2011 2+ Parasitology 02/25/2011 Negative Negative Negative Negative Negative Negative Negative Negative 02/25/2011 5.1 02/25/2011 0.8 3.3 3.2 1.3 8.6 02/25/2011 56.8 28.7 14.5

07/12/2011 273 6.0

Reference Range ≥201 μg/g 1.3–8.6 μmol/g

07/12/2011 <1.1 17

Reference Range ≤7.0 μg/g ≤50 μg/g

07/12/2011 46.8 8.5 6.9 1475

Reference Range ≥13.6 μmol/g ≥2.5 μmol/g 6.1–7.9 337–4433 U/g

1.20 0.73 1.64

0.65–5.21 mg/g 0.67–6.76 mg/g 0.39–2.07

07/12/2011 NG 3+ 4+ 07/12/2011 2+ 4+ 07/12/2011 NG

Reference Range ≥2+ ≥2+ 4+

07/12/2011 Negative Negative Negative

Reference Range 0.9–26.8 U/g Reference Range 0.2–3.3 mg/g 0.2–3.5 mg/g 1.3–23.7 mg/g 0.2–8.8 mg/g 2.6–32.4 mg/g Reference Range 44.5%–72.4% ≤32.1% 10.8%–33.5%

Abbreviations: CDSA, Comprehensive Digestive Stool Analysis; SCFA, short-chain fatty acid; LCA, lithocholic acid; DCA, deoxycholic acid; NG, no growth; NP, nonpathogen; LCFA, long-chain fatty acid.

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Kogan—Chronic Rhinosinusitis and IBS

Appendix 2. Yeast-free, Anti-Candida Diet Yeast-Free Anti-Inflammatory Food Plan Trillions of healthy bacteria live in our digestive tract, making up what is called microflora. These bacteria play a supportive role in your intestines, helping to make vitamins, release natural antibiotics, and break down toxins. Candida, a yeast-like fungus, is commonly present in your intestines, and its growth is usually limited by your immune system and by your microflora.

If Candida is allowed to grow due to a weakened immune system or disease such as diabetes, the harmonious balance between it and the “good” bacteria is upset, resulting in intestinal candidiasis. Not only can this imbalance cause problems such as vaginal infections, but Candida also releases byproducts, which are subsequently absorbed into the bloodstream, exposing the whole body to a variety of symptoms as the immune system tries to fight it off. Common symptoms include fatigue, bloating, gas, diarrhea and/or constipation, recurring bladder infections, menstrual irregularities, allergies, chemical sensitivities, and depression.

What increases the risk of Candida overgrowth, also called the yeast syndrome? The following list includes the most common factors: x Repeated use of antibiotics, oral contraceptives, and/or steroids such as prednisone. x Diet high in sweets. x Alcohol. x Chronic stress. x Diabetes. x Weakened immune system.

How is candidiasis treated? A comprehensive approach is necessary to reduce the overgrowth of Candida organisms.

The risk factors listed above must be reduced as much as possible, while supporting immune, digestive, and liver function. Because yeast feeds on carbohydrates, a food plan must be followed that starves yeast of its main fuel: simple sugars. Additional support in the form of healthy bacteria (called probiotics) is also used to compete with Candida in the intestines, resulting in a rebalancing of the microflora. Sometimes, antiyeast supplements or prescriptions are used to kill the yeast.

How is candidiasis prevented? It is important to reduce as many of the above risk factors as possible to keep a healthy balance between yeast and microflora. Eating greatly reduced amounts of refined sugars and avoiding alcohol is a good place to start. It is also helpful to begin to develop a practice of mind-body techniques for stress reduction. This might include meditation/visualization, yoga, tai chi, or whatever exercise you enjoy.

How will I feel when I start this type of program? Many of the symptoms associated with candidiasis are associated with absorption of yeast breakdown products. As these yeast die off, some of these organisms are reabsorbed into the bloodstream, increasing the load the liver must filter or detoxify. It is common to experience short-term reactions to this die-off, such as headaches, abdominal bloating, muscle and joint aches, or fatigue. It is also not unusual to crave the very food yeast thrives on, such as sweets, breads, and alcohol. (For further reading about intestinal candidiasis or yeast syndrome, refer to The Yeast Connection or The Yeast Connection Handbook by William Crook, MD.) Anti-Candida Food Plan Guidelines In general, foods are restricted because of their carbohydrate (sugar) content. Peanuts and pistachios are to be avoided due to their high mold content, which can exacerbate Candida. Mushrooms are in the fungus family and may cross-react with Candida. Fermented foods (vinegars, aged cheeses) may provoke symptoms because of similarities to Candida yeasts and may also feed Candida yeasts. These modifications are usually implemented for 2–4 weeks to assess response to the program. Follow-up modifications are made on an individual basis.

Patient Handout—Chronic Rhinosinusitis and IBS

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Category

To Include

To Exclude

Fruits

Fresh/frozen, unsweetened fruit 1–2/day

Banana, pineapple, papaya; all dried fruits and juices

Eggs, dairy, & dairy replacement

Eggs; plain unsweetened yogurt (cow, sheep, or goat), with live cultures; plain, unsweetened soy, almond, or hemp milk; coconut milk; unaged cheeses (only mozzarella, cottage cheese, ricotta); fresh goat cheese (unaged)

Milk and all aged cheeses; milk substitutes that contain any sweetener

Grains

100% whole grains only (brown or wild rice, quinoa, whole oats, barley, rye, buckwheat, whole wheat, whole spelt, etc), 1 serving/day

All refined grains, breads, sweetened baked goods

Flesh foods

Fish (fresh or canned) and other seafood, chicken, turkey, lean beef, pork, lamb, (preferably organically raised meats)

Cold cuts or processed meats

Legumes/beans

Tofu and tempeh; any dried beans, split peas, lentils, edamame, up to 1 cup (cooked)/day

None

Nuts & seeds

Walnuts, hazelnuts, filberts, pecans, almonds, cashews, flax seeds, pumpkin seeds, sunflower seeds, poppy seeds, sesame seeds (whole or as nut butters)

Peanuts (often considered a nut but are actually a legume), pistachios

Vegetables

Vegetable—raw, steamed, sautéed, juiced, or baked (see shopping list)

Mushrooms, potatoes, corn

Fats and oils

Avocado; butter; olives; cold pressed oils: olive, flax seed, coconut, sesame, safflower, pumpkin sunflower, almond, walnut, canola

Margarine, shortening, processed oils, prepared salad dressings, spreads and sauces, mayonnaise

Acidic & fermented foods

Lemon and lime juices and vitamin C crystals as replacements for vinegar

All vinegars and preserved foods: sauerkraut, pickles, other products preserved in brine or vinegar

Sweeteners

Stevia (herbal sweetener)

All white/brown sugars, honey, maple syrup, corn syrup, high-fructose corn syrup, molasses, brown rice syrup, fruit sweeteners

Beverages

Filtered, spring, or distilled water (drink 8 cups/day), herbal tea (chamomile, bergamot, hyssop, alfalfa, angelica root, lemon grass, Pau d’arco)

Soda pop, alcohol, coffee, nondairy creamers

An Alternative Program Your health care practitioner may decide that your issues with candidiasis indicate a need for a more restrictive regimen for a period after the initial 2–4 weeks. If this is the case, then you will need to avoid additional foods for a 7–14-day period.

Additional Foods to Avoid Include: x All fruit. x All grains. x All dairy products except for plain yogurt with live cultures.

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Patient Handout—Chronic Rhinosinusitis and IBS

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Food Reintroductions At the end of the additional 7–14 days, please add the 3 food groups listed on the previous page into your diet, very gradually: Day 1: Add 1 serving (0.5 cup) whole grain daily, such as quinoa, brown rice, or wild rice. After 3–4 days on grains, assess symptoms and if well tolerated with little or no digestive symptoms (or other symptoms that had been bothering you), add the next food group below. If not well tolerated, stay on only the grains for several more days until tolerance improves. It is best to do this as slowly as needed.

Day 3 or 4: Add 1 fruit, such as orange or apple, each day. After 3–4 more days, assess symptoms. If well tolerated, proceed to the next food. If not well tolerated, repeat the above procedure by waiting several more days.

Day 7 or 8: Add a dairy product, such as cottage cheese or ricotta. Continue to assess symptoms and report to your health care practitioner. You may proceed at this time on the less restrictive list of allowed foods on the previous page.

Meal Suggestions for the Candida Control Diet The following are menu suggestions. Because this meal plan is quite low in carbohydrates, you may experience cravings at first, but this will pass and you will soon feel quite satisfied. If you are hungry, you may increase your portion size because this is not a calorie-restricted program. Any recipe may be used for any meal; leftovers from dinner make a quick lunch. However, on a Candida control diet, it is best to use leftovers within 24 hours or discard.

Breakfast Suggestions Eggs: scrambled, hard-boiled, softboiled, or poached Scrambled tofu Mexi tofu scramble

Curried eggs and vegetables Spiced eggs Spanish omelet

Silken smoothie UltraBalance Protein Drink Plain cow or goat yogurt (add real vanilla, nuts, or seeds as desired)

Chilled shrimp Chinese soup Vegetable beef soup Creamy cold tomato soup Beans and greens soup

Lentil soup Vegetable soup Quick steamed greens Italian tofu Celery root salad

Dinner Suggestions Grilled vegetables Roasted veggies Stir-fried pea pods Roasted garlic Roasted red peppers Stir-fry vegetables and tofu, shrimp, chicken, or turkey

Ratatouille Curried lentils and cauliflower Broiled lamb chops Coconut chicken with rice Baked Cornish hen, chicken, or turkey; roast leg of lamb or pot roast tempeh stew

Broiled fish: trout, cod, salmon, halibut, swordfish, tuna, shellfish Any allowed fresh, baked, steamed, or sautéed vegetables in unlimited quantities, topped with tofu mash Coconut salmon

Snack Suggestions Fresh, raw vegetables with your choice of the following: nut butter, salsa, hummus, yogurt and dill, tofu mash, roasted garlic, walnut spread, or allowable salad dressing

Roasted or raw nuts and seeds (without peanuts, pistachios) Turkey chili Plain cow or goat yogurt with live cultures Cauliflower popcorn

Lunch Suggestions Mixed greens salad with tofu or tuna Deluxe tuna, chicken, or turkey salad Stuffed peppers Spinach salad Bean salad

Patient Handout—Chronic Rhinosinusitis and IBS

Dipping veggies: celery, carrot, daikon, jicama, red peppers, zucchini, yellow summer squash, whole green beans, broccoli, cauliflower, kohlrabi, endive, scallions, snap peas, cucumber, and cherry tomatoes

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Anti-Candida Food Plan Shopping List

Fruits ☐Watermelon ☐Apples (green), pears ☐Peaches, nectarines ☐Plums ☐Kiwi ☐Oranges, tangerines ☐Grapefruit

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Concentrated Proteins ☐Chicken, Cornish game hens, turkey, duck ☐Fresh ocean fish – Pacific salmon, halibut, haddock, cod, sole, tuna, mahi mahi, etc ☐Shellfish ☐Water-packed canned tuna, turkey, chicken, wild salmon ☐Lamb ☐Wild game ☐Lean beef or pork ☐Eggs ☐Tofu – regular and silken ☐Tempeh Grains ☐Quinoa ☐Millet ☐Buckwheat ☐Teff ☐Amaranth ☐Brown or wild rice ☐Steel cut oats Beans – 1 cup/day ☐All beans ☐Edamame (green soy beans) ☐Hummus ☐Lentils – brown, green, red ☐Split peas – yellow, green All the above beans can be bought dried or canned without added sugar.

Oils ☐Almond ☐Flax seed ☐Coconut ☐Canola ☐Olive ☐Safflower ☐Sesame ☐Soy ☐Sunflower ☐Walnut

Dairy and Substitutes ☐Plain cow yogurt with live cultures ☐Plain goat yogurt ☐Plain soy, almond, or hemp milk – read labels for sweeteners ☐Coconut milk ☐Fresh, unaged goat cheese ☐Cottage cheese ☐Mozzarella ☐Ricotta Nuts and Seeds ☐Almonds ☐Cashews ☐Flax seeds ☐Hazelnuts (Filberts) ☐Pecans ☐Pignoli nuts (pine nuts) ☐Poppy seeds ☐Pumpkin seeds ☐Sesame seeds ☐Sunflower seeds ☐Walnuts All of the above can be consumed as nut butters and spreads (eg, Tahini).

Vinegar Replacements ☐Lemon and lime juices ☐Vitamin C crystals Beverages ☐Herbal tea (noncaffeinated) ☐Mineral water ☐Spring water ☐Distilled water Miscellaneous ☐All spices ☐Olives (without vinegar)

Patient Handout—Chronic Rhinosinusitis and IBS

Vegetables ☐Artichoke ☐Asparagus ☐Bamboo shoots ☐Beets and beet greens ☐Bok choy ☐Broccoli, broccoflower ☐Brussels sprouts ☐Cabbage – all types ☐Carrots ☐Cauliflower ☐Celery ☐Cucumber ☐Eggplant ☐Garlic, chives ☐Green beans, yellow wax beans ☐Jicama ☐Kale, collards ☐Kohlrabi ☐Lettuce – red or green leaf and all types of greens, (arugula, endive, escarole, radicchio, dandelion, etc) ☐Okra ☐Onions, leeks, scallions, shallots ☐Peppers – all types ☐Radish, daikon ☐Sea vegetables – seaweed, kelp, nori, dulse, hiziki ☐Peas – all types ☐Spaghetti squash ☐Spinach ☐Sprouts (broccoli and bean) ☐Swiss chard ☐Tomatoes ☐Watercress ☐Winter squash – all types ☐Zucchini

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VIEWPOINTS

Datis Kharrazian, DHSc, DC, MS, MNeuroSci, CNS: Finding Hope for Neurological Autoimmune Disease Interview by Craig Gustafson

Datis Kharrazian, DHSc, DC, MS, MNeuroSci, CNS, is an associate clinical professor for the Department of Preventive Medicine at Loma Linda University School of Medicine and is an adjunct professor at National University of Health Sciences and Bastyr University. He is a fellow of the American College of Nutrition and the author of 2 bestselling books, Why Do I Still Have Thyroid Symptoms When My Lab Test Are Normal and Why Isn’t My Brain Working? Dr Kharrazian is currently in a postdoctorate clinical research scholar program at Harvard Medical School and publishes scientific papers in the literature in the fields of nutrition, autoimmunity, and toxicology.

Integrative Medicine: A Clinician’s Journal (IMCJ): Would you describe your educational path once you first started looking at health as a career?

Dr Kharrazian: I was injured in high school with a severe back injury. I ended up not being able to participate in sports or academically. I had to start taking pain medication and I remember all my grades started to drop. I could not do anything. A friend of the family took me to a chiropractor and I got an adjustment—started a treatment—and I immediately felt better. It was an “I want to do that right away” moment in my life.

Once I got my undergraduate in chiropractic, I went on to chiropractic school. Then in chiropractic school, I quickly learned the importance of nutrition. While I was in school, my mom was really ill. I met a person who was doing laboratory analysis and blood work. We ran a blood profile on her and figured out the things she needed nutritionally, and that made a big impact on her health. So, as soon as I finished chiropractic school, I went into earning a master’s degree in nutrition. I realized shortly after that, that there is a point where I need to understand research, so I followed that up with a doctor of health science research degree. After that, I realized I really needed to learn even more about statistics and research methodology, so I enrolled in a 1-year postdoctorate program at Harvard Medical School called the Clinical Scholar Research Training Program. For the next 2 years, I am going back to Harvard Medical School. I’ll be working on a master of medical science research degree.

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IMCJ: How does your neurology degree fit into that framework?

Dr Kharrazian: As a master of neurological sciences, in the chiropractic profession we have specialties. This is a 3-year specialty. Just like radiology or internal medicine, the chiropractic profession has a neurology specialty, and I went through that program. We also had a master of clinical neuroscience portion of that. Right now, we are actually developing a master of clinical neuroscience program for the National University of Health Sciences so we can teach people how to use neurology in a rehabilitative aspect and learn how to apply things like rehabilitation and nutrition to recovering brain or preventative brain disease models.

IMCJ: How has this foundation led you into toxicology and immunology?

Dr Kharrazian: I met a person a few years ago who had a dramatic influence in my life. His name was Aristo Vojdani, PhD. I heard Dr Vojdani speak at a conference. I was so blown away by his knowledge of autoimmune disease. At that time in my practice, I was seeing so many patients with autoimmune diseases that I basically did everything I could to be around him—whether it was trying to have lunch with him or call him up or call him on his phone asking about laboratory analyses I was getting back from his laboratory, which was Immunosciences Lab, Inc. Over the years, we have become good friends and he has really become a good mentor. We began publishing research together and I have been working in his laboratory doing a lot of research with toxicology as it relates to autoimmune diseases, and even neurological autoimmune disease.

IMCJ: How do you see nutrition impacting autoimmune disease and, in particular, neurological autoimmune disease?

Dr Kharrazian: For the most part, when people have neurological autoimmune disease, or autoimmune disease in general, they have it years before destruction of their tissue accumulates to the point where they will be diagnosed. So, for example, most people who have

Kharrazian—Viewpoints

neurological autoimmune disease will start to have some deficits in certain aspects of the brain function, whether it is memory, cognition, coordination, or balance. They are not really sure where the symptoms are coming from.

They go see a neurologist and the neurological exam findings are usually somewhat normal. They do not have any MRI findings. It won’t be until years later, when they really have started to progress, that they will be diagnosed, but that point is a little bit too late.

We know that with laboratory analysis, we can use antibodies against brain tissue, like myelin basic tissue protein or neurofilament antibodies, and be able to almost predict the progression of their disease process. We know these are early markers, so we’re learning to identify subtleties in the examination findings that are early stages of the symptoms and correlate that with laboratory analysis and then apply a preventative disease model using nutrition, diet, and lifestyle medicine to dramatically impact the laboratory markers.

We know we can also do that with people who are already progressed, but the outcomes are much better when we can catch the disease process early. When you look at autoimmune disease or neurological autoimmune disease, there really is nothing for medicine to offer these individuals who are suffering. The only mainline treatment would be steroids, and steroids have their own list of side effects that are almost as bad as the autoimmune disease for some people. Nutrition, diet, and lifestyle can have profound impacts—not curing the autoimmune disease, but dampening it and helping put the autoimmune disease in remission.

If you just look at the medical literature—your options when you have an autoimmune disease and what’s effective—and you were not biased, the only reasonable approach you would take, based on the evidence-based medicine model, is to apply diet and nutrition therapies.

We see this big void in how autoimmune disease is being managed in the health care mode. So, if we can get people to really connect what is being published in literature to identification of autoimmune individuals, I think we can help practitioners do a better job of helping their patients.

Patients will also feel better if we can make these connections happen. The information is already there, but we have two problems: One is, practitioners are not trained well enough to identify autoimmune diseases, and two, there is a shortage of knowing exactly what you can do for an autoimmune disease in both conventional and alternative medicine models.

IMCJ: What is needed to bring the levels of practitioner’s knowledge up so that they can identify these autoimmune diseases early?

Dr Kharrazian: When you look at all the different health care disciplines, whether it is medicine or alternative medicine, first of all, there is no real training in autoimmune

Kharrazian—Viewpoints

diseases. We have the specialty of rheumatology, which is isolated to a few joint-based, degenerative autoimmune diseases. But autoimmune diseases hit all types of medical specialties. They hit gastroenterology, they hit neurology, they impact even cardiology, and all the various specialties.

But those specialties do not have any real training or understanding of autoimmunity, so we have this void where no one is getting any treatment. In the medical specialty model, we do not have an autoimmunologist.

This does not exist as a specialty. We do not have even an immunologist; we have immunologists who are PhD-level researchers, but it is not a specialty in medicine. Medicine has an infectious disease specialty, and that does not address the autoimmune nature of it.

For the most part, we have this huge deficit in identifying autoimmune disease. This is one of the goals of the American Autoimmune Related Diseases Association, which looks at “What do we do to help autoimmune patients?” Its biggest concern is to actually train the medical community to identify autoimmune diseases early. It has to start with basic coursework in medical school and that has to also involve basic coursework in alternative medicine programs such as naturopathic programs, chiropractic programs, or osteopathic programs.

I really hope that would happen soon, but it does not seem like it will. Right now, if we can get into the postgraduate community, more and more, I think at least it will continue to have an impact.

IMCJ: What challenges are involved in bringing the standard of knowledge up?

Dr Kharrazian: Immunology, without question, is very complex. In the field of immunology, we know there are certain immunological reactions, but there is also an exception to every rule. As time goes on, we identify more and more messenger proteins and we identify more types of immune cells and their functions. So it is a very complex topic.

However, in a clinical setting, we know we can identify some biomarkers—markers for inflammation, markers for autoimmunity—and then we can take the literature and apply application—particularly simple things like using high amounts of turmeric, resveratrol, or other supplements like vitamin D, which we know impacts the immune system. We can use strategies such as those that are well published and look at laboratory markers that our patient has, then combine that with diet and nutrition lifestyle strategies. As a result, we can see some of these markers change even though we do not necessarily understand all the mechanisms.

We know, for example, that if you don’t sleep, your immune system dysregulates. So in the clinical scenario, by getting patients who have autoimmune diseases to sleep; getting them just a little bit of exercise, where they do not overtrain; teaching them how to stabilize their blood sugar

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levels; teaching them how to use antioxidants and antiinflammatory compounds; and changing their diets so they are not as inflammatory, they can have profound impacts on changing autoimmune disease. These sets of strategies can be employed, to some degree, without us understanding all of the complexities that are involved.

There are some basic things that are just common sense. We know that if we can change people’s lifestyle and support their diet to the point where it’s not so inflammatory or antigenic, meaning we identify food proteins and sugars—whether they are from food or from environment, such as chemical exposure—if we can identify those things and remove them, we can help their immune systems be less inflamed. We can give their immune systems modulators to support their autoimmunity, like vitamin A and vitamin D and different types of botanicals, and we can make a huge impact in a disease where no one is currently offering any options in the health care model.

people having antibodies to nervous system tissue, specifically myelin basic protein. A 1.0 correlation means you have perfect correlation. If one marker goes up, then the other goes up. These are called r values. We found an r value of 0.9 with immune reactions to plastics and neurological autoimmunity, which suggest that those people who are having immune reactions to plastic compounds are also having immune reactions to their own nervous tissue, including their brain and peripheral nervous system. We are now going through checking all the different tissue antibody proteins that we saw in our initial research and correlating those with these specific autoimmune diseases. The correlation is unbelievably high. So we think that plastic compounds and compounds like formaldehyde in commonly overlooked household items can be a trigger for autoimmunity, and it is not just heavy metals, which has really been the focus of alternative medicine when it comes to autoimmune disease.

IMCJ: How do toxins contribute to autoimmunity?

IMCJ: So you’ve kind of focused on the plastics, the bisphenol A, and the formaldehyde. What about volatile organic compounds?

Dr Kharrazian: Toxins are a huge component of autoimmunity, and I think one of the problems we have in alternative medicine is we blame everything on heavy metals. In the conventional model, I do not think we are at the point where there is real recognition of toxins being a contributing factor to autoimmune disease. So we have basically overlooked this whole vector for autoimmune disease. But we are realizing is it is not just heavy metals that have an effect on autoimmune disease. Things like BPA and bisphenol A, in plastic compounds, can trigger an inflammatory response and autoimmune disease.

Things like formaldehyde, which is found in glue used in carpet, in wallpaper, and in Scotch tape, and benzene compounds from cigarette smoke or from gas exhaust— these can be triggers in autoimmunity.

Last year, Dr Vojdani and I published a paper in the Journal of Applied Toxicology1 where we found that these toxic chemicals, like formaldehyde and fire retardants such as tetrabromobisphenol A and BPA, actually bind to our own proteins. So when we get exposed to these chemicals, we do not have 100% elimination of them through our bodies. When they bind to our protein, they become a new antigen. These antigens have potential to then become triggers for autoimmune disease.

We checked 400 samples to see what degree the healthy population has chemicals bound to proteins, which we then measured with antibodies. This means they are having an immune response to them. We found that these chemicals were in a range of anywhere from between 8% to 15% of the population. What we have been doing since then is correlating whether people have antibodies to their own tissues with specific chemicals.

We have a paper in submission right now where we found that plastic compounds, BPA, bind to human albumin and we found very high correlation with those

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Dr Kharrazian: Our research has been on chemicals that we encounter every day. We did check with mercury and heavy metals and we can produce antibodies to them when they bind to our own tissue proteins and become haptens. We are also finding research that has correlation between immune reactivity to chemicals bound to your proteins—albumin— and neurological autoimmune reactivity. The interesting thing is that we’re finding these exposures are unavoidable.

You are going to get exposed. You can not live in an industrialized nation and not be exposed to plastic compounds or benzene rings or fire retardants. They are everywhere.

So the key issue is a complete shift in paradigm of how we treat these things. It is not just about removal, because they are abundant everywhere and there is constant exposure. It is really about what we call, and what the literature calls, chemical tolerance. Our immune systems have something called tolerance, which means we can be exposed to something that is an antigen or potential immune trigger, but we may or may not react against it.

For example, look at food proteins. When people lose their oral tolerance and they start to react to every food protein they eat, then they get multiple food sensitivities and reactions. But the key issue is that they have lost tolerance in their gut immune system.

We can have the same thing happen with chemicals.

So, even though we may have one person who has very high levels of a chemical in their bodies—whether it is mercury or bisphenol A in plastics—their level is not necessarily reflective of how much of a problem it is for their autoimmunity. What really matters is their antibody level, not their total load level. You can have someone who has trace levels of mercury, but then very high immune reactivity to mercury, so then they may have very high

Kharrazian—Viewpoints

levels of mercury bound to albumin antibodies. Those are the people we are really concerned about. We know that when people become sick with chemicals from autoimmune disease, it is not just the exposure, even though that is a variable. The other concerns relate to their immune chemical tolerance. So things like intestinal permeability, regulatory T-cell function, dendritic cell activity, Th1 and Th2 cell polarization, or their ability to turn on TRAC cells—these are all key factors that then determine how a person may or may not react when they are exposed to chemicals.

In a clinical model, we have looked at people who have autoimmune disease and antibody levels to chemicals that are very, very high. If the chemicals we are concerned about are ones that they are going to get exposed to on a daily basis, then we try to do things to improve their chemical tolerance, like put them on high amounts of antioxidants, try to block their inflammatory pathways with flavonoids, and give them high amounts of vitamin D to get their Treg cells to work. When we employ these strategies, many times we will see that their chemical antibody reactions dramatically change and their autoimmune reactions dramatically change as well.

IMCJ: At what point in your career were you exposed to functional medicine?

Dr Kharrazian: When I was a student in chiropractic school, I heard Jeff Bland speak. It was one of those moments where I go, “Wow, that’s it, that’s what I need to do.” Since then, I have been involved in that community for the past 15 or 20 years. I think it is the future of health care to some degree.

IMCJ: You have done a lot of work to extend the functional medicine framework into the neurology specialty area.

How did you come to decide to pursue that?

Dr Kharrazian: I think one of the things that is really important to understand is that in order for a neuron to function, it has to have connections to other neurons. This is called plasticity. So a neuron has to branch into another neuron, and as they branch into each other, you can have functions for that specific pathway. The interesting thing is that nutrition and functional medicine approaches do nothing to develop plasticity. You cannot develop plasticity from a drug/nutrient/diet model. You just can’t. You can slow down neurodegeneration, you can dampen neuron formation, but you cannot make neurons connect to each other through a diet/nutrition/functional-medicine model. The only way you can make neurons connect is by activating them.

The analogy would be similar to muscle atrophy from wearing a cast. There is no supplement or functional medicine approach they could take to make their muscle develop again. They would actually have to move it. The brain is the same way. You cannot take someone who has

Kharrazian—Viewpoints

degeneration in their brain and just put them on an antiinflammatory diet, give them mitochondrial support, and give them fasting and expect that their brain’s neurons are going to connect to each other. You are actually going to have to activate the areas of the brain that are involved.

In my practice, I work with a lot of neurological autoimmune disease patients. One of the things we do with them is a complete functional medicine evaluation and try to identify dietary and lifestyle triggers that can impact the promotion of their neurodegeneration. Then we look at strategies to dampen that. We use nutritional strategies to improve their brain function from a neurochemical perspective, but then we find the areas of the brain that are involved and we actually have to have them do rehabilitation. One of the most common areas we see right now, involved in the neurological autoimmune disease model, is cerebellar autoimmune disease. With the explosion of celiac disease and these immune reactions to gluten proteins, we know that gluten has molecular mimicry, which can cross-react with the cerebellum, meaning antibodies made against gluten can attach to the brain’s cerebellum tissue target sites and provide the trigger for the immune system to destroy that tissue.

We see a lot of people who have, for example, cerebellar degeneration, and then they start to get ataxia, and they start to get vertigo, and they start to get nausea.

We know getting them off gluten helps with important things like intestinal permeability, and by putting them on an anti-inflammatory diet and lifestyle, it stops the progression. But in a large number of cases, we have to make their cerebellum gain function again. So this is where we do cerebellum rehabilitation exercises. I do things like balance rehabilitation or eye movement. A combination of trying to activate the brain to develop plasticity and employing a functional medicine model to provide the best chemical environment for their brain seems to work well. My interest in going into a functional neurology model, where you really do a very detailed examination of the brain and nervous system and provide exercises for it, merges with the functional medicine model, where we are looking at chemical factors that impact the brain.

IMCJ: So you have initiated clinical incorporation of functional medicine into neurology within your own practice. How is the process for formalizing this happening?

Dr Kharrazian: For the past 8 years, we have had an annual conference and we have an association. It is called the International Association of Functional Neurology and Rehabilitation. It is a multidisciplinary organization. We have almost a thousand members now from all over the world. We get together and we try to merge these concepts together. Some of the people in this group come from a physical therapy background, some come in chiropractic, some come in from natural medicine, and some are more

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conventional neurologists from medical backgrounds. We are all interested in one thing: How do we make the brain function better than it is? It becomes a combination of toxicology approaches, nutritional approaches, brain rehabilitation approaches, and lifestyle changes. We feel that this is something that is necessary in the population because we have an increase in neurodegenerative diseases taking place like never before in our history. The prevalence of neurodegenerative diseases has increased dramatically and so have neurodevelopmental disorders like ADD, ADHD, autism, and Tourette’s syndrome. We have a void in both conventional and alternative medicine in how to address this.

So the International Association of Function Neurology and Rehabilitation is an attempt to bring all the different fields and specialties together to help find a solution for the problem that we all face.

IMCJ: What kinds of results have been produced?

Dr Kharrazian: We have put together a course that we teach at functional neurology seminars where practitioners learn how to do really detailed examinations of the brain.

People throughout the world are now taking it. In addition to the conference, we have a journal, where we try to share

case studies and research with each other. We also have clubs in some of the chiropractic schools and some of the naturopathic schools and two of the medical schools. So we have students interested in an integrative functional neurology model. Right now, we are seeing a lot of interest and we are expanding it.

The goal is to train as many people who are interested in it, in addition to trying to get researchers to collaborate and find ways where we can improve brain function. Because at this point, if you have degeneration, you really do not have any medications to help you. Most medications for neurodegenerative disease are only to get rid of symptoms. If your child has autism, you are basically told there is nothing that can be done. If you have a brain injury, besides crossing your fingers hoping you recover, no one is doing serious intervention to make a difference. So we really feel we can fill that void by bringing everyone together and trying to teach people how to do very detailed exams and applications and bringing a multidisciplinary group of specialists together to have a common goal of finding the best approach to treating these types of neurological diseases.

Reference 1. Vojdani A, Kharrazian D, Mukherjee PS. Elevated levels of antibodies against xenobiotics in a subgroup of healthy subjects. J Appl Toxicol. 2016;36(5):748.

Call for Abstracts The Oncology Association of Naturopathic Physicians (OncANP) has opened a Call for Abstracts from individuals interested in presenting at the Association’s 6th Annual Naturopathic Oncology Conference. The conference will take place Friday-Sunday, February 17th-19th, 2017 at the Phoenix Marriott Tempe at The Buttes in Tempe, Arizona.

Submissions are due by Monday, July 18, 2016 at 9pm PDT/11:59pm EDT – no exceptions.

The abstract/application should be prepared as a Word document and emailed to Corey Murphy at oncanp@gmail.com.

The selection committee will evaluate all abstracts. Final speaker selection will be made by August 19, 2016. Lecture power points will be due Dec 19, 2016. All presentations will then undergo peer review prior to conference. Final presentations will be expected to reflect these critiques.

For more information, please visit http://oncanp.org/.

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Kharrazian—Viewpoints

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2013;20(24):2953-63. 3. Lynch AM, Loane DJ, Minogue AM, et al. Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus. Neurobiol Aging. 2007;28(6):845-855. 4. Heinrichs SC. Dietary omega-3 fatty acid supplementation for optimizing neuronal structure and function. Mol Nutr Food Res. 2010;54(4):447-456. 5. Saunders EF, Reider A, Singh G, Gelenberg AJ, Rapoport SI. Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment. Bipolar Disord. 2015;17(7):729-742. 6. Sinn N, Milte CM, Street SJ, et al. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr. 2012;107(11):1682-93. 7. Data on file, Prevention Pharmaceuticals Inc. New Haven, CT. omax3 is a registered trademark of Prevention Pharmaceuticals, Inc. ProResolv is a trademark of Prevention Pharmaceuticals, Inc. ©2015 Prevention Consumer Health Products. All rights reserved. OMPS007 12/2015

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CONFERENCE CALENDAR GPLUniversity Workshops by The Great Plains Laboratory, Inc August 6-7, 2016—San Jose, California Learn how to effectively integrate our comprehensive testing into your practice to enhance your bottom line and achieve greater outcomes for your patients. Upcoming workshops include those on organic acids testing and genetic testing in San Jose, CA, and Dallas, TX. For all workshop details, including all dates and locations, and to register, go to http://www.GPLUniversity.com/.

Re-Examining the Oath: Reversing Nutrient Depletion and Iatrogenic Toxicity September 8-11, 2016—Toronto Marriott Downtown Eaton Center Hotel, Toronto, Ontario The International College of Integrative Medicine is a nonprofit medical association that has been organizing CME conferences in the Great Lakes region for more than 30 years. Join us in Toronto to re-examine current approaches to cardiology, pain, autoimmune disorders, psychiatric care, and endocrinology. Our speakers will guide you through the maze of side effects, nutrient depletion, and toxicity, and we will reinvigorate your practice of medicine with new ideas to address iatrogenic damage and achieve break-through healing for your patients. For more information, please visit http://www.IntegrativeMedicineConference.com/.

14th Annual International Restorative Medicine Conference September 16-18, 2016—Sonesta Resort, Hilton Head Island, South Carolina The 14th Annual International Restorative Medicine Conference is an extraordinary opportunity to hear expert speaker’s present emerging research and up-to-date protocols that empower you to effectively treat your patients. The annual conference consistently lives up to its reputation for providing innovative educational opportunities for practitioners. For more information, please visit http://restorativemedicine.org/aarm2016/.

American College for Advancement in Medicine Annual Conference September 15-18, 2016—Hilton El Conquistador, Tucson, Arizona ACAM will host its annual conference titled “What’s Next: An Interdisciplinary Approach to Advanced Prevention.” For more information, please visit http://www.acam.org/.

Applying Functional Medicine in Clinical Practice (AFMCP) September 19-23, 2016—Marriott Baltimore Waterfront, Baltimore, Maryland AFMCP teaches health care practitioners to more effectively integrate science, research, and clinical insights to treat and prevent disease and maintain health. Established and emerging diagnostics, therapeutics, and prevention strategies are extensively covered. AFMCP integrates these approaches through the Functional Medicine Matrix Model (an innovative and practical assessment tool) and the emphasis on a therapeutic partnership between patient and practitioner. AFMCP is a well-orchestrated, comprehensive, patient-centered education program that helps you deepen your clinical understanding and practical application of the Functional Medicine Matrix Model. For more information, please visit https://www.functionalmedicine.org/.

The American Academy of Anti-Aging Medicine (A4M): BHRT Symposium September 21-24, 2016—Hyatt Regency Dallas, Dallas, Texas In this exclusive 3.5-day seminar, you will be able to analyze the medical evidence on BHRT, listen to experts who are actively practicing this specialty, and get the information needed to merge BHRT safely into your practice. The traditional medical view of aging is a process with inevitable complications such as cardiovascular disease, diabetes, cancer, dementia, and the general steady decline of quality of life. For more information, please visit http://www.a4m.com/anti-aging-conferences.html/.

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7th Annual Integrative Medicine for Mental Health Conference September 29-October 2, 2016—Reston, Virginia This international conference will explore the field of integrative medicine in the treatment of mental health, autism, and related disorders.

The current trial-and-error, polypharmacy approach to the treatment of psychiatric disorders may not work for everyone. Research studies have revealed that many disorders such as depression, bipolar disorder, anxiety, OCD, eating disorders, and autism spectrum disorders often have dietary and biological causes, which contribute to symptoms.

Patients have better outcomes when these causes are successfully addressed and treated through a combination of specialized testing and nutritional therapies, even in combination with traditional approaches.

For more information, please visit http://www.IMMH2016.com/.

Inflammation: Cooling the Heat September 30-October 1, 2016—Hilton Scottsdale Resort and Villas, Scottsdale, Arizona InnoVision Professional Media is sponsoring a unique health care symposium that will focus on inflammation. The event will combine the latest research and applications into a 2-day event with CMEs. Attendees will hear from leading health care thought leaders who will share their perspective on inflammation for your patient’s health. For more information, please visit http://innovisionhm.com/inflammation/.

11th Annual Cardiometabolic Health Congress October 5-8, 2016—Sheraton Boston Hotel, Boston, Massachusetts The Cardiometabolic Health Congress provides a one-of-a-kind opportunity to stay informed on the latest scientific and clinical developments in these overlapping disease areas through a comprehensive and integrated agenda.

The CMHC has grown to be the largest multidisciplinary conference addressing the prevention, diagnosis, and management of cardiometabolic diseases in the United States. CMHC offers new educational formats, 27+ credit hours, symposia and workshops, lively debates with ample time for Q&A, renowned faculty and Meet-the-Expert sessions, and an expanded exhibit hall showcasing technological innovations, products, and prevention tools to improve your practice. For more information, please visit http://www.cardiometabolichealth.org/2016/.

The American Academy of Anti-Aging Medicine (A4M): Metabolic Medical Institute October 5-8, 2016—Sheraton Boston Hotel, Boston, Massachusetts A4M “MMI Module IV—Gastroenterology” and “MMI Module VI— Toxicology” will be presented at this event. For more information, please visit http://www.a4m.com/anti-aging-conferences.html/.

AAEM 2016 Annual Meeting October 6-9, 2016—Marriott San Diego La Jolla, La Jolla, California The goal of this conference is to present current data regarding mitochondria as a therapeutic target in many disease states. The information presented will better train primary care clinicians with the knowledge and skills needed to help prevent chronic disease in their patients, as well as identifying mitochondrial dysfunction and formulating a more comprehensive and effective approach to managing and even eliminating many modern complex chronic disease states. For more information, please visit http://aaemconference.com/fall/.

IVC & Cancer Symposium October 13-15, 2016—Hotel at Old Town, Wichita, Kansas Biannually, Riordan Clinic IVC Academy holds an IVC and Cancer Symposium in Wichita that offers doctors from around the world the opportunity to visit our facilities, learn more about high-dose IV vitamin C (IVC), listen to leading doctors in functional medicine, and learn how to use IVC in their offices. For more information, please visit https://riordanclinic.org/riordan-ivc-academy-symposium/.

Conference Calendar

American Meditation: The Heart and Science of Yoga October 25-29, 2016—Cranwell Resort and Spa, Lenox, Massachusetts Dr Jyothi Bhatt will lecture on the benefits of the ancient chakra system as a complementary diagnostic tool at the 8th annual mind/body medicine CME conference. Dr Bhatt will explain how a basic understanding and practical application of Ayurveda can be used alongside allopathic medicine in a complementary manner. For more information, please visit http://americanmeditation.org/portfolio/physicians-cme-conference/.

Functional Medicine Advanced Practice Modules (APMs) October 28-30, 2016—Hyatt Regency, Chicago, Illinois “GI—Restoring Gastrointestinal Equilibrium: Practical Applications for Understanding, Assessing, and Treating Gut Dysfunction.” This Advanced Practice Module takes a whole-systems approach to evaluating and treating not only local gastrointestinal (GI) disease, but many systemic diseases that are linked to GI dysfunction. This course will supply you with the foundational background, insight, and in-depth clinical thinking to confidently work up and treat patients who may present with conditions, signs, and symptoms indicative of GI dysfunction. We will discuss in detail the important laboratory evaluations to be considered, the appropriate clinical connections that must be made, and the treatment approaches that should be used. For more information, please visit https://www.functionalmedicine.org/.

AIHM Annual Conference: People Planet, Purpose October 30-November 3, 2016—Paradise Point, San Diego, California Join the Academy of Integrative Health & Medicine annual conference and workshops. For more information, please visit https://www.aihm.org/.

GPL University Workshops by The Great Plains Laboratory, Inc November 5-6, 2016—Dallas, Texas Learn how to effectively integrate our comprehensive testing into your practice to enhance your bottom line and achieve greater outcomes for your patients. Upcoming workshops include those on organic acids testing and genetic testing in San Jose, CA, and Dallas, TX. For all workshop details, including all dates and locations, and to register, go to http://www.GPLUniversity.com/.

13th International Conference of Society for Integrative Oncology November 6-8, 2016—Miami, Florida Multidisciplinary oncology practitioners from around the globe, including stakeholders from major cancer centers, convene at SIO annual international conferences to discuss the evolution of evidence-based integrative oncology in practice, the steadily growing science base, and its continued rise in popularity use as patients demand a whole-person approach to cancer care with mind, body, and spirit. For more information, please visit https://integrativeonc.org/.

The American College of Nutrition’s 57th Annual Conference— Translational Nutrition: The Science of Personalized Nutrition November 9-11, 2016—Hilton San Diego Resort, San Diego, California Nutrition is the single most important determinant of human health.

Personalization maximizes nutrition’s impact, and health care practitioners can now use the science of personalized nutrition to maximize their patient’s long-term health. This interactive educational event offers an understanding of the latest research and clinical applications of nutrigenetics and nutrigenomics. It will provide strategies for designing optimized interventions that improve health and well-being and prevent nutrition-related diseases. Join us in San Diego for the nutrition science conference of the year! The ACN annual conference is a must-attend for anyone interested in the field of nutrition science and is a wonderful opportunity to connect with world-renowned researchers and clinicians to establish a network of like-minded professionals. Translate nutrition science into practice by exploring the science of personalized nutrition. For more information, please visit http://www.americancollegeofnutrition.org/conference/.

Gut-Brain Relationship Conference November 11-12, 2016—Marriott Marina del Rey, Marina del Rey, California InnoVision Professional Media is sponsoring a unique health care symposium that will focus on the unique relationship between the gut and the brain. The event will combine the latest research, testing techniques, and applications into a 2-day event with CMEs. Attendees will hear from leading health care thought leaders who will share their perspective on this important relationship for your patient’s health. For more information, please visit http://ivpmeducation.com/.

Nutrition Pro 2016 Symposium: Personalizing Medical Nutrition Therapy Saturday, November 12, 2016—Hilton San Diego Resort, San Diego, California This clinical symposium will bring together experts on 2 very important and timely topics and is geared to all health professionals who utilize nutrition as a practice tool. Join us and add to your nutrition science knowledge and enhance your clinical skills. For more information, please visit http://www.nutritionspecialists.org/NutriPro2016/.

The American Academy of Anti-Aging Medicine (A4M) 24th Annual Winter World Congress December 9-11, 2016—Venetian/Palazzo Hotel, Las Vegas, Nevada The American Academy of Anti-Aging Medicine (A4M) invites you to attend the 24th Annual World Congress on Anti-Aging, Regenerative, and Aesthetic Medicine. A4M is the largest antiaging and aesthetic event with more than 3000 health care practitioners, both domestic and international, attendees. This event will include board certification exams, fellowship modules, general conference activities, and exhibition.

For more information, please visit http://www.a4m.com/.

2017 South Beach Symposium February 9-12, 2017—Loews Miami Beach Hotel, Miami Beach, Florida Attend the 15th Annual South Beach Symposium, February 9-12, at the Loews Miami Beach Hotel. This must-attend conference features cutting edge educational sessions with educational tracks featuring the Masters of Pediatric Dermatology Symposium, the South Beach Clinical Dermatology Symposium, the South Beach Aesthetics Symposium, and the Practice Management Symposium. For more information, please visit http://www.southbeachsymposium.org/.

The Roots of Toxicity March 2-4, 2017—The Hyatt Regency, Savannah, Georgia Explore the connection between physicians and dentists at this joint meeting of the International Academy of Biological Dentistry & Medicine, International College of Integrative Medicine, American Academy of Environmental Medicine and International Academy of Oral Medicine and Toxicology. More than 500 dentists, physicians, and researchers are expected to attend. For more information, please visit https://iaomt.org/events/upcoming-meetings/.

2017 Joint American Homeopathic Conference (JAHC) March 31-April 2, 2017—Loews Atlanta Hotel, Atlanta, Georgia Join the Joint American Homeopathic Conference (JAHC) for its 12th annual conference. This special event is the largest gathering of the homeopathic community in the United States. Each year, the JAHC features some of the most well-known, experienced, successful homeopaths from around the globe. For more information, please visit http://www.homeopathycenter.org/.

For additional listings, please visit http://imjournal.com/.

Conference Calendar

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BACKTALK

The Case for Civility Bill Benda, MD, Associate Editor

A

s many of you are aware, a couple of months ago the British Medical Journal published a study ranking conventional medical care as the thirdleading cause of death in the United States.1 The paper was an immediate hit. Newspapers and blogs across the country headlined the findings, people were outraged, and accusations of killing patients for profit permeated the alternative forums. Given that I am one of the perpetrators by academic degree and therefore association, I purchased and struggled through the article in an attempt to understand the findings and meaning behind the authors’ conclusions. I must admit failure, as statistics and I have been enemies since I first encountered the term t test somewhere in college. But I also read the initial responses from other academicians, and while I and they accept the conclusions of Dr Makary, I would like to share a couple of my personal reflections, for what they are worth. They may not sway your opinions, dear readers, but I do hope they may add food for thought on this most important topic. Here goes: 1. First and most important, adverse reactions— especially death—are a huge problem in my profession. Despite the seeming novelty of this paper, the problem has been studied for decades with incredible effort going into strategies to solve it, with limited success. There is really nothing new here.

2. Second, and least important, I took this paper a bit personally. I am an emergency physician and have been for over 30 years. I don’t think I have killed all that many patients. In fact, I don’t think I have killed any, but no one has studied my personal data, and I suppose there is the possibility. Then again, I have saved many hundreds of lives. Go figure.

3. All medical research is inaccurate to some degree.

Initial study of Makary’s submission raised questions, and various academic sources reviewing the data place the number of deaths at 174 902 per year rather than his stated 251 454 per year. Despite the adjustment, it still remains the third-leading cause of death, however, so I do not question the underlying premise. It is real.

4. On that note, one issue with Makary’s data is that they classify all adverse events as preventable. Let’s think about this for a moment. The MD is the only professional who is expected to make no mistakes.

Ever. Zero. Nada. Zilch. Make an error, get sued— that’s a threat hanging over our heads every day. If my editors allow the following to make it into print,

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I have to say, this really, really sucks. It definitely influences our practice of medicine and becomes a primary factor in the enormous cost of health care.

Bottom line: We make mistakes. Do you?

5. The majority, if not all, of those rallying around this paper as a cause to dismantle our allopathic health care system did not actually read it. They did not read the academic rebuttals. They did not discuss it with the authors or those of us in the trenches, struggling to help without causing further harm.

And, likely, the more vociferous the criticism, the less informed the source.

OK, enough of that. The fact remains that no matter how the data are parsed, conventional medical care is likely the third-leading cause of death in the United States.

But we are also number 1 in a few categories. We are number 1 in eradicating diseases that have killed hundreds of millions over the past couple of centuries. We are number 1 in saving babies with Tetralogy of Fallot, and transposition of the great vessels, and premature birth. We are number 1 in women giving birth who could never have done so without our help. We are number 1 in saving children with blood cancers. We are number 1 in bringing people back from certain death from cardiac arrhythmias and arrest, and reversing massive neurologic deficits from stroke. And on. And on.

This may sound like I am negating Makary’s paper, or defending the unintentional harm we perpetrate with our therapies. I am not—this is a huge problem that demands our attention and energies and solutions. Where I have a problem is the anti-MD rhetoric from people who have never been responsible for another human life, have never been threatened with legal and financial disaster if they make an error, and have never had the means to either save or destroy in their hands and seconds to make the decision of whether to unleash it.

Don Berwick, MD, MPP, is a hero in our crusade to change health care for the betterment of the patient and society in general. But even he has stated, on multiple occasions, that “Everything possible begins with civility.” If one wishes to wave this paper as standard against conventional medicine, it is understandable. It is a discussion that has to happen—now. Let’s just have it with a mature voice.

Reference

1. Makary MA, Daniel M. Medical error-the third leading cause of death in the US. BMJ. May 2016;353:i2139.

Benda—BackTalk

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