44th Orthomolecular Medicine Today Conference

th

Annual International Conference

2015

Orthomolecular Medicine Today April 24 – 26

toronto Fairmont Royal York Hotel

International Society for Orthomolecular Medicine

Experience the best education for health care professionals in many areas of Orthomolecular Medicine at our 44th Annual International Conference.

Thirteen internationally known physicians and researchers will present five sessions over three days on current advances in general orthomolecular medicine, cardiology, psychiatry, and oncology.

International Society for Orthomolecular Medicine April 24, 2015 Dear Delegates, Welcome to our 44th Annual International Orthomolecular Medicine Today Conference.

We hope these next three days will provide fresh insight and clinical evidence for the advancement of your study and practice in the field of Orthomolecular Medicine.

This year we are pleased to bring together 13 speakers, 20 exhibitors and 200 delegates and guests from countries around the world, including Algeria, Brazil, Canada, 'HQPDUN, -DSDQ Mexico, Nigeria, Norway, Spain, Sweden, Switzerland, the United Kingdom and the United States of America.

We are celebrating the 21st anniversary of the founding of the International Society for Orthomolecular Medicine, which now has 20 country members representing over 30,000 individual members. The ISOM was established in 1994 to unite existing societies and to foster the growth of Orthomolecular Medicine through education, communication and advocacy.

2015 marks the 12th anniversary of the Orthomolecular Medicine Hall of Fame, as we induct four pioneers: Irwin Kahan; Aileen Burford-Mason, PhD; Hyla Cass, MD; and John Hoffer, MD, PhD. We thank you for your continued dedication to Orthomolecular Medicine and wish you a most memorable Conference.

With best regards,

Atsuo Yanagisawa, President

Steven Carter, Founding Director

ISOM Meeting Sunday, April 26 8:30 am – 10:00 am Please join us to hear reports on activities in education, communication and advocacy from Canada, Japan, Mexico, Spain, Sweden, Algeria and others from among the countries in attendance at the Orthomolecular Medicine Today Conference.

Don’t miss this opportunity to gain an international perspective on Orthomolecular Medicine.

Contents

Conference Schedule...................................................................................................................................3 Exhibitors.........................................................................................................................................................4 Exhibitor Floor Plan......................................................................................................................................5 Speaker’s Biographies..................................................................................................................................6

Session One - Orthomolecular Medicine

Neil Riordan

Secretions of Mesenchymal Stem Cells: The Next Generation

in Orthomolecular Medicine . .................................................................................................................8

Tom Levy

Controversies in Nutrition: Calcium - The Toxic Nutrient............................................................. 18

Atsuo Yanagisawa Orthomolecular Treatment for Adverse Effects of HPV Vaccine . ............................................. 29

Session Two - Orthomolecular Psychiatry

Hyla Cass

The Addicted Brain.................................................................................................................................... 33

Benjamin Brown

Brain Mitochondrial Metabolism and Psychiatric Illness ............................................................ 42

Garry Vickar The Abram Hoffer I Knew ....................................................................................................................... 51

Session Three - Orthomolecular Oncology

Ron Hunninghake

Thyroid Dysregulation and the Metabolic Roots of Cancer........................................................ 52

Burt Berkson Lipoic Acid’s Effects on the Mitochondrion and Human Disease Modification................... 70

John Hoffer Evidence-based Orthomolecular Medicine: Principles and Practice.......................................88

Session Four - Orthomolecular Cardiology

Aileen Burford Mason, PhD

Orthomolecular Cardiology: Unmasking the Magnesium Link to

Multiple Cardiovascular Risk Factors...................................................................................................90

Benjamin Brown Healing the Heart with Food and Food Bioactives........................................................................99

David Brownstein A Holistic Approach to Iodine Deficiency ......................................................................................108

Session Five - Orthomolecular Psychiatry

James Greenblatt

Lithium in the Treatment of Mood and Memory Disorders . ...................................................125

Jonathan Prousky Helping Patients to Overcome Psychosis and Schizophrenia: A Clinician’s Experience with the Orthomolecular Approach ...........................................134

Badge colour code: Red=Speaker; Blue=Full Delegate; Yellow=Sessional Delegate; Green=Exhibitor

Friday April 24 8:00 am Registration 8:30 am Exhibits open Session One • Orthomolecular Medicine 9:00 am

Welcome - Introduction

9:15 am

Dr. Rogers Prize Lecture Neil Riordan Secretions of Mesenchymal Stem Cells: The Next Generation in Orthomolecular Medicine

10:15 am Break - Visit Exhibits 10:45 am Annual Evan Shute Memorial Lecture

Tom Levy

Controversies in Nutrition:

Calcium - The Toxic Nutrient

12:30 pm Lunch - Visit Exhibits Session Four • Orthomolecular Cardiology 2:00 pm

Aileen Burford Mason, PhD Orthomolecular Cardiology: Unmasking the Magnesium Link to Multiple Cardiovascular Risk Factors

3:00 pm Benjamin Brown

Healing the Heart with Food and

Food Bioactives 3:30 pm Break - Visit Exhibits 4:30 pm David Brownstein

A Holistic Approach to Iodine Deficiency 5:30 pm Exhibits Close 12th Annual

12:00 pm Atsuo Yanagisawa

Orthomolecular Treatment for Adverse

Effects of HPV Vaccine

Orthomolecular Medicine Hall of Fame

12:30 pm Lunch - Visit Exhibits

7:00 pm Reception 7:30 pm Dinner and Induction

Session Two • Orthomolecular Psychiatry 2:00 pm Hyla Cass

The Addicted Brain

Sunday April 26

3:00 pm Benjamin Brown

Brain Mitochondrial Metabolism and

Psychiatric Illness

8:30 am

International Society for Orthomolecular Medicine meeting

10:00 am Break - Visit Exhibits 4:00 pm Break – Visit Exhibits 4:30 pm Annual Abram Hoffer Memorial Lecture

Garry Vickar

The Abram Hoffer I Knew 5:30 pm Exhibits Close

Session Five • Orthomolecular Psychiatry 10:30 am James Greenblatt

Lithium in the Treatment of Mood

and Memory Disorders

Saturday April 25

11:30 am

Jonathan Prousky Helping Patients to Overcome Psychosis and Schizophrenia: A Clinician’s Experience with the Orthomolecular Approach

Session Three • Orthomolecular Oncology

1:00 pm

Exhibits Close

9:00 am Ron Hunninghake

Thyroid Dysregulation and the

Metabolic Roots of Cancer 10:00 am Break - Visit Exhibits 10:30 am Burt Berkson

Lipoic Acid’s Effects on the Mitochondrion

and Human Disease Modification 11:30 am John Hoffer

Evidence-based Orthomolecular Medicine:

Principles and Practice

Public Workshop

Mental Health Regained featuring Orthomolecular Practitioners and Recovered Patients 2:00 – 4:00 pm

The Orthomolecular Medicine Today Conference is a program of the International Schizophrenia Foundation

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44th Orthomolecular Medicine Today Conference Please Visit Our Exhibitors Acquired Intelligence, Inc. 205 -1095 McKenzie Avenue Victoria, BC V8P 2L5 Canada 250 483 3640 sales@salvestrol.ca www.salvestrol.ca

Doctors Data Inc. 3755 Illinois Avenue St. Charles, IL 60174-2420 USA 800 323 2784 / 630 377 8139 inquiries@doctorsdata.com www.doctorsdata.com

Biotics Research Canada Box 283 Keswick, ON L4P 3E2 Canada 800 840 1676 orders@bioticscan.com www.bioticscan.com

Douglas Laboratories of Canada/ Pure Encapsulations 490 Elgin Mills Road East Richmond Hill, ON L4C 0L8 Canada 866 856 9954 info@douglaslabs.ca www.douglaslabs.ca

Canadian Society for Orthomolecular Medicine 16 Florence Avenue Toronto, ON M2N 1E9 Canada 416 733 2117 info@csom.ca www.csom.ca CanPrev Natural Health Products/ Orange Naturals 70 North Wind Place Toronto, ON M1S 3R5 Canada 888 226 7733 / 905 881 6800 info@canprev.ca www.canprev.ca College Pharmacy 101-3505 Austin Bluffs Parkway Colorado Springs, CO 80918 USA 800 888 9358 / 719 262 0022 info@collegepharmacy.com www.collegepharmacy.com Cyto-Matrix Inc. 300 March Road Kanata, ON K2K 2E2 Canada 613 599 1653 info@cyto-matrix.com www.cyto-matrix.com Designs for Health Canada 980 South Street Suffield, CT 06078 USA 877 414 9388 (Canada) canadaorders@designsforhealth.com www.designsforhealth.ca

Intellewave Inc 238 Rockaway Avenue, 2nd Floor Valley Stream, NY 11580 USA 516 341 0307 info@intellewave.net www.intellewave.net Login Canada klausstrankowski@gmail.com www.lb.ca/bookelite Metagenics Canada, Inc. 851 Rangeview Road Mississauga, ON L5E 1H1 Canada 800 268 6200 brendaparsons@metagenics.com www.metagenics.com Nature’s Source Dispensary 2 - 40 Ronson Drive Toronto, ON M9W 1B3 Canada 866 502 6789 info@natures-source.com www.natures-source.com NutriChem Compounding Pharmacy and Clinic 1303 Richmond Road Ottawa, ON K2B 7Y4 Canada 613 820 4200 info@nutrichem.com www.nutrichem.com

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Nutritional Fundamentals for Health (NFH) 3405 F.X. Tessier Vaudreuil-Dorion, QC J7V 5V5 Canada 866 510 3123 info@nfh.ca www.nfh.ca Rocky Mountain Analytical 32 Royal Vista Drive NW Calgary, AB T3R 1R8 Canada 403 241 4500 info@rmalab.com www.rmalab.com Seroyal International Inc. 490 Elgin Mills Road East Richmond Hill, ON L4C 0L8 Canada 800 263 5861 / 905 508 2050 sales@seroyal.com www.seroyal.com The Great Plains Laboratory Inc. 11813 W. 77th Street Lenexa, KS 66214 USA 800 288 0383 / 913 341 8949 customerservice@gpl4u.com www.greatplainslaboratory.com Truehope / Synergy Group of Canada 680 North, 300 East P.O. Box 888 Raymond, AB T0K 2S0 Canada 866 397 3121 shelley@truehope.com www.truehopeemp.ca York Downs Chemists 3910 Bathurst Street Toronto, ON M3H 5Z3 Canada 800 564 5020 / 416 633 2244 info@yorkdownsrx.com www.yorkdownsrx.com

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44th Orthomolecular Medicine Today Conference Exhibitors

Fairmont Royal York April 24 – 26 Canadian Room

5

12

13

20

3

6

11

14

19

Classroom Setup

Exhibit Area

Podium

2

7

10

15

18

1

8

9

16

17

Nutrition Break

4

Reception

1. Canadian Society for Orthomolecular Medicine/JOM 2. Cyto-Matrix Inc. 3. Acquired Intelligence Inc. 4. Designs for Health Canada 5. Nature’s Source Dispensary 6. Rocky Mountain Analytical 7. NutriChem Compounding Pharmacy and Clinic 8. York Downs Pharmacy 9. The Great Plains Laboratory Inc. 10. Nutritional Fundamentals for Health

11. Biotics Research Canada 12. CanPrev Natural Health Products/Orange Naturals 13. Intellewave Inc. 14. Truehope/Synergy Group of Canada 15. Doctors Data Inc. 16. College Pharmacy 17. Seroyal International Inc. 18. Douglas Laboratories/ Pure Encapsulations 19. Metagenics Canada 20. Login Canada

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conference speakers Burt Berkson, MD, PhD, practices integrative medicine in Las Cruces, New Mexico, and is an adjunct professor at New Mexico State University and Oklahoma State University College of Medicine. He is the expert consultant on alpha-lipoic acid and acute hepatic necrosis and mushroom poisoning at the Centers for Disease Control. He has worked as a researcher and professor at the Max Planck Institute, New Mexico State University, Chicago State University, and Rutgers University. In 2007, Dr. Berkson spoke at the National Cancer Institute on his successful experience in treating cancer and autoimmune disease with Low Dose Naltrexone and Alpha-Lipoic Acid. His three books are The Alpha-Lipoic Acid Breakthrough, All About the B Vitamins, and Syndrome X.

David Brownstein, MD is a Board-Certified family physician and is the Medical Director for the Center for Holistic Medicine in West Bloomfield, MI. He is a graduate of the Wayne State University School of Medicine and has received the Norman E. Clarke Sr. Award for Science and Practice and the ARC Excellence Award for Distinguished Clinician. Dr. Brownstein is a member of the American Academy of Family Physicians and the American College for the Advancement in Medicine. Dr. Brownstein has authored twelve books, including Iodine, Why You Need It, Why You Can’t Live Without It, B12 for Health, Drugs That Don’t Work and Natural Therapies That Do, and The Miracle of Natural Hormones.

Benjamin Brown, ND is a naturopath, science writer and speaker. He teaches nutritional medicine and speaks internationally as well as contributing regularly to industry magazines and scientific journals. Ben also works in natural product research and development and has previously maintained a private practice. Ben founded timeforwellness.org as a way to connect people with free evidence-based health information focusing on natural and lifestyle medicine for chronic disease prevention and the promotion of optimal health.

Aileen Burford Mason, PhD is an immunologist, cell biologist and medical researcher, whose many scientific papers have been published in leading medical and scientific journals. She is formerly Assistant Professor in the Faculty of Medicine, University of Toronto, and Director of The Connacher Cancer Research Laboratory at The Toronto General Hospital. Currently she divides her time between her private practice in orthomolecular nutrition and in lecturing to medical and allied health professionals on the evidence based use of diet and supplements in health maintenance and disease prevention. Her book, Eat Well, Age Better, is published by Dundurn Press.

Hyla Cass, MD, has practiced orthomolecular psychiatry for over 30 years, and is a noted public speaker, consultant, and educator on complementary medicine and psychiatry, women’s health, and natural treatments for anxiety disorders, depression and addiction. She is also a frequent commentator in the media and contributor to numerous books and journals. A former Assistant Clinical Professor of Psychiatry, UCLA School of Medicine, she graduated from the University of Toronto School of Medicine, interned at Los Angeles County-USC Medical Center, and completed a psychiatric residency at Cedars-Sinai Medical Center/UCLA. Dr. Cass is the author of a number of books, including Natural Highs, 8 Weeks to Vibrant Health, Supplement Your Prescription, and The Addicted Brain and How to Break Free. www.cassmd.com

James Greenblatt, MD, is the Chief Medical Officer of Walden Behavioral Care in Waltham, Massachusetts. Dr. Greenblatt has been treating patients with complex eating disorders since 1988. He received his medical degree and completed his adult psychiatry residency at George Washington University in Washington, DC, and completed a fellowship in child and adolescent psychiatry at Johns Hopkins Medical School. He maintains a private practice in Waltham, Massachusetts. Dr. Greenblatt is Medical Director of Comprehensive Psychiatric Resources, an orthomolecular treatment center in Boston, Massachusetts and is Assistant Clinical Professor at Tufts University Medical School, Department of Psychiatry.

John Hoffer, MD, PhD, is a professor of medicine at McGill University and an associate professor in McGill’s School of Dietetics and Human Nutrition. He is a full-time investigator in the Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, a Senior Physician in the Division of General Internal Medicine, and a member of the hospital’s nutrition support team.

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conference speakers Ron Hunninghake, MD, is the Chief Medical Officer of the Olive W. Garvey Center for Healing Arts, the clinical division of the Riordan Clinic. A 1976 graduate of the University of Kansas School of Medicine, Dr. Hunninghake has devoted his career to the emerging paradigm of Self Care: the patient as an informed medical partner. In addition to his full-time practice at The Center, Ron is a regular presenter at medical conferences, and The Center’s “Lunch & Lecture” series on timely, health-related topics. Dr. Hunninghake has published three books on health and wellness: The User’s Guide to Inflammation, Arthritis, and Aging (2005); The User’s Guide to EnergyBoosting Supplements (2006); Stop Prediabetes Now (2007).

Tom Levy, MD, JD, is a board-certified cardiologist and a bar-certified attorney. After practicing adult cardiology for 15 years, he began to research the enormous toxicity associated with much dental work, as well as the pronounced ability of properly-administered vitamin C to neutralize this toxicity. He has now written nine books, with several addressing the wide-ranging properties of vitamin C in neutralizing all toxins and resolving most infections, as well as its vital role in the effective treatment of heart disease and cancer.

Currently, Dr. Levy continues to research the impact of the orthomolecular application of vitamin C and antioxidants in general on chronic degenerative diseases. His book, Death By Calcium, makes the scientific case that chronic supplemental calcium is always toxic. It also demonstrates that the current protocols for treating osteoporosis, a focal scurvy of the bones, ultimately cause substantially greater disease and more death, largely via heart attacks and cancer, than the condition that is being treated.

Jonathan Prousky, ND, MSc, graduated from Bastyr University (Kenmore, WA) with a Doctorate in Naturopathic Medicine. He is the Chief Naturopathic Medical Officer at the Canadian College of Naturopathic Medicine and also supervises at the Robert Schad Naturopathic Clinic. He is a passionate advocate for patients having psychiatric disorders and focuses his clinical practice on optimizing mental and neurological health with nutrition and botanical (plant-based) medicines. He has lectured extensively on various healthrelated topics throughout North America and is the current editor of the Journal of Orthomolecular Medicine. His clinician-based research primarily involves the neuropsychiatric applications of vitamin B3.

Neil Riordan, PhD, earned his doctorate in Health Sciences at Medical University of the Americas. He is the founder and Chairman of Medistem Panama which was founded in 2007, and is at the forefront of research of the effects of adult stem cells on the course of several chronic diseases. The cGMP, cGLP compliant stem cell laboratory at Medistem Panama is a fully licensed by the Ministry of Health of Panama. Dr. Riordan has more than 60 scientific articles in international peer-reviewed journals. In the stem cell arena, he and his colleagues have published more than 20 articles on Multiple Sclerosis, Spinal Cord Injury, Heart Failure, Rheumatoid Arthritis, Duchenne Muscular Dystrophy, Autism, and Charcot Marie Tooth Syndrome. In 2007, Dr. Riordan’s research team was the first to discover and document the existence of mesenchymal-like stem cells in menstrual blood. For this discovery his team was honored with the “Medical Article of the Year Award” from Biomed Central. He is also an inventor or co-inventor on more than 25 patent families, including 11 issued patents. In 2010, Dr. Riordan was granted a patent for a new cellular vaccine for patients with cancer.

Garry Vickar, MD, is a psychiatrist who specializes in acutely ill patients. With an active, full-time private practice, Dr. Vickar is board certified by the Royal College of Physicians and Surgeons of Canada and the American Board of Psychiatry and Neurology. He is the chairman of the Department of Psychiatry at Christian Hospital Northeast where he is medical director of schizophrenia treatment and education programs. Dr. Vickar is a lecturer at Washington University Department of Psychiatry in St. Louis as well as a Professor and Clinical Chair in the Department of Psychiatry at St. Matthews University, Grand Cayman, BWI. He is a frequent radio/tv guest on the subject of general mental health issues and, in 2013-14, was listed in the “Best Doctors” of St. Louis. Additionally, Dr. Vickar received recognition as a Distinguished Life Fellow of the American Psychiatric Association.

Atsuo Yanagisawa, MD, graduated from the Kyorin University School of Medicine in 1976, and completed his graduate work in 1980 from the Kyorin University Graduate School of Medicine in Tokyo, Japan. Dr. Yanagisawa served as Professor in Clinical Medicine at the Kyorin University School of Health Sciences, and concurrently as Professor in Clinical Cardiology at Kyorin University Hospital until 2008.

Dr. Yanagisawa has served as the Director of The International Education Center for Integrative Medicine in Toyko, Japan, since 2008, and has been President of the International Society for Orthomolecular Medicine since 2012.

Thanks to our generous sponsor

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Controversies in Nutrition: Calcium - The Toxic Nutrient !"#$%"&%"'( Tom Levy, MD, JD

Reference Checking Go to: http://www.ncbi.nlm.nih.gov/pubmed/ In the PubMed search box, enter the seven or eight digit number, by itself, at the end of each reference in this presentation. This is the PubMed Identifier (PMID) number Then click on “Search” and you will go directly to the Abstract of that article, or for a few articles, you will have access to the full article. If there is no PMID number, it is not available on PubMed.

Calcium: The Toxic Nutrient

Calcium: Background Information

Calcium: Background Information

While calcium is essential for normal cellular function, elevations of calcium both inside and outside the cells are part of the final common denominator for nearly all chronic degenerative diseases, for the development and aggressiveness of any given cancer, and for premature cell death. The evidence also indicates excess calcium causes many chronic diseases, and is not just incidentally associated with them.

This presentation will give the scientific basis for the still little-appreciated toxicity of calcium in virtually all chronic degenerative diseases. Most importantly, it will be shown that although there is clearly a decreased content, or deficiency, of calcium in osteoporotic bone, there is a corresponding excess of calcium outside of the bone, more so the worse and more long-standing the osteoporosis has been. The degree of deficiency of calcium in the bone is actually the major measure of the degree of calcium excess throughout the rest of the body.

In other words, it will be shown that the vast majority of the adult population in the developed parts of the world suffer from body-wide excesses of calcium, not deficiencies, as so many in medicine today continue to assert.

Calcium: Facts and Fictions

Calcium: Facts and Fictions

Calcium is prominently featured in the popular press and medical literature primarily because of its still nearly universally-recommended usage in the treatment of osteoporosis, and even for good health in general.

Fiction #2: “Calcium supplementation prevents fractures.”

Fiction #1: “Calcium supplementation and increased dietary calcium are good for you.”

Many studies involving calcium supplementation that showed decreased fracture incidence also supplemented vitamin D, typically 800 IU daily, as 400 IU of D along with calcium did not consistently produce a benefit. (Jackson et al., 2006 [16481635]; Bischoff-Ferrari et al., 2005 [15886381]).

Adequate vitamin D alone reliably decreases fracture incidence. (Bischoff-Ferrari et al., 2012 [22762317]; Rizzoli et al., 2013 [23320612]) Calcium supplementation alone does not prevent fractures (Kurabayashi, 2012 [22549199])

This is the classical case of marketing completely trumping science. The truth: a prospective study over a 19-year period followed 61,433 women. Women with the highest dietary intake of calcium and who supplemented calcium as well had an all-cause mortality risk 2.5 times higher than those women who did not supplement calcium.

(Michaelsson et al., 2013 [23403980])

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Calcium: Facts and Fictions

Calcium: Facts and Fictions

Fiction #2: “Calcium supplementation prevents fractures.”

Fiction #3: “You cannot get enough calcium in your diet without dairy products.”

Calcium supplementation can minimally improve the results of the bone mineral density tests. However, this is a cosmetic change only, as the increased calcium content from such supplementation is really no different from a fresh coat of paint on a fence with rotting wood. It looks better, but it does not restore any structural integrity to the fence, and the fence will continue to deteriorate. The healthy structural matrix of the bone requires vastly more than calcium for repair and regeneration.

This improvement in the test appearance is not associated with any decreased propensity for bone fracture, the true “bottom line” is determining effectiveness of an osteoporosis therapy.

More marketing. Enjoy your dairy if you wish, but do not delude yourself into thinking that anything beyond a minimal amount of it in your diet is good for you. Bodywide states of calcium deficiency are very strongly entrenched myths, nothing more. As is too often the case with a number of strongly-promoted scientific/medical assertions and beliefs, the exact opposite is true.

Calcium: Facts and Fictions

Calcium: Facts and Fictions Fiction #4: “Everyone with osteoporosis has a calcium deficiency.”

Fiction #3: “You cannot get enough calcium in your diet without dairy products.”

In the bones, yes; in the body, no. Fully 99% of the body’s normal content of calcium is in the bone, and as osteopenia and osteoporosis relentlessly break down the integrity of the bone, a large amount of this calcium ends up where only 0.1% of it should be: in the rest of the body.

Dairy is not invariably bad for you, but dairy is one of the most manipulated foods available, and has been so for a very long time. Unpasteurized dairy products from properly raised cows have significant nutrient value. However, excess dairy can be expected to almost always have a net negative effect due to the excess calcium. If a little is good, more is not necessarily better.

Calcium: Facts and Fictions

Calcium, Vitamin C, and Oxidative Stress

Fiction #5: “The biggest danger faced by the osteoporosis patient is disability or death following a fracture.”

It is the biochemistry of vitamin C and redox chemistry that is the major key in understanding both the physiology of health and the pathophysiology of disease in man and animals.

The effects of all toxins and all infections are pro-oxidant in nature, and it is their ability to deplete (oxidize) vital biomolecules that allow them to cause and promote chronic diseases.

It is the ability of vitamin C as the body’s premier antioxidant to reduce (supply electrons to) pro-oxidant toxins directly or to reduce back to normal status the biomolecules they have already oxidized.

Another completely wrong but commonly held view.

In 10,000 postmenopausal women with low bone mineral density, a 60% increased chance of death was seen in the lowest quintile of BMD compared to the highest quintile.

However, most of the deaths did not relate to a fracture.

(Browner et al., 1991 [1677708]. Interpretation: osteoporosis is a risk factor for increased chance of death, but not primarily because of fracture (heart attack and cancer the primary reasons).

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Osteoporosis is a Focal Scurvy of the Bones

Osteoporosis is a Focal Scurvy of the Bones

The dynamics of bone physiology involve three important factors:

1. Increased oxidative stress (aka increased inflammation) in the bones, as tracked by higher levels of C-reactive protein, reliably predicts increased chances of osteoporotic fracture in elderly women (Nakamura et al., 2011 [20936400]) 2. Increased levels of many other inflammatory parameters relate to increased fracture risk (Lacativa and Farias, 2010 [20485900]) 3. C-reactive protein levels and multiple other inflammatory parameters are significantly reduced by high doses of vitamin C (Mikirova et al., 2012 [22963460])

1. Formation (minerals, collagen, proteins, calcium) 2. Destruction (the dissolution and release of minerals and calcium, which degradation of collagen and proteins, along with less cross-linking of these structural molecules) 3. Oxidative stress levels, with low levels favoring bone formation and high levels favoring bone destruction

Osteoporosis is a Focal Scurvy of the Bones

Osteoporosis is a Focal Scurvy of the Bones

4. Osteoblasts, the bone-forming cells, are stimulated to develop from precursor cells by vitamin C (Carinci et al., 2005 [15777530]) 5. The precursor cells from which osteoblasts develop are stimulated to proliferate by vitamin C (Choi et al., 2008 [18640597]) 6. Vitamin C is essential for the type III collagen required for the accelerated growth of osteoblasts (Maehata et al., 2007 [17306970]) 7. Osteoclasts, the bone-destroying cells, are inhibited by vitamin C (Gabbay et al., 2010 [20410296])

8. A vitamin C deficiency results in osteoclast proliferation, with resulting increased bone resorption (Hie and Tsukamoto, 2011 [20444587]) 9. Net bone loss, with demineralization and loss of integrated calcium, is accelerated when vitamin C levels get sufficiently depleted (Park et al., 2012 [22974214]) 10. The cross-linking of bone collagen (comprising 90% of the bone matrix protein) required for structural strength, is strongly supported by vitamin C (Munday et al., 2005 [15946412])

Osteoporosis is a Focal Scurvy of the Bones

Osteoporosis is a Focal Scurvy of the Bones

11. Supplemental vitamin C alone can lower the risk of osteoporotic fractures in elderly individuals (Leveille et al., 1997 [9425455]) 12. Dietary vitamin C intake (always vastly lower in amount than achieved with any significant supplementation) had no association with fracture risk (Sahni et al., 2009 [19347239]) 13. Elderly patients who already sustained an osteoporotic fracture had significantly lower vitamin C blood levels than those who were fracture-free (Martinez-Ramirez et al., 2007 [18622945])

14. Vitamin C supplementation, without calcium supplementation, resulted in significantly greater bone mineral density at all bone sites tested (Morton et al., 2001 [11149477]) 15. In mice with ovaries removed [no positive estrogen effect], vitamin C prevented the bone loss otherwise seen, establishing it as a skeletal anabolic agent (Zhu et al., 2012 [23056580]) 16. Vitamin C substantially accelerates the healing of experimental fractures (Yilmaz et al., 2001 [11510911]) 17. Vitamin C significantly improves the strength of healed fractures (Alcantara-Martos et al., 2007 [17356161])

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Calcium and Oxidative Stress

Calcium and Oxidative Stress

Calcium, which is concentrated up to 10,000 times more outside the cells of the body than inside, needs to be maintained within a fairly narrow range of normal inside the cells to permit optimal cellular function. Any intracellular calcium concentrations above this normal range are always accompanied by increased intracellular oxidative stress, and are probably the primary cause of this state. The very large gradient of calcium from extracellular to intracellular requires a significant consumption of energy in order to be properly maintained, and any significant compromise in energy availability (aka, more toxin presence) invariably leads to progressively increasing intracellular calcium concentrations.

The bones contain up to 99% of the calcium present in the body. The calcium in solution in the blood, the extracellular fluids, and the cytoplasm inside the cells is only approximately 0.1% of the total calcium content in the body. As osteoporosis and the osteopenia of aging evolve over time, an enormous amount of calcium chronically floods the extracellular fluids, and calcium deposition invariably results. The intracellular calcium levels also rise sufficiently to substantially increase intracellular oxidative stress, promoting all chronic degenerative diseases, while also being a required factor for malignant transformation.

Calcium, Intracellular Oxidative Stress, and Malignancy

Calcium, Intracellular Oxidative Stress, and Malignancy

Levels of Intracellular Oxidative Stress

Levels of Intracellular Oxidative Stress

1. None, or not readily detectable (as in dormant and non-replicating cells) 2. Minimal (baseline physiological level of oxidative stress, as in viable but non-replicating cells of less metabolically active organs) 3. Minimal to moderate (physiological oxidative stress in viable but nonreplicating cells of organs with a high level of physiological activity, like heart) (Santos et al., 2011 [21236334]; Bogeski et al., 2011 [21930299] 4. Moderate (can be normal or abnormal, depending on what the cell is doing; when normal, the moderate state is usually transient; if calcium and iron levels are elevated, moderate almost always represents the arrival or imminent arrival of the malignant state)

5. Moderate to elevated (characteristic of established and replicating cancer cells; never seen in normal cells unless transient, as in proceeding to programmed cell death) Parri and Chiarugi, 2013 [23146119] Many cancer cells have increased expression of calcium channels (Embi et al., 2012 [23216811]) 6. Elevated (most metabolically active of cancer cells, anaplastic or metastatic) Shen et al., 2013 [23373752] 7. Greatly elevated (in cancer cells with upregulated Fenton activity, as provoked by chemotherapy or high-dose vitamin C) 8. Maximal (very transient, proceeding promptly to apoptosis or frank necrosis)

Regulation of Intracellular Calcium Levels

Calcium, Intracellular Oxidative Stress, and Disease

1. Changes in cell permeability 2. The buffering and/or binding of calcium inside the cells (Yanez et al., 2012 [22453954]) 3. The sequestration or compartmentalization of calcium in intracellular organelles (Galva et al., 2012 [23077175]) 4. Regulation of energy-requiring active calcium extrusion from the cell [calcium pump] (Kurnellas et al., 2007 [17956247])) 5. Modulation of calcium channels (membrane proteins); of greatest importance in the control of intracellular calcium concentration (use of CCBs, natural and drug)

It is the highest elevations of intracellular calcium that ultimately result in cell death (Garcia-Prieto et al., 2013 [23250754]; Schwartz et al., 2013 [23220009]) Toxins routinely increase intracellular levels of calcium, with resulting increased intracellular oxidative stress, and ultimately cell death (Chi et al., 2012 [23160928]; Roos et al., 2012 [22927718]; Li et al., 2012 23049237]) Elevated intracellular calcium levels have been consistently seen in ALS, Parkinsonâ&#x20AC;&#x2122;s, and Alzheimerâ&#x20AC;&#x2122;s (Kawamata and Manfredi, 2010 [20493207]; Surmeier et al., 2011 [21884755]; Corona et al., 2011 [21697951])

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Calcium and Calcium Channel Blockers

Calcium and Calcium Channel Blockers

Calcium channels refer to proteins in the cell membrane that facilitate selective permeability to calcium ions.

Calcium channel blockers (CCBs), or calcium antagonists, comprise a class of drugs that prevents the ability of calcium to utilize these calcium channels and gain entry into the cells of the body.

Although widely used for different reasons today, CCBs were developed as antihypertensive agents, as they have vasodilating effects.

The only significant clinical side effect of CCBs is that of excessive calcium-blocking effect, which translates to impaired vascular contraction and hypotension.

For CCBs to work as antihypertensives, the direct implication is that a state of calcium excess inside the cells of the body must exist in the first place, causing the vasoconstriction. While the different CCBs can have additional effects, their most profound effect remains blocking calcium entry into the cells.

Therefore, a logical conclusion of the effects of CCBs throughout the body is that: The positive effects of CCBs in any disease process occur because the diseased cells have increased intracellular levels of calcium.

Calcium and Calcium Channel Blockers

Calcium and Calcium Channel Blockers

In addition to high blood pressure, many diseases are known to benefit from CCB administration: 1. Coronary artery spasm (Kusama et al., 2011 [21389642]); angina pectoris (Siama et al., 2013 [23016717]) 2. Anti-atherosclerosis (Ishii et al., 2012 [22653165]) 3. Pulmonary hypertension (Montani et al., 2010 [20543192]) 4. Raynaud’s phenomenon (Huisstede et al., 2011 [21704799] 5. Acute head trauma (Aslan et al., 2012 [22854593])

Diseases known to benefit from CCB administration: 6. Epilepsy (Ianneti et al., 2009 [19303743]) 7. Chemotherapy-induced peripheral neuropathy (Tatsushima et al., 2013 [23206755]) 8. Alzheimer’s disease (Anekonda and Quinn, 2011 [21925266]) 9. Parkinson’s disease (Pasternak et al., 2012 [22387374]) 10. Osteoporosis (rat study, Shimizu et al., 2012 [21881574])

Calcium, Intracellular Oxidative Stress, and Disease

Chronic Calcium Excess: The Rule, Not the Exception

Further support for the concept that increased intracellular calcium leads to intracellular oxidative stress (toxicity): 1. Calcium channel blockers prevent the neurological damage from methylmercury in rats (Sakamoto et al., 1996 [8882354]) 2. Long-acting calcium channel blockers decrease the chances of death from all causes (Gillman et al., 1999 [10323641]; Gibson et al., 2000 [10922432]; Lubsen et al., 2005 [15716708]; Costanzo et al., 2009 [19451836]) 3. Calcium channel blocker use is inversely related to prostate cancer incidence (Poch et al., 2012 [23280547]) 4. Calcium channel blockers can decrease cytoplasmic iron accumulation, an additional important factor in malignant transformation and the further elevation of intracellular oxidative stress (Chattipakorn et al., 2011 [21860702])

Five major causes of bodywide calcium excess: 1. Excess calcium intake (supplementation and/or diet) 2. Excess calcium mobilization from the bones 3. Deficient vitamin C and antioxidant stores in the bones and elsewhere 4. Sites of chronic infection and inflammation in the body (especially root canals and tonsils) 5. Chronic deficiencies of important regulatory hormones (testosterone, estrogen, thyroid)

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Chronic Calcium Excess: The Rule, Not the Exception

Chronic Calcium Excess Extracellular Calcium Excess

Extracellular Calcium Excess

Ectopic calcifications are very commonly seen in patients with cancer.

Using advanced magnetic resonance imaging, 22 of 23 prostate cancer patients were found to have prostatic calcifications (Bai et al., 2013 [23308170]) Women with the highest scores on bone density testing had an increased risk of developing breast cancer (Zhang et al., 1997 [9032046]) Mammography on women with breast cancer often have macro- and micro-calcifications (Holmberg et al., 2013 [23370209])

One third of American over the age of 45 have arterial calcification when assessed by computed tomography (Guzman, 2007 [17544025]). Anytime overt calcification is seen outside of the bones, a state of excess calcification exists by definition. Logically, a significant degree of calcium excess will be present well before frank calcium deposition finally occurs.

Chronic Calcium Excess: Modulating Role of Vitamin C

Chronic Calcium Excess Extracellular Calcium Excess

Extracellular Calcium Excess

Coronary artery calcium (CAC) scores reliably predict not only death from heart disease, but also death from all causes (Jacobs et al., 2012 [22357989]; Kiramijyan et al., 2013 [23206921]) This indicates that the main indicator of extracellular excess, ectopic calcium deposition, reliably predicts increased risk of death from any chronic degenerative disease. This further indicates that a presence of a chronic extracellular calcium excess will reliably indicate secondary chronic intracellular calcium excesses.

Men with the highest levels of plasma VC had the least CAC (Simon et al., 2004 [15003962]) Increased inflammatory markers, seen with lower levels of VC, also relate to an increased progression of CAC (Alman et al., 2013 [23340891]) Vitamin C has long been known to promote calcium solubility [Ruskin, S. (1938) Studies of the parallel action of vitamin C and calcium. American Journal of Digestive Diseases 5:408-411.

Individuals with the highest VC levels live the longest, and risk of all-cause mortality is reduced (Khaw et al., 2001 [11247548]; Jia et al., 2007 [17442130])

Chronic Calcium Excess

Osteoporosis Reversal Agents 1. Magnesium A. A natural calcium channel blocker (Fawcett et al., 1999 [10618948]); magnesium and calcium are biological antagonists (Anghileri, 2009 [20228002]) B. Dissolves calcium deposits (Steidl and Ditmar, 1990 [2133625]) C. Mg deficiency increases intracellular calcium (Fox et al., 2001 [11811859]) D. Increases bone density and decreases fracture incidence (Ryder et al., 2005 [16274367]) E. Decreases all-cause mortality (Woods and Fletcher, 1994 [7908076]; Shechter et al., 2003 [12845247]) F. Non-toxic at supplemented doses

Intracellular Calcium Excess and Cancer Well-established relation to the malignant state. Also, even further increases in intracellular calcium increase the degree of cancer cell proliferative and invasiveness/ metastatic capacity (Gudermann and Roelle, 2006 [17158754]; Kaufmann and Hollenberg, 2012 [22453980]; Ryu et al., 2013 [23328481]) Conversely, the removal of calcium from the intracellular space decreases metastatic capacity (Lin et al., 2010 [20824051])

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Osteoporosis Reversal Agents

Osteoporosis Reversal Agents

2. Vitamin K A. Activator of proteins known to inhibit ectopic calcification, like osteocalcin and matrix Gla protein (MGP) (Theuwissen et al., 2012 [22516724]) B. Helps dissolve existing calcifications (Schurgers et al., 2007 [17138823]) C. Neutralizes warfarin (an agent that causes ectopic calcification) (Price et al., 1998 [9743228]) D. Decreases risk of fracture (Shiraki et al., 2000 [10750566]) and improves bone quality (Saito, 2009 [19949271]) E. Decreases cardiac and all-cause mortality (Geleijnse et al., 2004 [15514282]) F. No definable toxicity at any dose level (Pucaj et al., 2011 [21781006])

3. Vitamin C A. Osteoporosis is bone scurvy, with a generalized deficiency of other antioxidants as well. The other agents discussed compensate for this scurvy to the degree that some antioxidant capacity is restored to the bone. However, the rebuilding of new bone requires adequate vitamin C B. Decreases bone resorption and increases bone synthesis; supplemental vitamin C results in greater bone density; accelerates fracture healing and is essential for normal bone integrity C. Highest VC levels, least fractures.

D. Decreases all-cause mortality.

E. Virtually non-toxic at any dose; no definable toxic level ever defined

Osteoporosis Reversal Agents

Osteoporosis Reversal Agents 5. Essential fatty acids

4. Vitamin D A. Normal vitamin D blood levels with most dietary regimens assures adequate calcium intake B. Critical for far more than bone and calcium metabolism, regulating up to 2000 genes (Wacker and Holick, 2013 [23306192]) C. Deficiency causes osteoporosis (Bolland et al., 2010 [19906799]) D. Excess worsens osteoporosis (Masterjohn, 2007 [17145139]) E. A key determinant of bone mineral density while growing up (Pekkinen et al., 2012 [22768331]) F. In therapeutic range, decreases all-cause mortality (Semba et al., 2010 [19953106]; Schottker et al., 2013 [23446902])

A. Some with calcium channel blocking activity (Ye et al., 2010 [20206488]; Pages et al., 2011 [21664114]) B. Highest levels afford protection against loss of bone mineral density (Farina et al., 2012 [22392875]; Moon et al., 2012 [22507833]) C. Blood levels inversely related to total mortality (Pottala et al., 2010 [20551373]) D. No clear toxic effects; some GI intolerance at high intakes

Osteoporosis Reversal Agents

Osteoporosis Reversal Agents

6. Estrogen A. Decreases ectopic calcification in the coronary arteries (Weinberg et al., 2012 [22747181]; Higher blood levels, lower CAC scores (Jeon et al., 2010 [20512078]) B. Inhibits a key protein that promotes calcification (Osako et al., 2010 [20595654]) C. Deficiency increases proinflammatory cytokines (Das, 2002 [11815671]) D. Lessens incidence of osteoporotic fractures (de Villiers and Stevenson, 2012 [22612613]) E. Deficiency increases all-cause mortality (Mansur et al., 2012 [22701354]) and promotes metabolic syndrome (Mauvais-Jarvis et al., 2013 [23460719])

7. Testosterone A. Deficiency a clear risk fracture for fractures (Torremade-Barrera et al., 2013 [23246104]) B. Has calcium channel blocking effects (Oloyo et al., 2011 [21439799]) C. Prostate cancer frequently associated with low testosterone levels (Mearini et al., 2013 [22068548]) D. Testosterone levels inversely related to CAC (Park et al., 2012 [22522505]) E. Deficiency increases all-cause mortality (Fukai et al., 2011 [21143567]; Grossman et al., 2012 [22280063])

24

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Osteoporosis Reversal Agents

Osteoporosis Reversal Agents

7. Testosterone Factors in restoration of deficiency (similar to restoration of estrogen deficiency) Dose, type, formulations, routes, duration, timing, accompanying antioxidants, serial clinical correlation and laboratory testing, target levels Also, PSA monitoring: Testosterone promotes preexisting prostatic cancer cell growth, but does not induce malignant transformation in the prostate. Testosterone therapy actually offers the benefit of exposing earlier the presence of preexisting prostate cancer with follow-up PSA testing.

8. Thyroid hormone A. Substantial effects of the metabolism of all the cells in the body (Boelaert and Franklin, 2005 [16214936]) B. Necessary for early skeletal development and the establishment of peak bone mass (Williams, 2009 [19885809]) C. High and low thyroid function increases fracture risk (Wojcicka et al., 2013 [22634735]) D. TSH has a direct bone-protecting effect, not involving the thyroid gland (Ma et al., 2011 [21745106]; Sun et al., 2013 [23716650])

Osteoporosis Reversal Agents

Reversing Osteoporosis and Chronic Degenerative Disease

8. Thyroid hormone E. High and low thyroid hormone levels are independent risk factors for death from all causes. This includes subclinical hypothyroidism (T4 normal, TSH elevated) and subclinical hyperthyroidism (Tseng et al., 2012 [22726629]; Ceresini et al., 2013 [23647402]) F. Thyroid status must be a routine part of all general medical evaluations, and needs to be rechecked every few years in the older population.

Primary goals: 1. Minimize new toxin exposure 2. Eradicate acute and chronic infections 3. Eliminate accumulated toxins 4. Normalize or improve deficient regulatory hormones (estrogen, testosterone, thyroid) 5. Optimize antioxidant and nutrient levels, especially vitamin C 6. Selectively and appropriately utilize prescription medications

Reversing Osteoporosis and Chronic Degenerative Disease

Reversing Osteoporosis and Chronic Degenerative Disease

1. Minimize new toxins

1. Minimize new toxins

A. No calcium, iron, or copper supplementation; no milk drinking, but just reasonable restraint with other dairy products; butter and cream, no problem B. Address dental toxins/infections a. Root canals b. Gums c. Cavitations d. Dental implants (inappropriately placed and maintained) e. Toxic dental materials (mercury, nickel)

C. Dietary/digestive (optimize bowel transit time) Food combining, chewing, liquids, enzymes, low glycemic, minimize meat quantities, minimize dairy (less calcium and poorer digestion) Poor foods digested perfectly produce less toxicity than optimal foods digested poorly.

25

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Reversing Osteoporosis and Chronic Degenerative Disease

Reversing Osteoporosis and Chronic Degenerative Disease

2. Eradicate infections Most infections significantly lowering antioxidant stores through the body will be found in dental sources. However, for many individuals, chronically infected tonsils will significantly impair or even block the recovery from many different chronic diseases. Usually tonsils that need extracting will be on the same side of the oral cavity as an existing or even previously extracted root canal-treated tooth. Generally, once a tonsil has drained a root canal for any significant length of time, it cannot recover even if the root canal is extracted. Rather, it becomes a source of chronic focal infection, seeding pathogens and toxins throughout the body. The protector becomes the infector.

(Issels, 2005, Cancer, A Second Opinion)

3. Eliminate old toxins Remember that detoxification is retoxification.

A. Traditional agents (DMSA, DMPS, BAL, EDTA, penicillamine, deferasirox) B. Nutrient agents (alpha lipoic acid, inositol hexaphosphate, any agent supporting and increasing intracellular GSH levels, such as NAC, whey protein, and liposome encapsulated GSH) C. Sweating (far infrared sauna, aerobic exercise) D. Always protect with adequate antioxidant coverage

Reversing Osteoporosis and Chronic Degenerative Disease

Reversing Osteoporosis and Chronic Degenerative Disease

4. Correct critical hormone deficiencies

5. Optimize antioxidant levels A. Vitamin C, regular form as tolerated; liposome-encapsulated, 1 to 2 grams daily; ascorbyl palmitate, 500 to 1,000 mg daily B. Lysine, 1,000 to 2,500 mg daily and proline, 250 to 500 mg daily (2x more for known CAD) C. Vitamin D3: aim for blood level of 50 to 80 ng/cc D. Vitamin K2, 3 to 6 mg daily E. Magnesium glycinate, 200 to 400 mg daily F. Omega-3 EFA, fish oil source, 2,000 to 4,000 mg daily G. Vitamin E as mixed tocopherols, 400 IU twice daily H. Beta carotene, 25,000 to 50,000 IU daily I. Vitamin B complex, one daily

Testosterone, estrogen, and thyroid deficiencies affect all the cells of the body. All three play prominent roles in calcium metabolism, in the bone and elsewhere Replacement must be low dose, slow to increase dose, and target lab values should be low to mid-range normal, no more, and even a lower target for the person over age 70.

Other critical laboratory tests, such as metabolic syndrome parameters, should be stable or improving during the treatment period.

Reversing Osteoporosis and Chronic Degenerative Disease

Reversing Osteoporosis and Chronic Degenerative Disease 6. Appropriate prescription medicines

6. Appropriate prescription medications Only really to be utilized when a satisfactory clinical response is not seen with the rest of the protocol. The side effects of selective estrogen receptor modulators (SERMs), bisphosphonates, calcitonin, strontium ranelate, and parathyroid hormone are substantial. This needs to be considered in the context that vitamin C, vitamin D, vitamin K, magnesium, EFAs, and properly adjusted hormone levels all decrease the chances of death from all causes. The prescription meds have side effects and only rarely positively impact longetivity.

Whenever clinical circumstances allow, consider using a long-acting calcium channel blocker, which also decreases all-cause mortality.

While not a recognized medical indication, it might be wise to consider such calcium channel blocker therapy in any older patient for the known positive effects of this drug class on basic disease pathology and longevity.

26

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Tracking Toxicity

Tracking Toxicity Parameters of calcium accumulation, along with routine laboratory testing and serial clinical evaluation, offer a fairly precise way to know that the patient is being treated optimally.

Many different treatment protocols exist for many different conditions, both in mainstream medicine and in complementary or alternative medicine.

Many different protocols can produce a net positive result, but still fall far short of an optimally positive result. Just getting some positive result does not mean that a protocol was optimal, if a greater positive effect was possible.

Infrequently, and mostly in older patients who have longstanding pathology and a large amount of secondary tissue and organ damage, the optimal protocol can only achieve a slowing of the ongoing disease pathology and a slowing of calcium accumulation. Taking the measures needed to mobilize calcium is much more effective at slowing aging to physiological levels, not reversing it. However, in younger individuals, some reversal of the parameters of aging is clearly achievable.

Calcium Toxicity: Recap

Calcium Toxicity: Recap

1. All chronic degenerative diseases feature increased extracellular and intracellular levels of calcium.

Calcium deposition often results in the extracellular space, where calcium concentrations are vastly higher than inside the cells. The increased extracellular calcium always leads to increased intracellular calcium, which always results in increased intracellular oxidative stress.

2. While a calcium deficiency is always present in the bones of individuals with chronic disease and is especially severe in those with osteoporosis, it is precisely the chronic loss of calcium from its large bony reservoir that continually feeds the excess presence of calcium elsewhere in the body. Calcium supplementation and excess dairy intake only further fuel this excess extraskeletal calcium presence.

Calcium Toxicity: Recap

Calcium Toxicity: Recap 4. While many different factors play a role in calcium intake, the most important factors are:

3. While vitamin D is essential for good health, it is essential that supplementation is monitored by blood testing, as both vitamin D deficiency and vitamin D excess promote osteoporosis and the redistribution of calcium from the bones to the rest of the body, as well as promote increased all-cause mortality.

A. Calcium content in the diet (especially dairy, as non-dairy sources of calcium do not significantly factor into causing a state of excess calcium) B. Calcium supplementation C. Vitamin D status

27

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Controversies in Nutrition: Calcium - The Toxic Nutrient!"#$%"&%"'( Tom Levy, MD, JD

Calcium Toxicity: Recap

For Contact and Further Information www.peakenergy.com (www.tomlevymd.com) Videos, newsletters, books, and general information

5. Death from all causes is increased by increased calcium intake, whether from calcium supplementation, or an increased dietary calcium intake, or both.

For questions or comments: televymd@yahoo.com

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Khan et al. BMC Medicine 2013, 11:99 http://www.biomedcentral.com/1741-7015/11/99

RESEARCH ARTICLE

Open Access

Slow CCL2-dependent translocation of biopersistent particles from muscle to brain

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Zakir Khan1,2, Christophe Combadière3,4,5, François-Jérôme Authier1,2,6, Valérie Itier1,2,11, François Lux7,8, Christopher Exley9, Meriem Mahrouf-Yorgov1,2,11, Xavier Decrouy1,2, Philippe Moretto10, Olivier Tillement7,8, Romain K Gherardi1,2,6,12*† and Josette Cadusseau1,2,11,12*† Abstract Background: Long-term biodistribution of nanomaterials used in medicine is largely unknown. This is the case for alum, the most widely used vaccine adjuvant, which is a nanocrystalline compound spontaneously forming micron/ submicron-sized agglomerates. Although generally well tolerated, alum is occasionally detected within monocytelineage cells long after immunization in presumably susceptible individuals with systemic/neurologic manifestations or autoimmune (inflammatory) syndrome induced by adjuvants (ASIA).

Methods: On the grounds of preliminary investigations in 252 patients with alum-associated ASIA showing both a selective increase of circulating CCL2, the major monocyte chemoattractant, and a variation in the CCL2 gene, we designed mouse experiments to assess biodistribution of vaccine-derived aluminum and of alum-particle fluorescent surrogates injected in muscle. Aluminum was detected in tissues by Morin stain and particle induced X-ray emission) (PIXE) Both 500 nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids (Al-Rho) were used.

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Results: Intramuscular injection of alum-containing vaccine was associated with the appearance of aluminum deposits in distant organs, such as spleen and brain where they were still detected one year after injection. Both fluorescent materials injected into muscle translocated to draining lymph nodes (DLNs) and thereafter were detected associated with phagocytes in blood and spleen. Particles linearly accumulated in the brain up to the six-month endpoint; they were first found in perivascular CD11b+ cells and then in microglia and other neural cells. DLN ablation dramatically reduced the biodistribution. Cerebral translocation was not observed after direct intravenous injection, but significantly increased in mice with chronically altered blood-brain-barrier. Loss/gain-of-function experiments consistently implicated CCL2 in systemic diffusion of Al-Rho particles captured by monocyte-lineage cells and in their subsequent neurodelivery. Stereotactic particle injection pointed out brain retention as a factor of progressive particle accumulation.

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Conclusion: Nanomaterials can be transported by monocyte-lineage cells to DLNs, blood and spleen, and, similarly to HIV, may use CCL2-dependent mechanisms to penetrate the brain. This occurs at a very low rate in normal conditions explaining good overall tolerance of alum despite its strong neurotoxic potential. However, continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in the case of overimmunization or immature/altered blood brain barrier or high constitutive CCL-2 production.

Keywords: Alum, Vaccine adverse effect, Vaccine adjuvant, Nanomaterial biodistribution, Nanomaterial neurodelivery, Macrophages, Macrophagic myofasciitis, CCL-2, Single nucleotide polymorphisms (SNPs)

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* Correspondence: romain.gherardi@hmn.aphp.fr; josette.cadusseau@inserm.fr Equal contributors 1 Inserm, U955, 8 rue du Général Sarrail, Créteil 94010, France 2 Université Paris Est, Faculté de Médecine, 8 rue du Général Sarrail, Créteil 94010, France Full list of author information is available at the end of the article †

© 2013 Khan et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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32

Q(

The Addicted Brain

2015-04-07!

Hyla Cass, MD

Biography: Hyla Cass, M.D.

The Addicted Brain & How to Break Free!

!! Integrative medicine and psychiatry: clinical practice, writings, lectures, and media !! Medical Advisory Board: Health Sciences Institute !! Associate Editor, Total Health Former Board Member American College for Advancement in Medicine (acam.org); California Citizens for Health

Hyla Cass, M.D.

Marina del Rey, CA, 90272

!! Author of Natural Highs, 8 Weeks to Vibrant Health, Supplement Your Prescription, The Addicted Brain & How to Break Free, and others

website: www. cassmd.com

!! Radio, TV (Dr. Oz, The View, E! Entertainment, etc)

CSOM 2015

1

Learning Objectives

Overview

1. Internal biochemistry including levels of blood sugar, hormones, & NTs affect mood & cognition & lead to addiction 2. Specific lab testing can help determine imbalance 3. Imbalances in biochemistry can be treated with specific supplements (vitamins, minerals, amino acids, herbs) 4. Using appropriate precautions, supplements can be used adjunctively both to enhance pharmaceutical effects, to allow for lower dosing, and to aid in medication discontinuation.

•! How to discover brain imbalances •! How the brain works •! How to intervene with lifestyle, diet, and supplements •! How to not only overcome symptoms, but achieve potential brain power

! !! ! "

Are We Programmed for Addiction?

! !! ! "

Addiction Basics •! Genetic

"

!

!

•! Inborn deficiency (in dopamine/motivator receptors) -> Reward Deficiency Syndrome (RDS)

•! Moral issue? Will power?!

•! Psychosocial aspects

"

!

!

•! Self –medicate in the form ! of drugs, alcohol, or thrill-seeking, dangerous behavior to feel energized, motivated or happy.

•! Biochemical

!

33

1!

The Addicted Brain

2015-04-07!

Hyla Cass, MD

Is it psychological?

Are We Programmed for Addiction? "

! 52% of cocaine addicts have the Ernest Noble & Ken Blum UCLA: Found A1 allele of the dopamine D2 receptor gene, vs only 21% of nonaddicts.

•! Prevalence of A1 allele increases significantly with 3 risk factors: Parental alcoholism and drug abuse •! Potency of the cocaine used by the addict (intranasal versus "crack" cocaine) •! Early-childhood deviant behavior, such as! conduct disorder.

With all three of these risk factors, prevalence of A1 allele rises to 87%, suggesting that childhood behavioral disorders may signal a genetic predisposition to drug or alcohol addiction (Noble et al. 1993).

"Ernest P. Noble, PhD, MD; Kenneth Blum, PhD! Alcoholism and the D2 Dopamine Receptor Gene!

JAMA. 1993! !

•!

!

•!

Specific laboratory testing

•!

•!

•!

•!!

•!!

•!!

•!!

•!!

!

!

Provide needed vitamins, minerals, and amino acids.

!

" •!

•!

Predisposition only: you are not a slave to your genes!

!

" !

Rule out medical conditions affecting brain function Food allergy Dysglycemia Thyroid Adrenal !

Sex hormone imbalances !

History, physical, labs as indicated

•! CBC •! Chem panel w fasting glucose •! If indicated: •! Hbg A1C (glycohemoglobin) •! Amino acids (plasma,urine) •! RBC vitamins and minerals •! Essential fatty acids •! Organic acids (metametrix.com)

!

Stress; stimulants Dopamine-> adrenaline and noradrenalinereleased when we are stressed or use stimulants •! Generates energy by mobilizing glucose -> alert, ! energized, focused •! We can become addicted to our own feel-good hormones: stress junkies •! If low serotonin-> eat carbs to feel good

!

!

•!

Laboratory Testing

Other Causes of Addiction: !

Alcoholic rats treated with amino acids lost their cravings and addiction!

Medical Aspects

! !! ! "

Nutrient and neurotransmitter deficiencies

•!

!

Biochemical factors •!

" Rats fed junk food became addicted versus healthy! diet

Nestler Eric J. Is there a common molecular pathway for addiction? Nature

Neuroscience. Published Online 26 October 2005.

34

•! Neurotransmitters (urine, red cell) •! Hormones : –! Thyroid (T3,T4,TSH) –! Cortisol –! DHEA-S –! Estradiol –! Progesterone –! Testosterone

2!

The Addicted Brain

2015-04-07!

Hyla Cass, MD

Natural Solutions

!"#$%&'()*$+(,(-.#& •!

•!

•!

•!

" !

Biochemical Individuality Synergy of nutrients Deficiencies: laboratory testing Specific supplementation with vitamins, minerals, amino acids, and herbs - mood, memory, cognition, interrupts cravings for sugar/carbs, caffeine, alcohol

•! Lifestyle changes •! Psychotherapy eg EFT (Emotional Freedom Technique), EMDR (Eye Movement Desensitization & Reprocessing; EMDR.org), TFT (Thought Field Therapy) •! Mind-body techniques: •! Meditation, neurofeedback, guided imagery

! !

http://www.eeginfo.com neuralrenewal.com

Brain Facts

Natural Solutions (cont’d) •! Nutritional (body-mind)

The brain is an organ, affected by body chemistry Weighs only 3 lbs, but uses 20% of glucose, O2, nutrients

•! Balance blood sugar •! Supply safe, effective alternatives to substances of abuse, antidepressants, anti-anxiety agents, with specific precursors and co-factors to restore brain and body chemistry

Neurons communicate via neurotransmitters •! Made from brain nutrients •! So are the receptor sites •! Influenced by your individual biochemistry

•! i.e. Treat underlying imbalance

Downsides of Sugar:"

Basic Requirements

•!

•! !•! !•! ! ! !

!

" Biochemical Individuality! – genetics, environment Synergy of nutrients – You are what you eat!

Deficiencies, toxicities: laboratory testing Specific supplementation with vitamins, minerals, amino acids, and herbs: !

•! Balances mood !

•! Often sufficient to stop the cravings for sugar/ carbs, caffeine, alcohol, even gambling, shopping!

•! Important in wt loss plan vs will-power

•!

" Toxic when consumed in! excess

•!

Goes into storage as quickly as possible

•!

Rebound low blood sugar-> cranky !

•!

Low blood sugar slump

!

Avena Nicole, et al. Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent, excessive sugar intake. Neuroscience Biobehavioral Review. 2008;32(1):20-39

35

3!

The Addicted Brain

2015-04-07!

Hyla Cass, MD

Brain: Food Basics “Let food be thy medicine”

Carbs: Low Blood Sugar

•! Carbohydrates as brain fuel (=>glucose)

•!

•! Protein for amino acids (=> neurotransmitters)

•!

•!

•! Smart fats (omega 3s)

•!

•!

•!

•! Antioxidants, vitamins and minerals •! Phospholipids

•! Frequent mood swings" Difficulty •! Forgetfulness or concentrating confusion" Palpitations Fainting, dizziness or •! Tendency to depression •! Anxiety or irritability shakiness •! Feeling weak Night sweats •! Aggressive outbursts or Excessive thirst crying spells Chronic fatigue

•! Water

The Addicted Brain

Blood Sugar Regulation •!

•!

Refined carbs, low glycemic index or glycemic load Rapid rise of blood sugar: sugar high •! Insulin release sweeps it into the cells •! Drop in blood sugar •! Adrenalin release •! Fight or flight, sympathetic nervous system response •! Anxiety symptoms •! Ultimately, develop insulin resistance D. Benton The impact of the supply of glucose to the brain on mood and memory, Nutr Rev Vol 59, S20-21, 2001.

The Addicted Brain

J Fig 10 - The Sugar Cycle

23

36

4!

The Addicted Brain

2015-04-07!

Hyla Cass, MD

Downsides of Alcohol: ! !! ! "

"

!

•!

Depressant, accidents

•!

GI, liver, and brain damage

•!

Vitamin depletion

•!

Need to repair and replete

•!

Liver support/rebuild

!

!

Downsides of caffeine

"

!

American Psychiatric Association: classifies caffeine as a substance…intoxication can present with disturbance in thinking, judgment, perception, attention, motor activity, and social functioning (1994).

Caffeine toxicity can induce restlessness, agitation, irritability, confusion, and delerium.

Overstimulation of the central nervous system, irritability, insomnia and rapid and irregular heartbeats, hypertension, GI problems (eg ulcers)! ! !

! http://www.naturaldatabase.com.

Caffeine. Natural Medicines Comprehensive Database.

Accessed Dec. 9, 2010.! !

Nehlig, A., Daval, J., Debry, G. Caffeine and the central nervous system: Mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Rev, 17 (1992): 139-170.!

!

Diagnostic and Statistical Manual of Mental Disorders Fourth Edition.

Washington: APA, 1994

-! substantially suppresses calcitriol receptor –> Vit D deficiency ss

!

-!

Downsides of Psychotropic (psychiatric) Medication:

Rapuri PB, et al 2007. J. Steroid Biochem. Mol. Biol. 103 (3–5): 368–71.

Diet and Supplements

"

!

! !! ! "

! !

•!Antidepressants, tranquilizers

•!

! !! ! "

! !! ! "

Downsides of caffeine

" Often sufficient to stop the cravings for ! carbs cocaine, heroin, benzodiazepines, sugar, caffeine; habits like gambling, shopaholic •

!

•!Band-aid approach: useful but insufficient

!

!

•!Not addressing basic imbalance

•!

•!Side effects including addiction; replacing one with another; be careful!

!

37

!

Substitution of sugar, caffeine, etc for drug of choice perpetuates the addictive cycle

5!

The Addicted Brain

2015-04-07!

Hyla Cass, MD

! !! ! "

! !! ! "

Basic Requirements

" Basic Requirements

"

!

Raw materials from diet: •!

•! !

Carbohydrates, fats, protein (amino acids) !

!

Vitamins, minerals, flavonoids: Co-factors to catalyze the chemical processes; antioxidants, neuroprotective

Mind- and Mood-Enhancing Neurotransmitters: Your Chemical Messengers •!

•!

Dopamine, Adrenaline & Noradrenaline

Endorphins - euphoria, pain control

•!

Acetylcholine - memory and alertness.

•!

Imbalance here leads to cravings, addiction, ! withdrawal

•!

End addictions by restoring balance

!

!

•!

Down regulation: ‘tolerance’- need increasingly more stimulant for effect

•!

Vicious cycle of stimulant dependence and ! fatigue

•!

Original fatigue (leading to stimulant cravings) can have many sources, including poor sleep and diet, chronic infection, and hormone imbalances.

!

! !! ! "

•!

Neurotransmitters: our brain messengers

"

energizing, focus, stress response, “feel-good” Serotonin - mood enhancement

•!

Dynamics of addiction

GABA - dampens, calms, balances

•!

!

! !! ! "

Natural Solutions: Natural Mood Elevators, Energizers "

Natural Solutions: Natural Mood Elevators, Energizers "

!

!

•! Amino acid precursors to serotonin:

Amino acid precursors to dopamine:

•! Depleted by long-term SSRI use

•! Tyrosine -500-2000 mg daily

•! Replace SSRIs and other serotonin enhancers both !

!

•! D,L-Phenylalanine (DLPA)- 500-2000 mg daily

!

!

in tx of depression, anxiety, drug withdrawal/

•! Supports replacing stimulant meds and drugs (eg

maintenance

cocaine, amphetamines)

•! Needs B6 and other micronutrient co-factors, found

•! No over- stimulation, no let-down!

in high quality, high potency multi

38

6!

The Addicted Brain

2015-04-07!

Hyla Cass, MD

! ! ! !

! !! ! "

Natural Solutions: N-Acetylcysteine (NAC) " for addiction

Natural Solutions: Natural Mood Elevators, Energizers " !

!

•! NAC is emerging as a useful agent in the treatment of addiction/cravings •! Studies in addiction: food, gambling, nicotine, cocaine, cannabis (2400 mg/day) !

•! Precursor to glutathione, master antioxidant, antiinflammatory •! Psychiatric illness related to brain inflammation

5-hydroxytryptophan -5HTP (100-300 mg) •! L-tryptophane (500-2000 mg) •! Needs carb/insulin response ! to cross blood brain barrier •! B6 as co-factor

!

!

Dean et al, J Psychiatry Neurosci. 2011 March; 36(2): 78–86. Nacetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action

Dean et al, J Psychiatry Neurosci. 2011 March; 36(2): !

78–86. N-acetylcysteine in psychiatry:! current therapeutic evidence and potential mechanisms of action! ! !

Omega 3 Fatty Acids •!

Mood, mind and memory booster: depression, bipolar, ADD/ADHD

•!

Building material for brain cell membranes and neurotransmitter receptor sites

•!

Increase acetylcholine and serotonin levels

•!

Precursor for prostaglandins, chemicals that influence mood and behavior

•!

References on Omega-3’s •! Frangou S, Lewis M, McCrone P. Efficacy of ethyleicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry. 2006 Jan;188:46-50.

•! Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: Omega-3 AD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8.

•! Osher Y, Belmaker RH, Nemets B. Clinical trials of PUFAs in depression: State of the art. World J Biol Psychiatry. 2006;7(4):223-30.

Anti-inflammatory Dose: 250-3000 mg a day as a fish oil supplement or eat fatty fish three times a week

! !! ! "

•!

Adrenal Support

Brain Cell Supplements TWICE DAILY: !

•!Multi for co-factors, anti-oxidants •!Vit C – 1 gm •!Omega 3 oil (fish oil)/Krill - 1-2 gms !

•!Methylating nutrients --B12-Folate, B-Complex •!Acetylcholine enhancers (memory, cognition) – Phosphatidyl Choline, Phosphatidyl Serine, DMAE, Acetyl-l- Carnitine

•!

•!

•!

•!

•!

!

39

For most (all?) of these individuals Amino acids (tyrosine, TMG) B Vits, especially B5; magnesium Adaptogens - rhodiola, reishi, eleuthero Boosts energy, focus, and endurance

7!

The Addicted Brain

2015-04-07!

Hyla Cass, MD

Combination Formula

Calming Nutrients Amino acids •! GABA – issues re BBB? •! L- Theanine •! Taurine •! L- Glutamine Herbs •! Hops, passion flower, lemon balm, valerian •! Useful for sleep too esp w increased valerian

•! Natural nutrient "shield protects mind & body from harmful effects of daily stress •! Enhances mood •! Sharpens mental acuity •! Supports inner calm and balance •! No drowsiness •! Use instead of sedating meds for withdrawal from both uppers and downers

Withdrawing from Alcohol, Sedatives or " Stimulants ! !! ! "

Sample Protocols

!

•!

•!

Multi vitamin-mineral formula Chromium (200 mcg) and glutamine (500 mg twice daily) and also as needed for cravings, to regulate blood sugar, reducing !brain fog and cravings for sugar, alcohol, or drugs.

•! 5-HTP- 100-300 mg 3x/day to boost serotonin levels both for depression and sleep problems (take separately from SSRI by 2 hr or more)!

For neurotransmitter balance especially in addiction & antidepressant recovery– best to avoid/minimize medication and use targeted nutrient support!

!

Withdrawing from Alcohol or Stimulants #3

Withdrawing from Alcohol or Stimulants #2 "

"

!

!

•! Specific brain cell nutrients – PS (100 mg) and PC or Citicholine 100 mg), acetyl-l-carnitine (500 mg), ginkgo (60 - 90 mg) to enhance acetylcholine, brain ! blood flow and brain cell health •! Adaptogenic herbs such as reishi, eleuthero, rhodiola + cofactors to support adrenal glands depleted by stress.

•! Deliver as formulas for better compliance

! !! ! "

•! Calming herbs valerian 100 mg (or 100-200 at bedtime) •! L-Theanine 200 m1-2 x daily !

•! Tyrosine (500-1000 mg) or phenylalanine (500-1000 mg) 2-3x/day to boost dopamine for enhanced mood and concentration, especially in the morning, or BID

!

!

40

8!

The Addicted Brain Hyla Cass, MD

2015-04-07!

Lifestyle, Diet, and Supplements

Withdrawing from Alcohol or Stimulants #4 "

•!

•!

•!

•!

•!

!

•! Omega 3 fatty acids in the form of fish oil 1000 mg twice daily to help restore the cell wall in which neurotransmitters are made !

•! Extra B vitamins (500-100 mg) and magnesium 200 mg (may be found in a high potency multi) to handle the depletion due to addiction and stress; needed as co-factors

!

•!

•!

•!

Begin with healthy diet Eliminate smoking, sugar, caffeine Exercise Restorative sleep - amount, quality Add supplements (vitamins, minerals, amino acids, herbs) to correct underlying chemical imbalances Remove meds and substances gradually Address psychological and spiritual aspects Wide range of available lifestyle techniques, including meditation, visualization, biofeedback, music, massage, yoga, movement and dance

Thank you!

HYLA CASS, M.D. Marina del Rey CA USA www.cassmd.com

41

9!

Brain Mitochondrial Metabolism and Psychiatric Illness Benjamin Brown, ND

42

Brain Mitochondrial Metabolism and Psychiatric Illness Benjamin Brown, ND

43

Brain Mitochondrial Metabolism and Psychiatric Illness Benjamin Brown, ND

44

Brain Mitochondrial Metabolism and Psychiatric Illness Benjamin Brown, ND

45

Brain Mitochondrial Metabolism and Psychiatric Illness Benjamin Brown, ND

46

Brain Mitochondrial Metabolism and Psychiatric Illness Benjamin Brown, ND

47

Brain Mitochondrial Metabolism and Psychiatric Illness Benjamin Brown, ND

48

Brain Mitochondrial Metabolism and Psychiatric Illness Benjamin Brown, ND

49

Brain Mitochondrial Metabolism and Psychiatric Illness Benjamin Brown, ND

50

The Abram Hoffer I Knew Garry Vickar, MD

51

Thyroid Dysregulation and the Metabolic Roots of Cancer!"#$%"&%"'( Ron Hunninghake, MD

Riordan Clinic

Thyroid Dysregulation

www.riordanclinic.org

and the Metabolic Roots of Cancer( (((()*+((,-++.+/0123(4565( ((70.38(439.:1;(<=:3>( ((((((((((((((().*>91+(7;.+.:(

Riordan IVC Protocol

•! Dr. Hugh D. Riordan

Dedication

The Riordan IVC Protocol

•! Riordan Clinic Founder

for Adjunctive Cancer Care Intravenous Ascorbate as a Chemotherapeutic and Biological Response Free Download of the PDF Modifying Agent IVC Protocol

•! Died – January 7, 2005 •! Developer: Riordan IVC Protocol for

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2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Toronto, 2015

Alpha-Lipoic Acid s Effects on the Mitochondrion and Human Disease Modification

Burton M. Berkson MD MS PhD The Integrative Medical Center of NM Las Cruces, NM 88011 Alpha-lipoic acid, (ALA), Thioctic Acid

ACTIONS OF ALA

Glycolysis: anaerobic Occurs in the cytoplasm Glucose is converted to pyruvate Cancer cells typically just go this far and convert pyruvate to lactate even in the presence of O2.

Alpha lipoic acid is fundamental, for the conversion of food to energy.

It is my hypothesis that ALA is the rate-limiting agent in the production of energy from food in aerobic cells

Tricarboxylic acid Glycolysis cycle Occurs in the anaerobic

â&#x20AC;˘! ALA

mitochondrion In the presence of oxygen aerobic

Pyruvate Dehydrogenase Complex

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2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Korotchkina LG, Sidhu S, Patel MS. Lipoic acid inhibits mammalian pyruvate dehydrogenase kinase.

Free Radic Res. 2004 Oct;38(10):1083-92.

ALA pushes anaerobic cell metabolism into aerobic cell metabolism ALA accelerates this process and it s more than just a cofactor.

Alpha Lipoic Acid inhibits Pyruvate Dehyrogenase Kinase (PDK) PDK inhibits the enzyme that converts Pyruvate into Acetyl CoA

GLYCOLYSIS Anaerobic

ALA

PDH

Kreb s cycle Aerobic

Pyruvate dehydrogenase kinase inhibits Pyruvate Dehydrogenase

ALPHA-LIPOIC ACID

FATS

More available Pyruvate Dehyrogenase results in increased Pyruvate being directed into the Krebs Cycle over the conversion of Pyruvate to Lactate

CARBS

PROTEINS

Glycolysis

GLYCEROL

PYRUVATE

Pyruvate Dehydrogenase PDH Complex PDH

ALPHA-LIPOIC ACID

ACETYL CO A

Since a young person produces enormous amounts of ALA,

What if a mitochondrion receives too much ALA? Lipoic acid LD50 Studies by Drs Vigil and Couch.

what happens when you feed a Thanksgiving dinner to a 2 year old child;

Couch RC, Vigil M. et al. A dose escalation toxicity study of DL-6-8 thioctic acid (lipoic acid) in Rhesus monkeys. 1997.

Poster display. Annual Meeting Society of Toxicology.

or a 80 year old man?

LOE B

71

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2015-03-09 Lipoic Acid’s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Healthy primate mitochondrion (hepatocyte) •! Following these studies I was asked to observe the necropsies and help with the electron microscopy work on the damaged tissues at NMSU. •! I observed extensive necrotic lesions in the liver, kidneys, heart, and the large muscles of the extremities.

Primate hepatocyte mitochondria following a LD50 IV lipoic acid dose of about 90mg/kg Mitochondria from animals who had received excessively high doses of ALA became extremely edematous, and demonstrated a disruption of all the crucial structures.

These mitochondria did not exhibit the regular double membrane wall structure, but showed a coalescence of these structures with a deliquescence of membranes thus exhibiting a complete disruption of normal ultrastructure.

LIVER MITOCHONDRIA SUFFERED SEVERE STRUCTUAL DAMAGE BY EXTREMELY HIGH DOSES OF INTRAVENOUS ALPHA LIPOIC ACID Global Advances in Health and Medicine January,2014, volume 3 number 1

•! In reality, much lower doses of IV lipoic acid may cause serious bouts of hypoglycemia and the doctor and nurse must all times watch carefully for possible problems.

Michael Vigil MD Adjunct Associate Research Professor, Department of Biochemistry NMSU Burton M. Berkson MD MS PhD Former Assistant Professor, Rutgers University Former Associate Professor, Chicago State University President, The Integrative Medical Center of New Mexico Adjunct Professor, NMSU bberkson@nmsu.edu (corresponding author) Ana Patricia Garcia DVM MS PhD Associate Research Professor and Veterinary Pathologist Yerkes Assistant Professor, Department of Pathology and Laboratory Medicine Emory University School of Medicine

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2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

If the mitochondrion is supplied with excessive amounts of ALA, it accelerates aerobic respiration and the process runs ahead of the other necessary constituents.

With appropriate ALA levels, the mitochondrion functions normally.

The mitochondrion heats up, free radicals accumulate, and its membranous components break down.

If the mitochondrion does not obtain sufficient ALA, it suffers, and the organism dies.

Severe damage to the mitochondrion is first seen by gross swelling and then severe damage to the cristae and matrix material.

It is interesting to note that therapeutic doses of intravenous ALA helps a liver regenerate but extremely high doses of the same agent causes liver necrosis.

Does ALA helps regenerate livers?

Of course, excessive and unreasonable amounts of any substance given intravenously can be lethal, including water and salt.

1st large scale clinical trial with IV alpha-lipoic acid at NIH. (Bartter, Berkson, et. al. 1977-1980)

B

We reported in 3 publications that we treated 79 people with acute hepatic necrosis and 75 regenerated their livers with the just the administration of intravenous Alpha-lipoic acid.

I was appointed FDA principal investigator 1983. That lasted 23 years.

Bartter FC, Barry Rumack, and Berkson B 1978 As visiting scientists at the Max Planck Institute in Heidelberg

73

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2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Amanita virosa Destroying angel

B

Our first paper.

Should have been titled ALA reverses Acute Hepatic Necrosis

If IV ALA reverses acute liver disease, will it reverse chronic liver disease, for example hepatitis C?

GERMAN JOURNAL OF INTERNAL MEDICINE ARTICLE

CIRRHOTIC LIVER

Berkson BM. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium.Med Klin (Munich). 1999 Oct 15;94 Suppl 3:84-9.

I took 3 cirrhotic hepatitis C patients in the process of liver transplant evaluation at University Hospital and administered ALA, silymarin and selenium (inhibition of replication).

The 3 recovered normal liver function within 6 months.

B

74

5

Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification 2015-03-09 Burt Berkson, MD, PhD

Most important laboratory tests for the evaluation of liver disease.

MR EA (hepatitis C) ALBUMIN LEVELS

Albumin Prothrombin Time Platelet count

6

5

4

3

ALT

2

1

0 2001 JUNE

MR EA PROTIMES

2001 AUG

2002 JAN

MR. EA-HEPATITIS C SECONDARY TO BLOOD TRANSFUSION PLATELET COUNT

200,000 20

180,000

18

160,000

16 14

140,000

12

120,000

10

100,000

8

80,000

6

60,000

4 2

40,000

0 2001 JUNE

2001 AUG

20,000

2002 JAN

0 JUNE O1

MR. EA ALT (SGPT) RESULTS

Conclusion of my 1999 paper.

The author offered a more conservative approach to the treatment of hepatitis C, that is exceedingly less expensive. One year of the triple ant-oxidant therapy described in this paper costs less than $ 3,000, as compared to more than $ 400,000 a year for liver transplant surgery.

140 120 100 80 60 40 20 0 1-Jun

AUGUST O1

AUG O1

2-Jan

75

JAN O2

B

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2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Are there other diseases that ALA might help?

Smith AR, Shenvi SV, Widlansky M, et al. Curr Med Chem. 2004 May;11(9): 1135-46.)

Baur, et al., Klin Wochenschr 69 (1991): 722-4.

Lipoic acid is a potential therapy for chronic diseases associated with oxidative stress.

Alpha lipoic acid has been shown to be an effective inhibitor of human immuno-deficiency virus (HIV-1) replication.

Most chronic diseases are associated with OS.

B B

Lipoic Acid prevents ischemia-reperfusion injury Suh JH, Shigeno ET, Morrow JD, et al. Faseb J. 2001;15(3):700-706.

Panigrahi M, Sadguna Y, Shivakumar BR, Kolluri SV, Roy S, Packer L, Ravindranath V. Brain Res. 1996;717(1-2): 184-188. -

Oxidative stress in the aging rat heart is reversed by supplementation with alpha-lipoic acid.

Alpha-Lipoic acid protects against ischemia reperfusion injury following cerebral ischemia.

B

B

What about ALA and diabetes?

Jacob S, Henriksen E, Schiemann A. et al.

Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid.

Arzneimittel-Forschung 1995, 45(8):872-874.

Singh U, Jialal l Alpha-lipoic acid supplementation and diabetes.

Nutr.Rev. 2008 Nov;66(11):646-57.

Henriksen et al. published the first human study to show that ALA increases insulin stimulated glucose movement into the cell, and out of the blood stream, in diabetes.

ALA improves insulin sensitivity, reduces oxidative stress, and improves neuropathy in diabetic patients.

B

B

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2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Tankova T, Cherninkova S, and Koev D. Treatment for diabetic neuropathy with IV alpha-lipoic acid.

Int J Clin Pract. 2005 Jun;59(6):645-50.

Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Free Radic Biol Med. 1999;27:309-14.

This study demonstrated that alpha-lipoic acid is an effective treatment for peripheral and autonomic diabetic neuropathy and also diabetic neuropathy of the cranial nerves leading to full recovery of the patients.

Administration of alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial.

At the Integrative Medical Center of New Mexico, we treat diabetic neuropathies with IV ALA every day.

B A

Thomas Seyfried Cancer As a Metabolic Disease

What about ALA and cancer?

Cancer cells hate oxygen.

(Wiley, 2012)

Warburg O. The chemical constitution of respiration ferment. Science. 1928;68:437â&#x20AC;&#x201C;443.

"All hallmarks of cancer including the Warburg effect can be linked to impaired respiration and energy metabolism, These are "downstream effects of damaged mitochondrial function."

Science.68.1767.437.

B

Shi DY, Liu HL, Stern JS, Yu PZ, Liu SL. FEBS Lett. 2008 May 28;582(12):1667-71.

Wenzel U, Nickel A, and Daniel H. .Alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration which results in O2-*-generation.

Apoptosis. 2005 Mar;10(2):359-68

Alpha-lipoic acid induces apoptosis and necrosis in hepatocellular carcinoma cells.

This study provided evidence that ALA and its reduced form can induce cancer cell death by a prooxidant mechanism that is initiated by an increased uptake of oxygen into the mitochondrion.

B B

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2015-03-09 Lipoic Acid’s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Kisurina-Evgen'eva OP, Onishchenko GE.

Alpha-lipoic acid triggers elimination of cells with abnormal nuclei in human carcinoma epidermoid cell line Tsitologiia. 2010;52(3):225-34.

Zachar Z, Marecek J, Maturo C, et al.

ALA disrupts cancer cell mitochondrial metabolism and is a potent anticancer agent in vivo J Mol Med (Berl). 2011 Nov;89(11):1137-48. Epub 2011 Jul 19.

Alpha-lipoic acid not only triggered apoptosis of carcinoma cells, but it also activated the mechanism of elimination of other cells with abnormal chromosome number.

Lipoic Acid causes disruption of tumor metabolism and this is followed by cell death by multiple, pathways, including apoptosis and necrosis.

B

Na MH, Seo EY, Kim WK Nutr Res Pract. 2009 Winter;3(4):265-71.

Alpha-lipoic acid stimulates apoptosis in human breast cancer cells. and

Choi SY, Yu JH, Kim H. Ann N Y Acad Sci. 2009 Aug;1171:149-55.

Alpha-lipoic acid induces apoptosis of lung cancer cells.

B From Cancer metabolic plan from Signaling And Metabolism In Cancer, Maurice Israël, Cancer Therapy, 2014

Non-Standard Cancer Protocol at IMCNM

Low Dose Naltrexone (LDN) •! 1.5 to 4.5 mg. LDN at hs •! Fools the brain. Not enough endogenous opiates in blood stream.

•! In AM, flood of endogenous opiates released.

•! At least one of the opiates, met-enkephalin binds to cancer cell receptors and promotes apoptosis.

•! Intravenous Alpha Lipoic Acid (ALA) (Bartter and Berkson).

•! Intravenous Vitamin C. •! Low Dose Naltrexone (LDN) (after Zagon and Bihari.)

•! Hydroxycitrate (HCA) (after Schwartz L.).

•! Healthy diet and life style.

•! Supplements (artemesinin, curcumin, etc) •! Prescription drugs (metformin, xanax, cimetidine, etc.)

Several papers by Ian Zagon and associates.

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2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

T helper 17 cell (Th17) is a type of T helper cells that produce interleukin 17 (IL 17).

These cells produce tissue injury by inflammatory processes Crohn s disease, juvenile diabetes, MS, rheumatoid arthritis, SLE, etc.

Normally, Th17 cells provide epithelial and mucosal anti-microbial immunity by producing interleukin 22, etc. which stimulates epithelial cells to produce Inflammatory proteins to kill microbes.

Transforming growth factor beta

From LDN website

Inflammation

Berkson BM, Rubin DM, and Berkson AJ Integrative Cancer Therapies Volume 5, Number 1, March 2006

Berkson BM, Rubin DM, Berkson AJ. Integr Cancer Ther. 2007 Sep;6(3):293-6.

The long-term survival of a patient with pancreatic cancer and metastases to the liver

Reversal of signs and symptoms of a B-cell lymphoma in a patient using low-dose naltrexone.

(Patient was on IV ALA for 2 weeks)

We published the first human study that demonstrated the therapeutic effects of ALA combined with LDN for cancer

B

B

Schwartz L, Guais A, IsraĂŤl M, et al.

Invest New Drugs. 2013 Apr;31(2):256-64. doi: 10.1007/ s10637-012-9849-z. Epub 2012 Jul 14.

Burton M. Berkson, Daniel M. Rubin, and Arthur J. Berkson Integr Cancer Ther. 2009 Mar;5(1):83-9.

Revisiting the ALA/N (!-Lipoic Acid/Low-Dose Naltrexone) Protocol for People With Metastatic Pancreatic Cancer: A Report of 3 New Cases

Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxycitrate, lipoic acid etc.

He added hydroxycitrate to our protocol.

B

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2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Schwartz L., Buhler L, Icard P, Lincet H, Steyaert J. Metabolic Treatment of Cancer, Anticancer Research 2014

Alpha Lipoic Acid and Hydroxycitrate target at least two major Enzymes in the metabolism of glucose.

The metabolic effects of ALA/HCA allows the reprogramming of cancer cells into oxidative aerobic metabolism rather than anaerobic metabolism.

Pyruvate Dehydrogenase Kinase and ATP Citrate Lyase

This ultimately should limit the availability of compounds necessary for the growth of cancer.

Hydroxycitric acid (hydroxycitrate)

HCA also inhibits pancreatic alpha-amylase (breaks down starch and glycogen) and intestinal alpha-glucosidase (breaks down starch into glucose), leading to a reduction in carbohydrate metabolism.

Hydroxycitrate (HCA) also inhibits ATP Citrate Lyase (ACL) which limits the conversion of cytoplasmic Citrate into Acetyl CoA available for the synthesis of Lipids and aerobic carbohydrate metabolism.

Studies of HCA have produced results that indicate a potential for modulation of lipid and carbohydrate metabolism.

ATP citrate lyase

Alpha Lipoic Acid (ALA) inhibits Pyruvate Dehyrogenase Kinase (PDK) (the enzyme that stops Pyruvate Dehydrogenase) More available Pyruvate Dehyrogenase (PDH), results in the increased Pyruvate Being directed into the Krebs Cycle over the conversion of Pyruvate to Lactate

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2015-03-09 Lipoic Acid’s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Mrs. MC

68 yo woman with breast cancer.

Initially refused Surgery, Chemotherapy, and Radiation.

Pathology-Invasive ductal adenocarcinoma Nottingham grade 2/3, Estrogen + Progesterone receptor -, pagetoid spread to skin Metastatic to L axilla lymph nodes

March 15, 2013

Pet scan March 20, 2013

March 15, 2013

Visit to oncologist Late June 2013

•! I suggested that Mrs. MC see a oncologist. She took my advice and tried taxol and herceptin for less than 3 weeks, became very ill, lost hair etc, and stopped conventional tx.

Early June, 2013 Ca 27.29--60…39 Ca 15.3—27.5…19.6

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2015-03-09 Lipoic Acid’s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Added Black Salve

July, 2013

August 5, 2013

Added Black Salve August 5, 2013

August 14, 2013

May 14, 2013----September 23, 2013

•! Ca 27.29---60---39.5---16---11.5 •! Ca 15.3---27.5---19.6---7.3 August 14, 2013

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2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

FIGURE ONE OCTOBER 8, 2002

The long-term survival of a patient with pancreatic cancer and metastases to the liver

Mr. TA

Berkson BM, Rubin DM, and Berkson AJ Integrative Cancer Therapies Volume 5, Number 1, March 2006

Berkson and associates published the first human study that demonstrated the therapeutic effects of ALA combined with LDN for cancer B

FIGURE 11 FEBRUARY, 2006

FIGURE 2 OCTOBER 8, 2002

Mr. TA

Mr. TA

Given no hope by MD Anderson

FIGURE 13 AUGUST 2008

FIGURE 12 FEBRUARY, 2006 Mr. TA

Mr. TA

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14

2015-03-09 Lipoic Acidâ&#x20AC;&#x2122;s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

FIGURE 14 AUGUST 2008 Mr. TA

Burton M. Berkson, Daniel M. Rubin, and Arthur J. Berkson Integr Cancer Ther. 2009 Mar;5(1):83-9.

Revisiting the ALA/N (!-Lipoic Acid/Low-Dose Naltrexone) Protocol for People With Metastatic Pancreatic Cancer: A Report of 3 New Cases

B

AdenoCarcinoma Pancreas

Pet Scan JUNE 2006 Mrs. JK

Pet Scan JANUARY O6 Mrs JK

Mrs JAL October 2006

Hepatocellular Carcinoma following Hepatitis C Mrs. JAL 60 year old RN

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2015-03-09 Lipoic Acid’s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

MRS JAL January 2009 28 months later

Berkson BM, Rubin DM, Berkson AJ. Integr Cancer Ther. 2007 Sep;6(3):293-6.

Reversal of signs and symptoms of a B-cell lymphoma in a patient using low-dose naltrexone.

MR TM DECEMBER 2005

MR. TM MAY 2006 6 months later

Mr. JT Renal Cell Carcinoma 68 YO male •!

•!

•!

•!

•!

•!

•!

•!

Diagnosis June, 2008 Urinating blood.

CT mass L kidney with possible mets to lung.

Nephrectomy L. kidney.

MD Anderson administered biological response modifiers and chemotherapeutics. TS continued To deteriorate. No effect on TS s RCC. TS told to get his affairs in order, no hope for survival June, 2010.

TS presents to IMCNM August 16, 2010.

Put on IMCNM protocols.

March 2015, healthy, working, with no signs of disease.

Mr. JT August 2010

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2015-03-09 Lipoic Acid’s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

Mr.JT JAN. 2014

Mr. JT January 2011

Lipoic Acid Plus Low-Dose Naltrexone Reviewed for Cancer Treatment

The cases being presented today by Dr. Berkson were submitted and given rigorous scientific evaluation under the NCI Best Case Series (BCS) protocol.

•! NCI staff and invited guests listen to Drs. Berkson and Donahue discuss their research and treatments on March 19, 2012 •! A panel of researchers and clinicians was convened by the National Cancer Institute (NCI) for presentations and a roundtable discussion about The State of the Science of Alpha-Lipoic Acid plus LowDose Naltrexone for the Treatment of Cancer. The meeting was hosted by the Cancer Therapy Evaluation Program (CTEP), both part of the NCI Division of Cancer Treatment and Diagnosis (DCTD).

The meeting provided an opportunity for NCI staff and outside experts to review and discuss case reports from Dr. Burton M. Berkson, an integrative medicine physician and Ph.D. in Biological Sciences, and Adjunct Professor. Dr. Berkson presented on his experience treating patients with alpha-lipoic acid plus low-dose naltrexone for various cancers and autoimmune diseases. The group also heard from Dr. Renee N. Donahue, (Zagon Group) Research Fellow at NCI about her pre-clinical research on the efficacy and proposed mechanism of action of LDN for the treatment of cancer.

The ultimate goal is to identify those integrative medicine interventions that have enough evidence to support NCI-initiated research.

Dr. Berkson reported that a combination of ALA (intravenously and orally) and LDN (orally), along with diet, vitamins, and lifestyle changes caused several cancers to go dormant.

Earlier in his medical career, Dr. Berkson published papers using ALA to repair liver damage in patients from mushroom poisoning and chronic infections with hepatitis C virus.

He also cited a number of research articles in European medical journals showing ALA s beneficial effects on cancer.

Europe and Asia very interested in Alpha lipoic acid.

Very little interest in the United States.

Routes of Administration of Alpha Lipoic Acid •! Oral power in capsule.

•! Tablet •! Liposomal Alpha Lipoic Acid (phospholipids from soy lecithin) •! Intra Muscular Alpha Lipoic Acid dissolved in Trametamol •! Intravenous Alpha Lipoic Acid dissolved with sodium hydroxide and buffered and delivered in D5W or Normal Saline

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2015-03-09 Lipoic Acid’s Effects on the Mitochondrion and Human Disease Modification

Burt Berkson, MD, PhD

ALA plus LDN for SLE and RA

SLE (ANA)

2 18 23 24 64 70 71

best 3 point data 3000

What about ALA/N for systemic lupus erythematosus and rheumatoid arthritis?

Raw 3 Point Data RA (Chart 2) (RF)

28 30 32 33 37 38 42 43 44 45 46 47 48 49 50 51 53 59 62 63

700

2500

600

2000

500

400

1500

ANA Levels 300

1000

200

500 100

0 0

2

4

6

8

10

12

Months

0 0

2

4

6

8

10

12

Months

Drug Company Vice President confidential statement following Mayo Clinic positive results treating 1200 plus DM neuropathy patients with IV ALA.

Summary ALA is necessary for aerobic cell life. because ALA is essential for the conversion of pyruvate to acetyl Co A in the mitochondrion.

ALA is the rate-limiting factor for the production of energy from our cells.

ALA inhibits pyruvate dehydrogenase kinase.

ALA forces cells from an anaerobic metabolism into aerobic metabolism.

ALA has many uses in human medicine.

The efficacy, the apparent lack of toxicity, the long clinical track records of this agent in human medicine, all points toward the need for a clinical trial.

Why aren t there any large scale clinical trials? The agent has too many successful indications.

•!

•!

•!

•!

•!

•!

Diabet Med. 2004 Feb;21(2):114-21.

Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid.

Ziegler D, Nowak H, Kempler P, Vargha P. Low PA.

•! We want a drug with one indication. ALA has too many indications.

Med Klin (Munich).1999 Oct 15;94 Suppl 3:84-9.

A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories.

Berkson BM

Most of the patients that I see have hepatitis C, diabetes complications, SLE, RA, etc.

Patients sign informed consent forms.

Conventional therapies explained carefully with complete objectivity.

Companies are working hard to change the alpha lipoic molecule so it can be used as a patented drug and not as useful for so many indications, however, up until now, the corrupted molecules don t work nearly as well as the natural molecule.

Most cancer patients that I see are end stage.

They are told by their oncologist that nothing medically can be done.

This lecture is just my experience and is not an authorization for others to experiment with these protocols.

87

18

Evidence-based Orthomolecular Medicine: Principles and Practice John Hoffer, MD, PhD Principles and Practice of Evidence-based Orthomolecular Medicine (for practitioners and seekers of sound and reassuring health care)

L. John Hoffer, MD PhD FRCPC McGill University

Evidence-based medicine (EBM) is an imperfect, demanding but immensely useful decision-making tool that ought to be widely used in mainstream and orthomolecular medicine (EBOM). EBM is indeed widely endorsed and espoused in conventional mainstream medicine, but the sad fact is that it’s vastly misconstrued and improperly used. In this presentation I will explain what EBM is and isn’t, and the important role that a proper employment of EBOM can play in your practice and your own self care.

Basic Concepts. EBM follows 3 steps: (1) Obtain and analyze the most reliable scientific evidence pertaining to a particular therapy stripped of bias and error, optimally (but not necessarily) in the form of average comparative group responses in unbiased, well conducted and analyzed randomized clinical trials (RCTs).

(2) Determine the pertinence of the general statistical evidence to the situation of a specific patient. (3) Develop the recommended treatment plan with explicit attention to and respect for the patient’s attitudes, values and preferences.

Correctly used, EBM provides a sound framework for making individualized therapeutic decisions based on reliable, unbiased information. The basic aim of EBM/EBOM is to mitigate bias and misinformation. But bias has such a powerful grip on the human psyche that doctors and patients will go to enormous lengths to retain their cherished biases, attitudes and preferences. As a result, a lot of what’s called EBM isn’t really EBM, but rather a distortion of it that misuses the EBM logo to promote old-fashioned biased thinking.

EBM properly used and EBM misconstrued. Here are some examples of EBM misconstrued. Example 1.

EBM that includes only step 1. (I call this very common error the Richard M. Nixon bias. Nixon, who was President of the United States from 1969-73, said, “This would be an easy job if it weren’t for people.”)

Example 2. “Ultra-orthodox EBM.” In this misconstruction, a therapy that one is biased against is rejected on the grounds that “there’s no evidence” when in fact there’s lots of evidence, but the evidence isn’t felt to be good enough, or pristine enough, to satisfy the critic. Example 3. “Streetlight bias.” There’s no interest in even thinking about a therapy despite evidence for it, either because the therapy is held in disregard or because methods to test it don’t fit existing pharmacological testing models.

EBM is about mitigating bias. Bias is everywhere. Bias needs to be mitigated in the clinical data, but it also has to be recognized, acknowledged, and mitigated in the mind of therapist. I will provide a handy summary of cognitive distortions that all people use to defend their biases. This list can help us recognize bias in others and – more painfully – in ourselves as well. It is worthwhile to recognize and concede our emotionallyrooted, irrational, self-serving prejudices and biases when advising patients.

88

Evidence-based Orthomolecular Medicine: Principles and Practice John Hoffer, MD, PhD EBOM is a powerful persuasive tool. I will use specific examples to illustrate this assertion.

Example 1. A patient has atrial fibrillation with a CHADS2 score < 2. What stroke prevention therapy should be recommended: systemic anticoagulation or aspirin? Would it make sense to combine aspirin with vitamin E?

Example 2. A New Zealand farmer develops life-threatening influenza pneumonia and is expected to die. His physicians adamantly refuse high-dose vitamin C therapy because “there’s no evidence” it could help. Under court order the physicians provide high-dose vitamin C and the patient makes a miraculous recovery. In the ensuing media storm medical experts assert that vitamin C could not possibly have played a role in the patient’s recovery. Who is right?

Example 3. Experts have long claimed that taking multiple vitamins is wasteful since the normal diet provides plenty of vitamins and minerals, and indeed, vitamins can be dangerous. The best-designed, largest and longest RCT of its kind (15,000 participants, 11 years), published in JAMA in 2012, indicated that taking a daily multiple vitamin reduces the risk of cancer in male physicians by about 8%. Experts responded to this study by recommending that people should not take it seriously because the reduction in cancer risk was unexpected and “small.” More clinical trials will be required to justify taking a daily multiple vitamin, they assert. It’s highly unlikely a study as costly and difficult as this one will ever be repeated.

Example 4. A patient falls on her outstretched hand and suffers a wrist fracture. Should she take vitamin C 500 mg per day for 50 days to prevent the dreaded complication of immobilizing fractures, the complex regional pain syndrome? What are the pros and cons?

89

Orthomolecular Cardiology: Unmasking the Magnesium Link !"#$%"&%&"' to Multiple Cardiovascular Risk Factors Aileen Burford Mason, PhD The growing burden of heart disease

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Orthomolecular Cardiology: Unmasking the Magnesium Link !"#$%"&%&"' to Multiple Cardiovascular Risk Factors Aileen Burford Mason, PhD '

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Ratio of Calcium to Magnesium: Ancestral Diets

Ratio of Calcium to Magnesium: Modern Diets

Burford-Mason AP. Magnesium. In: Scientific Evidence for Musculoskeletal, Bariatric and Sports Nutrition. CRC Press 2006

Burford-Mason AP. Magnesium. In: Scientific Evidence for Musculoskeletal, Bariatric and Sports Nutrition. CRC Press 2006

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Effects of dietary magnesium deficiency in the rat with special reference to ultrastructural examination

Ikeda T et al. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyysho Hokoku

Ikeda T et al. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyysho Hokoku

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Titrating magnesium to bowel tolerance (2)

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Intervention

Angioplasty/ Stent

Statins

MediterraneanStyle Diet

N/A

1%

30%

No Data

18%

76%

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A Holistic Approach to Iodine Deficiency David Brownstein, MD

6*"(7"#%/"5(

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“I know that most men, including those at ease with problems of the greatest complexity, can seldom accept even the simplest and most obvious truth if it would oblige them to admit to the falsity of conclusions they have delighted in explaining to their colleagues.”

David Brownstein, M.D. Center for Holistic Medicine 5821 W. Maple Rd. Ste. 192 West Bloomfield, MI 48322 248.851.1600 www.drbrownstein.com

)*+$'8#(9"+":0";$'%(3#8$<(9"+$,*( 384%*%=>( •!

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–! F**(G8%%"H*.(

Dr. G. Abraham, 2004

108

1

A Holistic Approach to Iodine Deficiency David Brownstein, MD

705."$+(S"+4#*%(8,+(9"+$,*((

Periodic Table

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Benign thyroid nodules contain 56% of the iodine content as compared to normal thyroid tissue Malignant thyroid nodules contain 3% of the iodine content as compared to normal thyroid tissue Analyst. March 1995, Vol. 120

!$%/".5("-(9"+$,*(

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(@2U2XA($,(6",+",((

J. Royal Soc. Of Med. 2011;104:15-18

RDA for Iodine

S8&",8#(!*8#/0(8,+(S4/.$&",(F4.H*5(

RDA

Adult Male

150µg/d

Adult Female

150µg/d

Pregnancy

220µg/d

Lactation

290µg/d

•! 2Z[2K1Q21(S!?S\F( %0"J*+($"+$,*(#*H*#%( +*'#$,*+(PQ]($,(/0*( ^,$/*+(F/8/*%(

35

Urinary iodine levels !g/dl

Life Stage

30 25 NHANES I 1971-4 NHANES 2012

20 15 10 5 0

1970

2012

http://www.cdc.gov/nutritionreport/pdf/ Nutrition_Book_complete508_final.pdf#zoom=100

109

2

A Holistic Approach to Iodine Deficiency David Brownstein, MD F*H*.*(9"+$,*(T*O'$*,'5($,(^>F>(V."<( 2Z[QK1QQX(

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)&"!!#$

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)%"!!#$

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)!"!!#$ ("!!#$ '"!!#$

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NHANES CDC Thyroid 2011. Vol. 21. Number 4, 2011

9"+$,*(T*O'$*,'5(8,+(W"<*,("-( 30$#+;*8.$,C(?C*_((S!?S\F(1QQPKU(

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+!$

% Women Iodine Deficient

'!$

70% of samples below 100ug/L and 18% below 50ug/L.

,!$ ;),!<7=>$

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Presented at Society for Endocrinlogy BES 2011: April 11, 2011-14.

Thyroid. Vol. 21 N. 4. 2011

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&!$ Percentile of FT4 at term

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All groups supplemented with KI until end of lactation.

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All children given a neurocognitive evaluation at 18 months of age Thyroid.Vol. 19. N. 5. 2009. 511-519

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Thyroid.Vol. 19. N. 5. 2009. 511-519

110

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)!!$

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Percentile of FT4 at term

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Thyroid.Vol. 19. N. 5. 2009. 511-519

Thyroid.Vol. 19. N. 5. 2009. 511-519

Mean IQ

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Delayed neurobehavioral performance was observed in 36% of children in group 3 and 25% of children in group 2 and none in group 1. “A delay in 6-10 weeks in iodine supplementation of hypothyroxinemic mothers at the beginning of gestation increases the risk of neurodevelopmental delay in the progeny.”

Iodine has a major physiologic role in the inflammatory process

Med Hyppothesis. 1988;25:125-9

Thyroid.Vol. 19. N. 5. 2009. 511-519

W05(9"+$,*f(

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111

Lancet. 2003;362:1859-60 Lancet. Vol. 350. 9.13.97. p. 771-773 WHO J. Clin. Endocrinand Metabl. 2007;92:437-442 Anderson, M. 2007 Iodine deficiency in Europe: a continuing public health problem. Geneva: WHO. 2007.

4

A Holistic Approach to Iodine Deficiency David Brownstein, MD

30"#*%/*."#(8,+(9"+$,*(

3?T_((?,(^,+*.#5$,C()*'08,$%<(

@2A(

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•! i*%*8.'0*.%(#""E*+(8/(/0*(+*H*#":<*,/("-( 8/0*."%'#*."%$%($,(.8;;$/%( –! 3",/."#(C."4:_((i8;;$/%(-*+(0$C0('0"#*%/*."#(+$*/( –! 7.*8/<*,/(C."4:_(i8;;$/%(-*+(0$C0('0"#*%/*."#(+$*/(8,+( /.*8/*+(J$/0_(

Trans. Jpn. Path. 8:221-4, 1918.

•! 7Y( •! T*%$''8/*+(/05."$+( •! 9"+$,*(

Arch. Exp. Pathol. Pharmokol. 159:265-274, 1931 Z. Gesamte. Exp. Med. 87: 683-702, 1933 J. Exp. Med. 58: 115-25, 1933 Res. Commun. Chem. Pathol. Pharmacol. 1:169-184, 1970

!$C0(30"#*%/*."#(T$*/%(38,(\M8'*.;8/*(9"+$,*( T*O'$*,'5(

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–! 9"+$,*(+*O'$*,/(+$*/(H%>(9"+$,*(%4j'$*,/(+$*/( –! 9"+$,*(%4j'$*,/(+$*/(.*%4#/*+($,(8(<4'0(#"J*.(/05."$+( J*$C0/(@2Q>a(H>(Ya>Y<CA>( When the rats were fed a high cholesterol diet, thyroid weight significantly increased in both groups. The high-cholesterol diet was also found to increase the body’s excretion of iodine.

This study showed that iodine has an independent positive benefit in a cholesterol-rich diet as well as a synergistic effect with desiccated thyroid hormone.

Metabolism. 15;714-9. 1966

J. Exp. Med. 58: 115-25, 1933

6"J(9"+$,*(G"%/:8./4<(8,+(705."$+( T5%-4,'&",(

W05(9"+$,*f( •! b,#5(1U]("-(:.*%'.$:&",(:.*,8/8#(H$/8<$,%('",/8$,( $"+$,*( •! ?H*.8C*($"+$,*('",/*,/("-(9K:.*,8/8#(H$/8<$,%(J8%( -"4,+(/"(;*(;*#"J(/0*(iT?(-".(9(@22ZkCA( •! b-(/0*(:.*,8/8#(H$/8<$,%(/08/(+"('",/8$,($"+$,*D( ",#5(2P](08H*(<".*(/08,(2PQkC("-($"+$,*(:*.(+8$#5( +"%*(

•! 2YZ(J"<*,(8/(X(<",/0%(:"%/:8./4<(8,+(ZU('",/."#%( -"##"J*+(-".(21(5*8.%( •! ^.$,8.5($"+$,*(8/(X(<",/0%(:"%/:8./4<(8,+(/05."$+( -4,'&",(8/(21(5*8.%(-"##"JK4:( •! i*%4#/%_( –! T*'.*8%*+(^93(:.*+$'/*+(05:"/05."$+$%<(8/(21(5*8.%(-"##"JK4:( –! ^93(l2QQ4CL6(8,+(lPQ4CL6(8%%"'$8/*+(J$/0(%$C,$O'8,/#5(<".*( 05:"/05."$+$%<(

This is a public health disaster that is unparalleled!

Clin. Endocrin. 2011.74:631-5

FP News. 11.15.08

112

5

A Holistic Approach to Iodine Deficiency David Brownstein, MD W05(9"+$,*f(

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113

6

A Holistic Approach to Iodine Deficiency David Brownstein, MD

RDA for Iodine Life Stage

9"+$+*(8,+(9"+$,*( RDA

Adult Male

150µg/d

Adult Female

150µg/d

Pregnancy

220µg/d

Lactation

290µg/d

•! 9"+$,*($%(.8.*(*#*<*,/( –! X1,+($,(8;4,+8,'*("-(/0*(*#*<*,/%("-(/0*(*8./0( •! B"n"<(/0$.+("-(*#*<*,/%($,(/*.<%("-(8;4,+8,'*(

•! i*+4'*+(-".<("-($"+$,*($%(E,"J,(8%($"+$+*( –! \M/.8(*#*'/.",( –! V4##('"<:#*<*,/("-(*#*'/.",%(

9"+$,*L9"+$+*(B$,+(/"(T$N*.*,/(?.*8%("-(B"+5((

Iodine

Iodide

Breast

Thyroid

Prostate

Salivary Glands Skin

Stomach

W0*.*($%(9"+$,*(V"4,+($,(/0*(B"+5f(

!"J()4'0(9"+$,*(F/".*+(9,(70*(B"+5f(

•! \H*.5('*##($,(/0*(;"+5('",/8$,%(8,+(4&#$m*%($"+$,*(

•! S8L9(F5<:"./*.(/.8,%:"./%(9(8'."%%(/0*('*##( <*<;.8,*D(8C8$,%/(C.8+$*,/(

–! WB3h%('8,,"/(*N*'&H*#5(C48.+(8C8$,%/($,-*'&",(J$/0"4/( 8+*g48/*(8<"4,/%("-($"+$,*(

–! )8M$<4<(oXQQkCL+85(9($,(/05."$+(C#8,+(

•! 3",'*,/.8/*+($,(/0*(C#8,+4#8.(%5%/*<( •! 705."$+(C#8,+('",/8$,%(/0*(#8.C*%/('",'*,/.8&",("-($"+$,*( @PQ<C(8+4#/(%8/4.8&",A( •! B.*8%/%D(%8#$H8.5(C#8,+%D(:8."&+(C#8,+%D(:8,'.*8%D( '*.*;."%:$,8#(e4$+D(;.8$,D(%/"<8'0D(%E$,D(#8'.$<8#(C#8,+%D( */'>(

114

7

A Holistic Approach to Iodine Deficiency David Brownstein, MD

!"J(T"(p"4(9,C*%/(9"+$,*f(

!"J()4'0(9"+$,*(F/".*+(9,(70*(B"+5f( •! ?::."M$<8/*#5(2>PK1C<(%/".*+($,(;"+5(8/( %4j'$*,'5(

•! 7.8'*(*#*<*,/D(,"/(H*.5('"<<",($,(<"%/(-""+%( •! b'*8,(-""+%(

–! V8/(&%%4*_(([QQ<C( –! F/.$8/*+(&%%4*_((XPQ<C( –! 705."$+_((PQ<C(

–! 3"+D(%*8(;8%%D(08++"'ED(:*.'0( –! F*8(q*C*/8;#*%(%4'0(8%(%*8J**+(

•! 38,(;*(-"4,+($,(-""+(:."+4'/%($-($"+$,*($%(8++*+(/"( 8,$<8#(-**+(".(/0*(-""+(%"4.'*(

\H*.5(".C8,(8,+(8##(&%%4*%('",/8$,($"+$,*(

–! F8#/(

9"+$m*+(F8#/(

9"+$m*+(F8#/_(6"J(B$"8H8$#8;$#/5(

•! G"/8%%$4<($"+$+*(

•! 1(c."4:%(

–! [YµC($"+$+*LC.8<("-(%8#/(

–! c."4:(2_(9"+$m*+(%8#/( –! c."4:(1_(9"+$m*+(;.*8+(

•! 3"%/(*N*'&H*(J85(/"(:.*H*,/(C"$/*.(

•! o[PQkCL+85($"+$+*($,(;"/0(C."4:%(

–! \N*'&H*(/""#(/"(+*'.*8%*(/0*(:.*%*,'*("-(C"$/*.( –! 9,8+*g48/*(/"(:."H$+*(/0*(;"+5h%(,**+(-".($"+$,*(

( ((

(

(

(

(

((

Expected result: 17.2!g/L (Serum)

Pittman NEJM 1969; 280:1431

9"+$m*+(F8#/_(6"J(B$"8H8$#8;$#$/5(

9"+$m*+(F8#/_(6"J(B$"8H8$#8;$#$/5(

20 18 16 14 12 10 8 6 4 2 0

18 16 14 12 10

Expected

8 6 4 2 0

Serum Levels (mcg/L)

Expected Bread

Serum Levels (mcg/L)

Pittman NEJM 1969; 280:1431 Pittman NEJM 1969; 280:1431

Abraham, G. 2004

Abraham, G. 2004

115

8

A Holistic Approach to Iodine Deficiency David Brownstein, MD

116

A Holistic Approach to Iodine Deficiency David Brownstein, MD

W05(/0*(F"$#($%(T*O'$*,/($,(9"+$,*(

9"+$,*($,(V""+( Food Ready to eat Cereal Dairy-based desert Fish Milk

•! )".*($,#8,+(8,+(<"4,/8$,"4%(8.*8%( –! )$+J*%/*.,(^,$/*+(F/8/*%(

•! c.*8/(68E*%(B8%$,( •! )$'0$C8,D(b0$"D(9,+$8,8D(W$%'",%$,(

•! F"$#(\."%$",(

–! c#8'$*.%( –! T*-".*%/8&",( –! G"".(-8.<$,C(/*'0,$g4*%(

Overall diary products

Eggs Bread Beans, peas, tuber Meat Poultry

•! G"##4&",(

–! G*%&'$+*%(8,+($,%*'&'$+*%(

•! B."<$+*D(e4".$+*(8,+('0#".$,*( •! S8&",8#LJ".#+J$+*(:.";#*<(

W05(?.*(G*":#*(T*O'$*,/($,(9"+$,*f(

µg iodine/serving 87 70 57 56 49 27 27 17 16 15

T$*/8.5(i*8%",%(-".(9"+$,*(T*O'$*,'5( •!

•!

•!

•!

•! F&C<8("-(4%$,C(%8#/(

–! !5:*./*,%$",( –! lPQ]("-(^>F>(0"4%*0"#+%(4%*($"+$m*+(%8#/(

•! i8+$"8'&H*($"+$,*(4%*($,(<*+$'$,*(

–! \M8'*.;8/*(8,($"+$,*K+*O'$*,/(%/8/*(

•! 30*<$'8#(*M:"%4.*%_((c"$/."C*,%(

–! B."<$,*D(30#".$,*(8,+(V#4".$+*(@e4".$,*A( –! T.4C%(

T$*/%(J$/0"4/("'*8,(O%0(".(%*8(H*C*/8;#*%( 9,8+*g48/*(4%*("-($"+$m*+(%8#/($,'#4+$,C(#"J(%"+$4<(+$*/%( q*C8,(8,+(H*C*/8.$8,(+$*/%( B."<$,*($,(-""+(8,+(+.$,E( –! B."<$,8/*+(H*C*/8;#*("$#%(

•! F"<*(c8/".8+*(:."+4'/%D()"4,/8$,(T*J(8,+("/0*.(%"d(+.$,E%(

•! V#4".$+*D(;."<$+*( •! 3"<:*&&H*#5($,0$;$/($"+$,*(;$,+$,C(8%(J*##(8%(+*'.*8%*($"+$,*(4:/8E*(

•! B8E*.5(:."+4'/%(

–! S$/.8/*D(:*.'0#".8/*D(/0$"'58,8/*(

–! B.*8+D(:8%/8D('*.*8#D(*/'>((

•! 3"<:*&&H*($,0$;$/".%("-($"+$,*(8/(S9F(

•! 3",/8$,(;."<$,*(

•! T*'#$,$,C((<$,*.8#(#*H*#%(

–! F"$#(*."%$",D(:"".(-8.<$,C(/*'0,$g4*%D(*/'>(

•! T$*/>(

W08/(!8::*,*+(/"(B8E*.5(G."+4'/%f(

B."<$,*(-".(9"+$,*_((!"#$%&'()**+,,'

•! 2ZXQh%($"+$,*(J8%(8++*+(/"(;8E*.5(:."+4'/%(8%(8( '",+$&",$,C(8C*,/(

2>((W".%*,*+(8,($"+$,*K+*O'$*,'5(:.";#*<(8#.*8+5( :.*%*,/($,(/0*(^,$/*+(F/8/*%( 1>! 3"<:*&&H*#5($,0$;$/*+($"+$,*($,(/0*(;"+5(;5( 8++$,C(8(C"$/."C*,(@;."<$,*A(/"(;8E*.5(:."+4'/%(

–! 2(%#$'*("-(;.*8+('",/8$,*+(/0*(iT?(-".($"+$,*_(2PQkC(

•! 9,(/0*(2Z[Qh%D(;."<$,*(J8%(%4;%&/4/*+(-".($"+$,*( +4*(/"(<$%$,-".<8&",(8;"4/($"+$,*(

((

(( (

This could be the most asinine act (amongst many) in the history of the food industry.

What did this substitution do?

117

10

A Holistic Approach to Iodine Deficiency David Brownstein, MD

!8#"C*,%( MW

•!

•!

•!

•!

•!

V#4".$,*(@V#4".$+*A ( ( ( (2Z( 30#".$,*(@30#".$+*A( ( ( (aX( B."<$,*(@B."<$+*A( 9"+$,*(((((@9"+$+*A((((((((((((((21[( ?%/8&,*((@?%/8&+*A( ( ( (12Q(

Fluorine

!8#"C*,%( V#4".$,*(@V#4".$+*A ( 30#".$,*(@30#".$+*A( B."<$,*(@B."<$+*A( 9"+$,*(((((@9"+$+*A ( ?%/8&,*((@?%/8&+*A(

( ( ( ( (

Bromine

Iodine

B."<$,*((( •! ?,$<8#(%/4+$*%(%0"J(/08/(;."<$,*($,/8E*('8,( 8+H*.%*#5(8N*'/(/0*(8''4<4#8&",("-($"+$,*($,(/0*( /05."$+(8,+(/0*(%E$,( •! !$C0(;."<$+*($,/8E*(.*%4#/%($,($"+$,*(;*$,C( *#$<$,8/*+(-."<(/0*(/05."$+(C#8,+(8,+(.*:#8'*+(;5( ;."<$,*( •! 9,C*%&",("-(;."<$,*(08%(;**,(%0"J,(/"('84%*( 05:"/05."$+$%<($,(8,$<8#%(

MW

•!

•!

•!

•!

•!

Chlorine

(2Z( (aX( (UQ( (21[( (12Q(

When iodine deficiency is present, the toxicity of bromine is accelerated in the body.

9"+$,*(7.8,%:"./(

!"J()4'0(9"+$,*(F/".*+(9,(70*(B"+5f( •! 705."$+_((oPQ<CL+85(( •! B.*8%/%_(()$,$<4<("-(P<CL+85@PQEC(".(22Qr(J"<8,A(-".( <8$,/*,8,'*("-(,".<8#(;.*8%/(&%%4*(

To achieve the maximum transport of iodine "600!g/day across the cell membrane, there must be sufficient iodine in the serum:

–! 68.C*.(J"<8,(".(J"<8,(J$/0(#8.C*.(;.*8%/%(J$##(08H*($,'.*8%*+( .*g4$.*<*,/( –! )*,(08H*(%<8##*.(;.*8%/%(8,+(8(#"J*.($"+$,*(.*g4$.*<*,/(

"10-5-10-6 M These numbers are impossible to reach at the RDA (150!g/day) for iodine!

•! b/0*.(C#8,+4#8.(&%%4*_(()$,$<4<("-(1<CL+85( •! ?+.*,8#%D(/05<4%D("H8.$*%D(05:"/08#8<4%D(:$/4$/8.5(8,+("/0*.%>(

However, 50mg/day iodine/iodide can reach a 10-5 M!

118

11

A Holistic Approach to Iodine Deficiency David Brownstein, MD

!"J(7"(30*'E(9"+$,*(6*H*#%(

7.8,%:"./("-(9"+$,*(

•! B#""+(#*H*#%( •! F8#$H8(

•! 9"+$,*(:.*%*,/($,(*H*.5('*##($,(/0*(;"+5( •! )8,5(+$N*.*,/(C#8,+%(8,+('*##%('",'*,/.8/*($"+$,*( 8C8$,%/(C.8+$*,/( •! S8L9(%5<:"./*.(

–! F8#$H8L%*.4<((

•! FE$,(/*%&,C(

–! i4;($"+$,*(",(%E$,(8,+(";%*.H*(-".($/%h(+$%8::*8.8,'*( •! 9,8''4.8/*(<*8%4.*("-(;"+5h%($"+$,*(%/8/4%( •! ?::."M>(UU]("-(9(*H8:".8/*%((-."<(%E$,( –!

@2A(

–! 7.8,%:"./%($"+$+*(8/(8('",'*,/.8&",(C.8+$*,/(1QKPQ( &<*%(/08/("-(:#8%<8( (

s>(G08.<>(\M:>(70*.8:>((2Za1tYP_UPK2Q[(

•! ^.$,8.5(*M'.*&",(

–! ?''*:/*+(<*8%4.*(

One iodine atom is transferred into cell with two atoms of sodium transported inside of cell.

•! 9"+$,*(#"8+$,C(/*%/(

Angewandte Chm. Int. Ed. 2011. 50 p. 11610

!"J(/"(F:"/(T*-*'/%($,(9"+$,*(i*/*,&",( F5%/*<(

T*-*'/%($,(9"+$,*(i*/*,&",(F5%/*<( •! S".<8#(C8%/."$,/*%&,8#(8;%".:&",("-($"+$,*( •! T*-*'&H*($"+$,*(.*/*,&",(%5%/*<(

•! S",K.*%:",+*.%(/"($"+$,*(%4::#*<*,/8&",( •! ?+H*.%*(*N*'/%(/"("./0"$"+"%4::#*<*,/8&",( •! q*.5(0$C0($"+$+*(*M'.*&",(",($"+$,*(#"8+$,C(/*%/( @uZQ](*M'.*&",(",(O.%/(/*%/A(J0*,(,"/(*M:*'/*+(

–! S8L9(%5<:"./*.(+*-*'/(@".(G*,+.$,(+*-*'/A( •! 3",C*,$/8#(T*-*'/( –! i8.*(

•! bM$+8&H*(+8<8C*(

–! V#4".$+*(".(:*.'0#".8/*( »! 7.*8/(J$/0(8,&"M$+8,/%(

–! ?+H*.%*(*N*'/%(/"(O.%/($"+$,*(+"%*(/8E*,(

•! 9,0$;$&",("-(%5<:"./*.($"+$+*(4:/8E*(;5('"<:*&&",(

•! G8#:$/8&",%D(<*/8##$'(/8%/*($,(<"4/0D(*/'>((

–! c"$/."C*,(;$,+$,C(/"(.*'*:/".( »! 9"+$+*('8,("H*.'"<*('"<:*&&H*($,0$;$&",(

Iodine loading test will come back >90% excretion!

35

Serum inorganic iodide levels (mg/L)

7.*8/<*,/("-(T*-*'&H*(i*/*,&",(F5%/*<( •! T*-*'&H*($"+$,*(.*/*,&",(%5%/*<( –! S8L9(%5<:"./*.(+*-*'/( •! c*,*&'(+*-*'/_((f( •! bM$+8&H*(+8<8C*_((?,&"M$+8,/( (( •! c"$/."C*,(;$,+$,C(/"(.*'*:/"._(T*/"M$O'8&",(8,+(3"<:*&&H*( 9,0$;$&",( –! 9"+$,*( –! F8#/(

30

= Mean of 6 normal female subjects

3

= Patient with Grave’s Disease Prior to intervention

2.5

– % iodide load excreted = 90% – Baseline serum iodide = 0.016 mg/L

2 1.5 1 0.5 0

v

Pre 0.5

1

2

3

4

5

6

7

8

9

10

11

12

24 hrs

Time Post ingestion of Iodoral! 50 mg load Fig. 1

Deni

119

Serum profile of inorganic iodide levels following the iodine/iodide load (50 mg) in 6 normal female subjects; and in a patient with iodide transport defect. Patient excreted 90% of the iodine load, but her basal serum inorganic iodide level was very low at 0.016 m/L. This pattern suggests a defect in the iodine retention mechanism.

12

A Holistic Approach to Iodine Deficiency

250

Serum inorganic iodide levels (mg/L)

Serum inorganic bromide levels (mg/L)

David Brownstein, MD

24 hr urine bromide level = 192 mg

200 150 100 50

0

1

2

4

6

8.5

11

= Mean of 6 normal female subjects = Patient with iodide transport defect Post 3 months Vitamin C 3g/day

2

– % iodide load excreted = 49.2% – Baseline serum iodide = 0.42 mg/L

1.5 1 0.5 0

0

v

Pre 0.5

1

2

3

4

5

6

7

8

9

10

11

12

24 hrs

Time Post ingestion of Iodoral! 50 mg load

hrs

Time post ingestion of Iodoral! 50 mg load

Fig. 2

Serum profile of inorganic iodide levels following the iodine/iodide load (50 mg) in 6 normal female subjects; and in a patient with iodide transport defect following 5 years of intervention with a sustained release Vitamin C at 3 gm/day. Her serum level was 0.42 mg/L, evidence of improved function of the iodine cellular transport mechanism.

35

Serum inorganic iodide levels (mg/L)

T*,,$_((P(p*8.%(68/*.( •!

•!

•!

•!

3 2.5

V**#$,C(;*n*.(J$/0(4,.*O,*+(%8#/(8,+((((H$/8<$,(3( \4/05."$+( 7Gb(&/*.%_(WS6( ?C.**+(/"(+"(8,"/0*.(#"8+$,C(/*%/(@[>1X>22A(

Denni: 5 Years Later

30

= Mean of 6 normal female subjects

3

= Patient with Grave’s Disease 5 years later

2.5

– % iodide load excreted = 90% – Baseline serum iodide = 0.016 mg/L

2 1.5 1 0.5 0

v

Pre 0.5

1

2

3

4

5

6

7

8

9

10

11

12

24 hrs

Time Post ingestion of Iodoral! 50 mg load Fig. 1

Serum Inorganic Bromide Level (mg/L)

Denni: 5 Years Later

Serum profile of inorganic iodide levels following the iodine/iodide load (50 mg) in 6 normal female subjects; and in a patient with iodide transport defect. Patient excreted 90% of the iodine load, but her basal serum inorganic iodide level was very low at 0.016 m/L. This pattern suggests a defect in the iodine retention mechanism.

T*,,$_((1Q2Y(

%,!$

•! V**#$,C(J*##(-".(%$M(<",/0%( •! S"(?,&/05."$+(<*+$'8&",%( •! ?C.**+(/"(+"(8,"/0*.(#"8+$,C(/*%/(

%!!$ ),!$ %!!,$ %!))$

)!!$ ,!$ !$

!$

)$

%$

&$

'$

($

%&$

Time Post Ingestion of Iodoral® 50mg Load

120

13

A Holistic Approach to Iodine Deficiency David Brownstein, MD Denni: 2014

Denni: 2014

30

= Mean of 6 normal female subjects

3

= Patient with Grave’s Disease 5 years later

2.5

– % iodide load excreted = 90% – Baseline serum iodide = 0.016 mg/L

2 1.5 1 0.5 0

v

Pre 0.5

1

2

3

4

5

6

7

8

9

10

11

12

24 hrs

Serum Inorganic Bromide Level (mg/L)

Serum inorganic iodide levels (mg/L)

35

Time Post ingestion of Iodoral! 50 mg load Fig. 1

%,!$ %!!$ ),!$

%!!,$ %!))$

)!!$

%!)&$

,!$ !$

!$

)$

%$

&$

'$

($

%&$

Time Post Ingestion of Iodoral® 50mg Load

Serum profile of inorganic iodide levels following the iodine/iodide load (50 mg) in 6 normal female subjects; and in a patient with iodide transport defect. Patient excreted 90% of the iodine load, but her basal serum inorganic iodide level was very low at 0.016 m/L. This pattern suggests a defect in the iodine retention mechanism.

9,(705."$+D(W08/(!8::*,%(/"(9"+$,*(?d*.( ?;%".:&",f(

9"+$,*(7.8,%:"./(G.";#*<%( •! W0*,(:.";#*<%(+*H*#":(J$/0($"+$,*(4%*D(/0$,E( +*/"M$O'8&",( –! q$/8<$,(3( –! F8#/( –! W8/*.( –! 6$H*.(8,+(E$+,*5(%4::"./( –! \M*.'$%*( –! 3#*8,(T$*/(

NIS

I-

I-

Oxidation (H202+ TPO)

I2

Organification 100x RDA

TSH

TG

# –Iodolactone and other iodinated lipids

RDA

MIT, DIT, T3, T4

However, organification of lipids will only occur with iodine intake in excess of the RDA.

Horm. Metab. Res. 1994;26:465

9"+"#8'/",*(

Iodine + arachidonic acid

TPO

b.C8,$O*+(9"+$,*(( •! i*C4#8/*%(/0*('*##('5'#*($,(/05."$+(C#8,+(;5($,+4'$,C( 8:":/"%$% (

#-iodolactone

#-iodolactone is a key regulator of apoptosis and cellular proliferation in the thyroid. #-iodolactone is not detected in human tissue when iodine deficiency is present, but is present with iodine administration at 100x the RDA.

G0,1: growth and preparation of the chromosomes for replication S:synthesis of DNA G2: Preparation for Mitosis (G1 and G2)

Eur. J. of Endocrin. 132. 735-43, 1995 Horm. Metab. Res. 26. 465-69. 1994

Endocrin. 126. 984-92

121

14

A Holistic Approach to Iodine Deficiency David Brownstein, MD 9,(705."$+D(W08/(!8::*,%(/"(9"+$,*(?d*.( ?;%".:&",f@1A(

9,(705."$+D(W08/()85(!8::*,(9-(9"+$,*( 6*H*#%(?.*(7""(6"Jf( Early

NADPH-Oxydase System Calcium

NIS

I-

I-

NADPH-Oxydase System

Iodinated Lipids

Oxidation (H202+ TPO)

I2

NIS

Organification

I-

TG

TSH

Iodinated Lipids

Calcium

# -Iodolactone

I-

TSH

MIT, DIT, T3, T4

Basolateral membrane

Apical membrane

Oxidation

H202+ TPO

Anti TPO Anti TG

I2

Organification TG # -Iodolactone

MIT, DIT, T3, T4

Treatment: Iodine, Magnesium, B2 and B3, Selenium, Vitamin C, as well as Antioxidants

!1b1(3",/."#_((F*#*,$4<(

!"J(/"(T"%*(9"+$,*(

•! c#4/8/0$",*(G*."M$+8%*(

•! ^%*(8('"<;$,8&",("-($"+$,*L$"+$+*( •! 64C"#h%(F"#4&",(

–! !$C0(*M:.*%%$",($,(/0*(/05."$+(C#8,+( •! G."+4'*+(8,+(%*'.*/*+(;5(/05."'5/*%( (

–! 2(+.":_(X>1P<C(@1>P<C($"+$,*(LY<C($"+$+*A(

•! 9"+"m5<*(!G( –! 2(/8;#*/_((21>P<C(@P<C($"+$,*L[>P<C($"+$+*A(

H2O2

GPx3

2H2O Therapeutic doses of iodine/iodide combinations vary between 12.5-50mg/day.

!"J()4'0(9"+$,*(F0"4#+(p"4(78E*f(

!"J()4'0(9"+$,*(F0"4#+(p"4(78E*f(

•! W0*,(/0*.*($%($"+$,*(%4j'$*,'5D(/0*.*($%(#$n#*(@".( ,"A(.8+$"8'&H*($"+$,*(4:/8E*(;5(/0*(/05."$+(C#8,+((

•! 705."$+( –! aKP<C(9L+85(+*'.*8%*+(8;%".:&",("-(.8+$"8'&H*($"+$,*( ;5(/05."$+(;*#"J(P](

How much iodine is required to achieve sufficiency?

Saxena. Science. 138:430-31. 1962

122

15

A Holistic Approach to Iodine Deficiency David Brownstein, MD

!"J()4'0(9"+$,*(F0"4#+(p"4(78E*f( Amt. Iodide Ingested (12 days) 10mg

% Uptake Radioactive Iodide by Thyroid 4%

15mg

1.9%

30mg

1.6%

50mg

1.2%

100mg

0.6% Sternthal. N. .Eng. J. Med. 303:1083-1080. 1980

9"+$,*(T"%8C*(c4$+*#$,*%( •!

•!

•!

•!

V$,8#(70"4C0/%( •! 9"+$,*(+*O'$*,'5($%('"<<",( •! S"/(.*'&O*+(;5(/0*(4%*("-($"+$m*+(%8#/( •! 9"+$,*(+*O'$*,'5(<85(;*(/0*(4,+*.#5$,C('84%*("-(84/"$<<4,*( /05."$+(+$%".+*.%( •! ^%$,C(8('"<;$,8&",("-($"+$,*L$"+$+*(<".*(*N*'&H*(/08,(4%$,C( $"+$+*(8#",*( •! B*%/(.*%4#/%(8'0$*H*+(J$/0(8(0"#$%&'(8::."8'0(

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A Holistic Approach to Iodine Deficiency David Brownstein, MD

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First year off lithium: suicide rate rose 20-fold&

Shorter E. Bipolar disorders 2009;11(0 2):4-9

James Greenblatt MD

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Cipriani A et al. Am J Psychiatry 2006; 163:550.

Guzzetta F. J Clin Psychiatry 2007;68: 380-3.

Ciprani et al. BMJ 2013; 345:f3646.

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Schrauzer GN, Shrestha KP. (1990). Biol Trace Elem Res, 25(2),105-13.

Kapusta, N.D., et al. (2011). The British Journal of Psychiatry, 198, 346-350.

James Greenblatt MD

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LITHIUM—A SIMPLE METAL AND THE OLDEST DRUG IN PSYCHIATRY—MIGHT PROTECT THE BRAIN AGAINST MENTAL ILLNESS, ALZHEIMER’S, AND OTHER DISEASES. ONE PROBLEM: THERE’S NO PROFIT IN IT.

BY PAUL RAEBURN; ADDITIONAL REPORTING BY MONICA HEGER

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Bluml V et al. J Psychiatric Res 2013; 47:407-411.

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Forlenza OV et al et al. Br J Psychiatry 2011; 198:351-356.

Nunes MA et al. Current Alzheimer Research 2013, 10, 104-107.

Nunes PV et al. Br J Psychiatry. 2007 Apr;190:359-60.

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Action at intracellular sites to inactivate G-proteins and second messenger systems stimulated by the binding of dopamine to postsynaptic receptors

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Not as intense

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Behavior

Hot

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