40th Orthomolecular Medicine Today Conference by Journal of Orthomolecular Medicine

International Society for Orthomolecular Medicine

April 29, 2011 Dear Delegates, Welcome to our 40th 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 this important field. Four decades – a long time for one conference to sustain the interest and attention of its delegates! This event had its beginning as the annual meeting of the Canadian Schizophrenia Foundation; in 1986 it became the Nutritional Medicine Today Conference as it was directed more toward health professionals and, in 2006, it evolved to its current form as the Orthomolecular Medicine Today Conference. This year we are pleased to be joined by 15 speakers, 26 exhibitors and over 170 delegates and guests from 15 countries worldwide. We thank you for your continued dedication to Orthomolecular Medicine and wish you a memorable Conference. With best regards,

Director, ISOM

Thanks

ISOM and CSOM Meeting Friday, April 29 5:30Generous pm – 6:30 Sponsors pm to Our

Please join us after Dr Burke’s presentation to hear the update from CSOM, the Canadian Society for Orthomolecular Medicine. A brief report will be given on our activities in education, communications and advocacy. In addition, members from some of the 13 countries in attendance will also provide an update of activities. Don’t miss this opportunity to hear an international perspective on Orthomolecular Medicine.

April 2011 It is a pleasure to extend my warmest greetings to those in attendance at the 40th Orthomolecular Medicine Today Conference. With respect both to our aging demographic and to environmental challenges affecting our lifestyles, innovation in medicine will be crucial in the foreseeable future to maintaining the health of individuals and of society. It is therefore very encouraging to witness doctors and scientists from around the world gathering in Toronto to exchange information, experiences and opinions. Japan faces now a tremendous challenge to cope with the disaster caused by the earthquake and tsunami on March 11 and the subsequent radiation problems of the affected nuclear power station. Japan for the foreseeable future will be devoting itself to efforts for reconstruction of devastated infrastructure and communities. It would give me great pleasure if the work and insights provided by Orthomolecular medicine specialists could also assist this tremendous undertaking. I truly hope this conference will prove fruitful and inspiring for all of you as you continue your invaluable work.

Nobuaki Yamamoto Acting Consul-General of Japan ______________________________________________________________________________ 第４０回「今日の分子濃度調整論医学会議」開催にあたり、メッセージを送らせて頂く機会を得ましたことを嬉しく思います。

私たちの生活スタイルに大きな影響を与えている、高齢化や環境問題への取り組みの中で、医学の革新は予見し

得る将来において、個人及び社会全体の健康維持のために不可欠なものとなっています。従って今般、世界中から医師や科学者の先生方がここトロントに集われ、医学の革新に関する情報、経験及び意見を交換されることは、たいへん勇気づけられるものであります。

日本は、去る３月１１日に起こった地震と津波による甚大な被害及びその後の原子力発電所の放射線汚染問題への対処という、未曾有の試練に直面しております。当面我が国は、破壊された社会基盤と地域社会の再建に専念

していくこととなりますが、分子濃度調整論医学専門家の先生方によりもたらされる成果と洞察が、これからの私たちの復興に対する大きな支援となれば、これに勝る喜びはありません。

先生方が今後活動していかれるに当たり、この会議が実り多きものとなりまた各先生方を鼓舞するものとなるよう心から祈念しております。在トロント日本総領事館総領事代理山本信明

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National Orthomolecular Orthomolecular Health Health Campaign Campaign We are proud to offer the series of six thought-provoking posters for sale at the OMT Literature Table. These attractive 12â&#x20AC;? x 16â&#x20AC;? electrostatic posters cling to any smooth surface without adhesives. The complete set of six is available for the cost of $60.00.

Table of Contents Exhibitor Floor Plan.............................................................................................................................................................6 Our Exhibitors.......................................................................................................................................................................7 Speaker Biographies............................................................................................................................................................8 Conference Schedule...........................................................................................................................................................9 Presentation Notes Christine Miller, PhD Abram Hoffer Memorial Lecture -Nutrition and Schizophrenia: The Genes Tell the Story....................................................11 Laurie Mischley, ND, MSc Enhancing Mitochondrial Function as a Therapeutic Strategy in Parkinson’s and other Neurodegenerative Diseases............................................................................................................................................20 James Greenblatt, MD An Orthomolecular Approach to Suicide Prevention.....................................................................................................................27 L. John Hoffer, MD, PhD Vitamin C as Cancer Therapy: What is the Evidence?......................................................................................................................39 Atsuo Yanagisawa, MD IV Vitamin C and Quality of Life in Cancer Treatment in Japan....................................................................................................50 Hyla Cass, MD Orthomolecular Intervention for Nutrient Depletion from Pharmaceutical Use.....................................................................58 Bud Rickhi, PhD Dr. Rogers Prize Lecture - Orthomolecular Therapy for Childhood Asthma.............................................................................65 Aileen Burford Mason, PhD Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy..............................................70 Phyllis Bronson, PhD The GABA- Receptors and the Etiology of Anxiety..........................................................................................................................80 Joan Jory, MSc, PhD Autism: an Evidence Base for Orthomolecular Intervention........................................................................................................ 84 Bonnie Kaplan, PhD Treating Mental Disorders with Multiple Nutrients.........................................................................................................................97 Patrick Holford An Orthomolecular Approach to Alzheimer’s Disease............................................................................................................... 105 Michael Schachter, MD The Role of a Comprehensive Mineral Program in Orthomolecular Treatment.....................................................................115 Joe Pizzorno, ND Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers.........................................................125 Ron Hunninghake, MD Orthomolecular Treatment for Heavy Metal Toxicity...................................................................................................................134

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

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40th Orthomolecular Medicine Today Conference Exhibitor Floor Plan Convention Floor Concert Hall, Royal York EXHIBITORS (by booth number) 1. BDR INT, Inc. 2. CanLabs Inc 3. Smith’s Pharmacy 4. Canadian Association of Naturopathic Doctors (CAND) 5. Metabolistics 6. Restorative Formulations 7. Vibrant Health/GUNA Canada 8. Bioclinic Naturals 9. Douglas Laboratories 10. Rocky Mountain Analytical 11. York Downs Pharmacy 12. Protocol for Life Balance 13. The Great Plains Laboratory, Inc. 14. Metagenics Canada, Inc. 15. Nutri-Chem Pharmacy Ltd. 16. Nutritional Fundamentals for Health (NFH) 17. College Pharmacy 18. CanPrev Premium Natural Health Products Ltd. 19. Seroyal International Inc. 20. Boston Mills Allergy Group Vita Aid Professional Nutrition Products 21. Orthomol pharmazeutische Vertriebs GmbH 22. Acquired Intelligence, Inc. 23. Nature’s Source 24. Integrated Health Practitioner Magazine

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40th 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 BDR INT, Inc. 4245 No. 4 Side Road Burlington, ON L7M 0S4 Canada 866 634 8075 bdrint@gmail.com www.nanovitaminc.ca Bioclinic Naturals 1550 United Boulevard Coquitlam, BC V3K 6Y2 Canada 877 433 9860 yfenton@bioclinicnaturals.com lcasavant@bioclinicnaturals.com www.bioclinicnaturals.com Boston Mills Allergy Group Inc. 15023 Chinguacousy Road Caledon, ON L7C 3H7 Canada 888 838 3351 / 905 838 3351 bmagi@xplornet.com Canadian Association of Naturopathic Doctors (CAND) 20 Holly Street, Suite 200 Toronto, ON M4S 3B1 Canada 800 551 4381 / 416 496 8633 info@cand.ca www.cand.ca CanLabs Inc. Suite 112, 5-420 Erb. W Waterloo, ON N2L 6K6 Canada www.canlabs.ca CanPrev Premium Natural Health Products Ltd. 11 – 60 West Wilmot Street Richmond Hill, ON L4B 1M6 Canada 888 226 7733 / 905 881 6800 info@canprev.ca www.canprev.ca College Pharmacy 3505 Austin Bluffs Parkway Colorado Springs, CO 80918 USA 800 888 9358 / 719 262 0022 info@collegepharmacy.com www.collegepharmacy.com

Douglas Laboratories of Canada/ Pure Encapsulations 552 Newbold Street London, ON N6E 2S5 Canada 866 856 9954 / 519 439 8424 info@douglaslabs.ca www.douglaslabs.ca The Great Plains Laboratory, Inc. 11813 W. 77th Street Lenexa, KS 66214 USA 800 288 0383 / 913 341 8949 cgram@gpl4u.com / 919 747 9729 www.greatplainslaboratory.com Integrated Health Practitioner Magazine 1106 - 60 Bloor Street West Toronto, ON M4W 3B8 Canada 416 203 7900 web@rivegauchemedia.com www.ihpmagazine.com Metabolistics 9125 50th Street Edmonton, AB T6B 2H3 Canada 800 429 7608 / 780 993 3866 sslupsky@metabolistics.com www.metabolistics.com Metagenics Canada, Inc. 851 Rangeview Road Mississauga, ON L5E 1H1 Canada 800 268 6200 philcappellano@metagenics.com www.metagenics.com Nature’s Source 5029 Hurontario Street, #2 Mississauga, ON L4Z 3X7 Canada 905 502 6789 info@natures-source.com www.natures-source.com Nutri-Chem Compounding Pharmacy and Clinic #205-1305 Richmond Road Ottawa, ON K2B 7Y4 Canada 613 820 4200 info@nutrichem.com www.nutrichem.com Nutritional Fundamentals for Health (NFH) 3405 F.X. Tessier Vaudreuil-Dorion, QC J7V 5V5 Canada 866 510 3123 info@nfh.ca www.nfh.ca Orthomol pharmazeutische Vertriebs GmbH Herzogstr. 30 40764 Langenfeld, Germany 0049 2173 9059-0 export@orthomol.de www.orthomol.com

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Protocol for Life 7018 Wellington Road, #124 S. Guelph, ON N1H 6J4 Canada 800 265 7245 ext 721 debra.greene@protocolforlife.com www.protocolforlife.com Restorative Formulations 93 Barre Street, Suite 1 Montpelier, VT 05602 USA 800 420 5801 penny@restorativeformulations.com www.restorativeformulations.com Rocky Mountain Analytical Unit A, 253147 Bearspaw Road NW Calgary, AB T3L 2P5 Canada 866 370 5227 info@rmalab.com www.rmalab.com Seroyal International Inc. 490 Elgin Mills Road East Richmond Hill, ON L4C 0L8 Canada 800 263 5861 sales@seroyal.com www.seroyal.com Smith’s Pharmacy 3463 Yonge Street Toronto, ON M4N 2N3 Canada 416 488 2600 info@smithspharmacy.com www.smithspharmacy.com Vibrant Health/GUNA Canada 600 Blvd Sir Wilfrid Laurier Mont-Saint-Hillaire, QC J3H 4X6 Canada 450 536 1295 / 877 486 2226 info@VibrantHealth.com info@GunaCanada.com www.GunaCanada.com Vita Aid Professional Nutrition Products #302-20285 Stewart Crescent Maple Ridge, BC V2X 8G1 Canada 800 490 1738 / 416 452 9585 info@vitaaid.com steve@vitaaid.com www.vitaaid.com York Downs Pharmacy 3910 Bathurst Street, Room 304 Toronto, ON M3H 5Z3 Canada 800 564 5020 / 416 633 2244 info@yorkdownsrx.com www.yorkdownsrx.com

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Speaker Biographies Christine Miller, PhD, received her doctorate in Pharmacology from the University of Colorado Health Sciences Center. She is currently president of MillerBio, a small biotechnology company developing technologies for determining genetic haplotype. During the academic phase of her career, she investigated a schizophrenia endophenotype in animal models (auditory gating), eventually proceeding to molecular profiling of postmortem brain samples in cases versus controls while an instructor at Johns Hopkins University. This research culminated in a genetic association study of loci involved in regulating the kynurenine pathway, the route for de-novo synthesis of NAD under conditions of dietary insufficiency of niacin and nicotinamide.

2004, Dr. Burford-Mason co-founded and currently serves as Board President of the Holistic Health Research Foundation of Canada. Phyllis J Bronson, Ph.D. is a biochemist with an emphasis on the physical chemistry of the molecules she studies and the correlation to mood and emotion. She has just completed a ten year study on the molecular spectra of bioidentical hormones and what this means in terms of understanding female mood. For many years she has also had a clinical practice with Kenton Bruice, M.D., a board certified ob/gyn specializing in bioidentical hormones. Women come from all over the globe for help looking at mood/ body issues from a science-based perspective, much based on original research. Phyllis is currently working on a book entitled “Hormones Mood and Emotion”- a journey into the female psyche.

Laurie K Mischley, ND earned her BS in Nutrition Science from Pennsylvania State University in 1997 and her ND from Bastyr University in 2001. Her private practice is devoted to the care of individuals with neurological disorders. She is author of the book, Natural Therapies for Parkinson’s Disease. In 2010 she was awarded The Bernard Osher Foundation/ NCCAM CAM Practitioner Research Career Development Award (K01); with the support of this award, she is conducting a Phase I Study of Intranasal Glutathione in Parkinson’s Disease at Bastyr University Research Institute and enrolled in the Masters of Public Health program in Epidemiology at University of Washington.

Joan Jory, RD, MSc, PhD, is an independent private practitioner with an MSc from the University of London Graduate School of Hygiene and Tropical Medicine (UK), PhD from the University of Guelph, and graduate dietetic internship (RD) from McMaster. She has been specializing in autism and Down Syndrome for 10 years, receiving a $10,000 US research grant from the Autism Research Institute for case-control investigation of trace mineral and heavy metal levels in autism. Joan works collaboratively with physicians and allied health practitioners, and has presented to scientific and lay audiences provincially, nationally and internationally. She has a full practice in Guelph.

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 ou patient treatment center in Boston, Massachusetts and is Assistant Clinical Professor at Tufts University Medical School, Department of Psychiatry.

Bonnie Kaplan is an academic researcher in the Faculty of Medicine, University of Calgary, where she is a Professor in the Departments of Pediatrics, and Community Health Sciences. She initially trained as an experimental psychologist, followed by postdoctoral training in neurophysiology, which led to her longstanding interest in the role of nutrients in brain development and function. Two research programs occupy most of her time: 1) The role of micronutrient treatment for mood, aggression, and explosive rage. Most of this work has used the formula called EMPowerplus. 2) The role of prenatal nutrition on the developing brain and maternal mental health (APrON: Alberta Pregnancy Outcomes and Nutrition; www.apronstudy.ca).

John Hoffer, MD, PhD, is a professor of medicine at McGill University where he conducts research at the Lady Davis Institute for Medical Research. He earned his medical degree from McGill and his doctorate in Human and Clinical Nutrition from M.I.T. Dr Hoffer is also a senior physician in the divisions of Internal Medicine and Endocrinology in Montreal’s Jewish General Hospital. His research interests are in protein-energy malnutrition and vitamin therapy for chronic disease. Dr. Hoffer has served for many years on the Nutrition and Metabolism Committee of the Canadian Institutes for Health Research.

Patrick Holford is a pioneer in new approaches to health and nutrition, specializing in the field of mental health. While com- pleting his bachelor degree in Experimental Psychology at the University of York, he became a student of Dr. Carl Pfeiffer, director of Princeton’s Brain Bio Center, and later a student of Dr. Abram Hoffer. In 1984 Patrick founded the Institute for Optimum Nutrition (ION), now the largest school in the UK offering degree-accredited training. Patrick retired as Director of ION in 1997 to focus on writing, teaching and researching. Since 1997 Patrick has written 29 books selling more than a million copies worldwide including: The Optimum Nutrition Bible, Optimum Nutrition for the Mind, The Holford Low GL Diet, and Natural Highs.

Atsuo Yanagisawa, M.D., Ph.D., F.A.C.C. 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.

Michael B Schachter MD, CNS, a Board Certified Psychiatrist has been involved in orthomolecular medicine since the mid 1970’s. He directs the Schachter Center for Complementary Medicine in Suffern, NY, which services patients with all kinds of health challenges. He was President of the American College for theAdvancement in Medicine (ACAM) from 1989 through 1991 and frequently lectures at their conferences and workshops. He has also presented at ISOM and Orthomolecular Health Medicine Society conferences. His book What Your Doctor May Not Tell You about Depression (Warner) is available and an article “Integrative Oncology for Clinicians and Cancer Patients” can be found in a recent issue of ISOM.

Hyla Cass M.D. is a nationally acclaimed physician, board-certified psychiatrist, and expert on the subject of integrative medicine. She combines the best of leading-edge natural medicine with modern science in her clinical practice, writings, lectures, and nationwide media appearances. Quoted widely in new papers and magazines, she also appears regularly on radio and television, including The View, the CBS Evening News, and The Dr. Oz Show. She is the author of several popular books including User’s Guide to Herbal Remedies, St. John’s Wort: Nature’s Blues Buster, Natural Highs, 8 Weeks to Vibrant Health, and her latest, Supplement Your Prescription: What Your Doctor Doesn’t Know About Nutrition.

Dr. Joseph E. Pizzorno, ND, through education, research, publishing, policy advancement, and solution-driven innovation, has earned international r spect for his dedication to sharing the profound efficacy of science-based natural medicine. Beginning with the founding of Bastyr University and its preeminent naturopathic doctoral program, Dr. Pizzorno’s career is highlighted by his service to two Presidents in White House committee appointments on CAM policy, his expertise published via 7 acclaimed books on natural medicine, including the Textbook of Natural Medicine and the Encyclopedia of Natural Medicine, and his work to bring natural medicine concepts into corporate wellness programs that make a real difference.

Badri (Bud) Rickhi is a psychiatrist and an Associate Clinical Professor, Faculty of Medicine, University of Calgary. He is the Director and Research Chair of the Canadian Institute of Natural and Integrative Medicine (CINIM). Dr. Rickhi studied Traditional Chinese Medicine and has received training in varying levels of Ayurvedic, Tibetan, Ryodoraku medicine, functional and energy medicine. He has been an appointed advisor to Health Canada on complementary therapies and with the World Health Organization. He has participated as an expert in Integrative Medicine in televised documentaries and his workshops in spirituality have been broadcasted on the Wisdom Channel.

Ron Hunninghake, MD, is the Chief Medical Officer of the Olive White Garvey Center for Healing Arts, the clinical division of The Center for the Improvement of Human Functioning, International. He is a 1976 graduate of the University of Kansas. Dr. Hunninghake was associated with the Family Practice Group in Minneapolis, Kansas, from 1978 to 1980, and Salina Family Physicians, KS, from 1982 to 1989. In addition to his full-time practice at The Center, Ron is a regular presenter at medical conferences, and at 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 Energy-Boosting Supplements (2006); Stop Prediabetes Now (2007).

Aileen Burford-Mason, PhD, is an Immunologist, Cell Biologist and Nutritionist with a deep interest in the evidence base for orthomolecular health. She graduated in biochemistry from University College, Dublin, and received a PhD in immunology from the University of Hertfordshire. Her scientific papers cover many fields including gastroenterology, pathology, cancer and infectious diseases. She has published articles on gastrointestinal colonization with Candida and its relationship to health. She was Assistant Professor in the Dept. of Pathology in the Faculty of Medicine, University of Toronto. In

PROGRAM FRIDAY, APRIL 29

Session Three cont’d • Vitamin D

8:00 am Registration 8:00 am Welcome

11:30 am Phyllis Bronson, PhD The GABA- Receptors and the Etiology of Anxiety

Session One • Orthomolecular Psychiatry (A)

12:30 pm Lunch – Visit Exhibitors

9:00 am Christine Miller, PhD Abram Hoffer Memorial Lecture -Nutrition and Schizophrenia: The Genes Tell the Story

10:00 am Break – Visit Exhibitors 10:30 am

Session Four • Orthomolecular Psychiatry (B)

2:00 pm Joan Jory, MSc, PhD Autism: an Evidence Base for Orthomolecular Intervention

Laurie Mischley, ND, MSc Enhancing Mitochondrial Function as a Therapeutic Strategy in Parkinson’s and other Neurodegenerative Diseases

3:00 pm Bonnie Kaplan, PhD Treating Mental Disorders with Multiple Nutrients

11:30 am James Greenblatt, MD An Orthomolecular Approach to Suicide Prevention

4:00 pm Break – Visit Exhibitors 4:30 pm Patrick Holford An Orthomolecular Approach to Alzheimer’s Disease

12:30 pm Lunch – Visit Exhibitors 2011 Orthomolecular Doctor of the Year

Session Two • Orthomolecular Oncology

5:30 pm Exhibit Area Closes

2:00 pm L. John Hoffer, MD, PhD Vitamin C as Cancer Therapy: What is the Evidence?

Classical Concert with

Anton Kuerti, Piano Koerner Hall, 8:00 pm

3:00 pm Atsuo Yanagisawa, MD IV Vitamin C and Quality of Life in Cancer Treatment in Japan

SUNDAY, MAY 1

4:00 pm Break – Visit Exhibitors

8:30 am Exhibit Area Opens

4:30 pm Hyla Cass, MD Orthomolecular Intervention for Nutrient Depletion from Pharmaceutical Use

Session Five • Orthomolecular Medicine 9:00 am 10:00 am

5:30 pm Exhibit Area Closes

2011 Orthomolecular Medicine Hall of Fame Reception 6:30 pm Dinner and Induction Program 7:00 – 9:00 pm

Break – Visit Exhibitors

10:30 am Joe Pizzorno, ND Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers

SATURDAY, APRIL 30

11:30 am Ron Hunninghake, MD Orthomolecular Treatment for Heavy Metal Toxicity 12:30 pm Exhibit Area Closes

8:30 am Exhibit Area Opens

Session Three • Orthomolecular Medicine 9:00 am Bud Rickhi, PhD Dr. Rogers Prize Lecture: Orthomolecular Therapy for Childhood Asthma

Public Workshop

10:00 am Break – Visit Exhibitors 10:30 am

Michael Schachter, MD The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

Mental Health Regained

Aileen Burford Mason, PhD Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy

featuring Patrick Holford, Orthomolecular Practitioners and Recovered Patients 2:00 pm – 4:00 pm

Join us for the

41st Annual International

Orthomolecular Medicine Today Conference

April 27 - 29, 2012 Fairmont Hotel Vancouver Subscribe Today!

ince 1970, this quarterly Journal for health professionals has published the

best of nutritional research and clinical trials. New articles describing the orthomolecular approach to health management and treatment of disease are accompanied by lively editorials, case reports, book reviews, and correspondence. The Journal of Orthomolecular Medicine has led the way in presenting new health concerns and treatments. Join health professionals like yourself in 35 countries who subscribe to the Journal of Orthomolecular Medicine–you’ll wonder how you practised without it!

Feed Your Head A New ISF Documentary Feed Your Head, the new ISF documentary about the life and work of Dr. Abram Hoffer, won the Founder’s award “for an outstanding production exemplifying historical Canadian characters or events” at the Yorkton Film Festival in Saskatachewan in May this year. Shot across Canada over a three year period from 2006 to 2009, the 45 minute film tells the gripping story of Dr. Hoffer and Humphry Osmond, who met in 1951 and embarked on a quest to find what psychiatry said didn’t exist: a cure for schizophrenia. They showed that mental illness could be controlled with natural foods, a healthy lifestyle, and large doses of vitamins. Linus Pauling called this approach “orthomolecular.” Sixty years later thousands have been helped by these heretical ideas, and educated consumers have begun to demand more common sense in mental health care. Feed Your Head is produced by Connie Littlefield, Kyle Cameron and Steven Carter and directed by Connie Littlefield. Order your Feed Your Head DVD from the ISF for $25, including tax and shipping within North America. Call: 416 733 2117 or email: centre@orthomed.org or order online

Abram Hoffer Memorial Lecture -Nutrition and Schizophrenia:11-04-05 The Genes Tell the Story Christine Miller, PhD ! The Abram Hoffer I came to know !  Kynurenine alterations in schizophrenia

! "!#$%&'()$!*+,!$)'--.!#'$)(!'/,%0!+1&! 2'3)40&! !

Nutrition and Schizophrenia: The genes tell the story

!  The niacin receptor and other genes associated with schizophrenia

Friday, December 15, 2006 1:36 PM Dear Dr Miller: Yesterday I saw a chronic paranoid who was one of the sickest I have ever seen. ………. My office always treated him with respect and consideration, and when he was abused by the system I became his advocate, writing letters and making calls on his behalf. I did not treat his paranoid ideas. I did not try to persuade him they were wrong, and no matter how bizarre they were, I still listened. He would have made an excellent science fiction writer on the morbid side. His paranoid delusions are playing a much lesser role because his schizophrenia is coming under

Christine L. Miller, Ph.D. MillerBio, Baltimore, MD

!  How nutrition regulates kynurenine pathway function !  Why poor nutrition and epidemics may have forced human evolution

control. One does not treat the paranoid delusions; one treats the basic disease present in the human being....................... Abram

!  Key aspects of Abram Hoffer’s legacy to pursue

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Monday, September 08, 2008 11:32 PM Dear Christine: Did you know that our aboriginal people also depended on bannock which was white flour baked into flat cakes. When all while flour was enriched in the US about 1942 the Director of Indian Affairs, Government of Canada in Ottawa

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insisted that all Indian(aboriginals) be given that enriched flour, I was then against the law to enrich flour in Canada.

Abram

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Thursday, June 19, 2008 3:07 PM Dear Christine: I've attached Chapter 11 from my book which describes how we discovered that niacin decreased total cholesterol levels. Prof Altschul using the niacin I gave him discovered this effect in rabbits and then the three of use did the same for humans. Altschul did use baked egg yolk cake and he was on to the oxidant idea so many years ago.………………

Wednesday, February 22, 2006 3:06 PM Dear Dr Miller: Thank you. You really do not owe me any apology. How could you possibly have discovered that book edited by D Hawkins and Linus Pauling

This was not a serendipitous finding, It arose from some of my ideas which luckily were pretty good.

so many years go............. Abram

Abram

Abram Hoffer Memorial Lecture -Nutrition and Schizophrenia:11-04-05 The Genes Tell the Story Christine Miller, PhD LLM#7$N9!O#?P8$9!.*?#.>9!Q8>&,8$9!6!H.*&>9!6&$+*.! LLRS//S122T! H7*!$*U!.*9*&.+7(!?=-A897*%!8$!>7*!F#=.$&A!6&$+*.!6*AA;;;;;;;;;;;;;;;;;;;;;;! !;;;;;;.*9*&.+7*.9!A*%!-'!).;!678!)&$E(!&!?.#@*99#.!#@!,*%8+8$*!&$%!#$+#A#E'!&>!M#7$9!O#?P8$9!V$8C*.98>'!8$!W&A:,#.*(! @#=$%!>7&>!&$:#X8%&$>9!&??*&.!>#!-*!U#.P8$E!8$!&!%8Y*.*$>!U&'!SS!=$%*.,8$8$E!&!>=,#.‘9!&-8A8>'!>#!E.#U!=$%*.!

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"!()-1:+;%-!&)4&)!,9!+%7,$! Sunday, June 17, 2007 2:07 PM !

Dear Christine: .....would not give grants to investigators who were interested in our work.……….

Luckily he was not on niacin and I have outlived him. Abram

K$%!9#!,=+7!789>#.'! And so much history

The Kynurenine Pathway " Function Diseases Pathway diagram Pathway metabolites

Friday, February 15, 2008 3:15 PM Dear Christine;

Pathway enzymes

Fort San is in the Qu.Appelle Valley and is about 60 miles east of Regina and about 250 miles south east of North Battleford......... You also know that the diet of our native population was atrocious , It was way too heavy in white flour that they ate in the form of bannock. I wonder if any one has ever looked at the natives who still ate the way their parents did in the prairies My wife and I used to holiday in a cabin in that Valley.........

•  Active both in peripheral tissues and the brain •  Utilizes tryptophan producing several intermediate metabolites and degradation products. Serves the following primary functions:

Pathway receptors

•  Degrades tryptophan: a) homeostatic control of tryp levels b) inhibits survival of infectious Genetic results organisms (scz and bipolar) c) reduces T-cell proliferation (autoimmunity)

Abram

•  Regenerates NAD

Diseases causing kynurenine pathway activation Function " Diseases Pathway diagram Genetic results (scz and bipolar)

•  •

Pathway metabolites

Genetic results (scz and bipolar)

•

kynurenine formamidase

Diseases

Nutritional and Metabolic diseases:

" Pathway diagram

Pellagra – niacin deficiency leads to loss of feedback inhibition

Pathway metabolites

Porphyria – a partial heme deficiency; leads to dissociation of TDO2 tetramer and accumulation of monomers; when heme restored, can result in rapid activation of pathway.

Pathway enzymes Pathway receptors

Function

Infectious disease: any infection that causes elevation of interferon gamma [HSV,CMV, HIV, S. typhi, T. gondii, P.falciparum (malaria)]

L-tryptophan Activated by low IDO TDO2 Activated by infection NAD, stress, cortisol N-formyl kynurenine

Pathway enzymes

CNS genetic diseases:

Pathway receptors

Huntington’s disease

Genetic results (scz and bipolar)

Schizophrenia

kynurenine KYNU

CCBL1 KMO KAT2

anthranilic acid non-specific hydroxylation

3-hydroxykynurenine

kynurenic acid

KYNU I

3-hydroxyanthranilic acid HAAO

quinolinate QPRT

nicotinate mononucleotide NMNAT NaPRT1

Bipolar disorder

niacin feedback regulator of TDO2

NADE

feedback regulator of TDO2 nicotinamide

PARP

NAD

feedback regulator of TDO2

Abram Hoffer Memorial Lecture -Nutrition and Schizophrenia: The Genes Tell the Story Christine Miller, PhD

Abram Hoffer Memorial Lecture -Nutrition and Schizophrenia:11-04-05 The Genes Tell the Story Christine Miller, PhD NIACR1 in confocal microscopy

Dr. Fernand Gobeil University de Sherbrooke Quebec, Canada

midsection of human brain microvascular endothelial cells

NIACR2 in confocal microscopy

Field 2

Field 1

midsection of human brain micro-vascular endothelial cells

3-D

Dr. Fernand Gobeil University de Sherbrooke Quebec, Canada

Unpublished data

Unpublished data 10

QPCR

The high affinity niacin receptor protein NACR1 was significantly decreased in schizophrenia anterior cingulate sections;

NIACR1 4.1-fold higher in scz, p=0.04

no difference in the low affinity niacin receptor protein NACR2 (quantitative Western blots).

anterior cingulate NIACR2 4.8-fold higher in scz, p=0.12

Function Diseases

NIACR1

Pathway diagram

NIACR1 mRNA Schizophrenia cases

NIACR2 mRNA Schizophrenia cases

Pathway metabolites Pathway enzymes " Pathway receptors Genetic results (scz and bipolar)

NIACR1 mRNA Controls

cycle number

(Miller et al., 2008)

NIACR2 mRNA Controls

!"""""""#$""""""""!$"""""""%$""""""""&$"""""""""

cycle number

(Miller and Dulay, 2008)

Genetic Association Study

Function Diseases

To test for interaction between genes that activate the kynurenine pathway and those that respond to its products:

Pathway diagram

TDO2

Pathway metabolites

Pathway enzymes

The two niacin receptors, NIACR1 and NIACR2 (Shink et al., 2005 – association with bipolar disorder)

Pathway receptors " Genetic results (scz and bipolar)

Melanotropin receptors (MCHR1, MCHR2, MC5R) a)  markers within 1MB of MC5R (bipolar disorder, p<0.001, Lin et al., 2005; schizophrenia, p= 0.02, Schwab et al., 1998) b)  markers within 1cM of MCHR2 (bipolar disorder, p< 0.05, Dick et al., 2003; Lambert et al., 2005; and schizophrenia, unweighted MLS p<0.01, Levinson et al., 2000) c)  SNPs within the MCHR1 gene significantly associated with schizophrenia and bipolar disorder (Severinsen et al., 2006).

•  563 cases with schizophrenia •  100 cases with bipolar disorder •  240 controls (Miller et al., 2004, 2006, 2008a, 2008b)

Abram Hoffer Memorial Lecture -Nutrition and Schizophrenia: The Genes Tell the Story Christine Miller, PhD

Abram Hoffer Memorial Lecture -Nutrition and Schizophrenia: The Genes Tell the Story 11-04-05 Christine Miller, PhD

A key piece of the Abram Hoffer legacy to pursue: The matter of pigmentary products, harmful…..

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

………..or not

"#$%&'(!M=A'!1/(!1220!T4`0!5"! )*&.!67.89:$*4

a>7*.!=$+#,,#$!98%*!*Y*+>9!&.*!!8$+.*&9*%!-.#U$!?8E,*$>&:#$!#@!! +*.>&8$!&.*&9!#@!>7*!9P8$(!=9=&AA'!>7*!b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

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

ceruloplasmin (regulatory chaperone) Cu2+

o-quinone reactive intermediates

adrenochrome

1.9

melanin

laccase

Cu2+ HAAO

Thioridazine

1.8

ceruloplasmin (regulatory chaperone)

3-hydroxyanthranilic acid

ALTERNATIVE HYPOTHESIS: Redox effects on dopamine versus antipsychotic potency

Dopamine oxidation effect

epinephrine

LONG-STANDING THEORY:

melanin

o-quinone reactive cinnabarinic acid intermediates (pigmented antibiotic)

1.7

Promazine

Prochlorperazine

1.6 1.5 1.4 1.3

Fluphenazine

Chlorpromazine

1.2 1

100

1000

10000

Antipsychotic potency (mg per day)

quinolinic acid

SYNAPSE 1:133-152 (1987)

Adapted from: Seeman et al. (left) and: “Interaction of phenothiazine drugs with human ceruloplasmin” Nicolaas J. De Mol Biochemical Pharmacology 1985; 34(15):2605-2609

20 8

Abram Hoffer Memorial Lecture -Nutrition and Schizophrenia: 11-04-05 The Genes Tell the Story Christine Miller, PhD hallucinogenic potency

adrenochrome

100

LSD

HYPOTHESIS: adrenolutin

CH3

The potential to form quaternary amines

dimethyltryptamine

psilocybin

mescaline

F$9#:$0,#-#$)*$8"#$F/1&3$G)4#1$'#>&-:$8)$0(1.(#E!F+)!3714:!,9! 41'#14!'(7141&0$'3,4!

A key piece of the Abram Hoffer legacy to pursue: The decreased rate of suicide

[.8%&'(![*-.=&.'!20(!1220!141c!5"! )*&.!67.89:$*4! !! !!!K9!&!,&d*.!#@!8$>*.*9>!#=>!#@!#C*.!c222! 9+78I#?7.*$8+!?&:*$>9!>.*&>*%!<!7&C*!$#>!7&%!&$'! 9=8+8%*9;![#.!*C*.'!#>7*.!>.*&>,*$>!8>!89!&-#=>!>*$! ?*.+*$>;! !! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!K-.&,!

Source: Jonathan Prousky, MSc, ND

ACKNOWLEDGMENTS Collaborators: "

Genetic association study: Dr. Sherry Leonard, Dept. Psychiatry, University of Colorado, CO Dr. Ingo Ruczinski, Dept. Biostatistics, Johns Hopkins University, MD Peter Murakami, Dept. Biostatistics, Johns Hopkins University, MD

Immunohistochemistry and confocal microscopy studies: Dr. Serge Weis and Dr. Ida Llenos, Department of Neuropathology, Wagner Jauregg Hospital, Linz, Austria Jeannette Dulay, Holy Cross Hospital, Silver Spring, MD Dr. Fernand Gobeil, University of Sherbrooke, Quebec

Stanley Brain Bank: Dr. Maree Webster, The Stanley Medical Research Institute, MD

Stewardship and funding: Theodore and Vada Stanley

Inspiration, encouragement and mentorship: Dr. Abram Hoffer CMiller@millerbio.com

Enhancing Mitochondrial Function as a Therapeutic Strategy in11-‐03-‐25 Parkinson’s and other Neurodegenerative Diseases Laurie Mischley, ND, MSc

As A Neuroprotective Strategy Laurie K Mischley, ND http://thescienceupdate.blogspot.com/2010_09_01_archive.html

  At one time, an independent, self-sustaining dynamic, energy-producing life form.   Believed to have evolved from an endosymbiont alpha0proteobacterium (a relative of brucella and rickettsia). (Manfredi AA, et al. 2010)   Merger between:   Two prokaryotes or   One prokaryote + One eukaryote

  Maternal lineage   OX Phos (Pic: Wiki:OxPhos)

  Concentration is determined both genetically and environmentally

  Generates ROS

  Energy production   Heart   Brain   Muscles   Sperm

Enhancing Mitochondrial Function as a Therapeutic Strategy in11-‐03-‐25 Parkinson’s and other Neurodegenerative Diseases Laurie Mischley, ND, MSc

  Everyone knows they exist   Nobody knows   The cause   The solution   The extent of the consequences

Enhanced Requirements for: 

Substrate



Cofactors



Excretory Processes



Repair Processes

Existing, established, conventionally-recognized disorders associated with mitochondrial dysfunction:

  Difficult to recognize

Mitochondrial Myopathies

  Different presentations in different people, different ages

Leber hereditary optic neuropathy, Leigh syndrome, MELAS, MERRF, MIDD, MNGIE, NARP, Pearson syndrome, Isolated myopathy, severe myopathy of infancy/ childhood, chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome Developmental Delay ??

  Difficult to evaluate   Muscle/CNS biopsies, functional tests, symptoms

  Difficult to treat   Difficult to prevent

  Substrate/Environment- provide prn   e.g. Healthy lipid membranes   Autism

  Aging

  Alzheimer’s disease

  Infertility

  Parkinson’s disease

  Developmental Delay

  Huntington’s disease

  Fatigue

  Multiple Sclerosis

  Congestive Heart Failure

  Cofactors- provide prn   e.g. Q10, carnitine   Excretory Processes- support prn   e.g. Reduce inflammation   Repair Processes- encourage prn   e.g. Encourage mt biogenesis

Enhancing Mitochondrial Function as a Therapeutic Strategy in 11-‐03-‐25 Parkinson’s and other Neurodegenerative Diseases Laurie Mischley, ND, MSc

  Composition of the lipid bilayer   Influence on cytokine production   Insulation for an electrical system   Prone to peroxidation   Require carnitine to shuttle into mitochondria http://thescienceupdate.blogspot.com/2010_09_01_archive.html



Fatty acyls



Glycerolipids



Glycerophospholipids



Sphingolipids



Sterol lipids



Prenol lipids



Saccharolipids



Polyketides

scienceblogs.com

Brain ~ 60% FAT

  ROS results in oxidative damage to   Nucleic acids, proteins, carbohydrates, lipids   Lipid peroxides à aldehydes (acrolein)   Aldehydes bind covalently with thiol groups of proteins à PROTEIN DYSFUNCTION

David Horrobin The Madness of Adam & Eve

eg. AD: Abeta & tau aggregation

Enhancing Mitochondrial Function as a Therapeutic Strategy in11-‐03-‐25 Parkinson’s and other Neurodegenerative Diseases Laurie Mischley, ND, MSc

  Curcumin (PMID: 19049818, 16236451, 15591646, 14729307 (Pb, Cd), 20021100 (nicotine))

  Resveratrol (PMID: 20870710, 20029519, 19552907 , 18823437)

  Melatonin (PMID: 20338863, 19590980)   Flavonoids: quercitin, luetolin, genistein (PMID: 18372528, 16828712)

  Glutathione (PMID: 20835408, 18847228) Environmental Threats to Healthy Again- Greater Boston PSR

“In short, the immune system recognizes mitochondria released from dying tissues as the bacteria they (the mitochondria) once were… This tragic “misunderstanding” could have a role in several human diseases…”

Which comes first?

Harmony in the assembly line?

Enhancing Mitochondrial Function as a Therapeutic Strategy in11-‐03-‐25 Parkinson’s and other Neurodegenerative Diseases Laurie Mischley, ND, MSc

  NADH

  Cofactor for mt respiratory chain

  Niacin precursor   Supplement NADH?

  High doses (1200-2400 mg/ d) safe in PD   Preliminary data suggests may have neuroprotective potential

  Ubiquinol   Supplement Coenzyme Q10?

  Large, Phase III study underway

  Membrane integrity

  Dose? Brand? Form?

  Clearing mechanisms

Dietary supplementation in the water of young & aged rats

  :Treatment with 17b-oestradiol significantly rescued the following in Leber’s hereditary optic neuropathy

  Increased the proliferation of intact mitochondria

        

  Reduced the density of mt associated with vacuoles and lipofuscin.   Feeding these nutrients to old rats sig. reduced the number of severely damaged mt (P=0.02)& increased the number of intact mt in the hippocampus (P<0.001) (PMID: 18373733)

Overproduction of ROS Decrease in mt membrane potential Increased rate of apoptosis Loss of cell viability Hyper-fragmented mt morphology

  L-carnitine was protective in a rat model of mt neurodegeneration (PMID: 16179521)

  17b-osestradiol induced a general activation of mt biogenesis & improvement in energetic competence. (PMID: 20943885)

  Words very well to improve health and mass of mitochondria in skeletal muscle.

  A flavonol, a type of flavonoid, that has been isolated from tea, broccoli, grapefruit, brussels sprouts, applas, & Witch-hazel.

  Yet to be evaluated in CNS

  Enhances autophagy in vitro in neurons exposed to rotenone; evidence of:   Reduced ROS   Reduced itochondrial corbonyls   Preservation of mitochondrial network, transmembrane e- potential, and oxygen consumption   Enhancement of mitochonddrial turnover by autophagy (PMID: 20594614)

  What about ‘Exercising your Brain?’   Higher education associated with reduced incidence of AD.   Currently attributed to cognitive reserve.   Analogous to exercising a muscle?

Enhancing Mitochondrial Function as a Therapeutic Strategy in11-‐03-‐25 Parkinson’s and other Neurodegenerative Diseases Laurie Mischley, ND, MSc

  Loss of glutathione is one of the earliest reported changes in PD, even preceding formation of Lewy bodies.

  Quercitrin & quercetin protected mitochondria from MeHg-induced changes in lipid peroxidation and ROS generation in vivo. (PMID: 19902180)

  Glutathione depletion causes disruption of mitochondrial function, fueling a cascade of ROS, inflammation, debris.   Preliminary data on GSH in PD, et al.

  Phenolic compounds from H. perforatum:   Quercetin   Kaempferol   Biapigenin

  Ketone bodies confer neuroprotection against diverse types of cellular injury (PMID 16940764)

  All 3 signifcantly able to reduce neuronal death against excitotoxic insults (kainate + NMDA)

  Results in a notable improvement in mitochondrial function, a decrease in the expression of apoptotic and inflammatory mediators, and increase in neurotrophic factors (PMID: 18845187)

  All 3 reduced mitochondrial lipid peroxidation & loss of mitochondrial transmembrane electric potential caused by ROS induced by ADP+ Fe.   Biapigenin sig. improved mitochondrial bioenergetics and decreased capactiy of mt to accumulate Ca. (PMID: 18522906)

  embryonic stem cells their self-renewal capacity   Process by which cells increase their individual mitochondrial mass.

  Differentiation of neural progenitors into postmitotic neurons

  Thus far, poorly studied (PMID: 19682571)

  Enable neurite outgrowth   Axon formation & outgrowth regulation   Neural polarization

Enhancing Mitochondrial Function as a Therapeutic Strategy 11-‐03-‐25 in Parkinson’s and other Neurodegenerative Diseases Laurie Mischley, ND, MSc

  Mitochondrial respiration   ATP production   Membrane potential   Calcium handling   Biogenesis   Movement throughout cell   Fission/ Fusion

(PMID: 21275887)

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD

Suicide: U.S. Statistics •  In 2007, 11th leading cause of death in the U.S., accounting for 34,598 deaths

An Orthomolecular Approach to Suicide Prevention

•  11.3 suicide deaths per 100,000 people

James '(ee)*+a,, MD May 1, 2011

•  An estimated 100-200 attempted suicides occur per every suicide death Goldsmith SK, Pellmar TC, Kleinman AM, Bunney WE, editors. Reducing suicide: a national imperative. Washington (DC): National Academy Press; 2002.

Suicide: Canadian Statistics According to one study, approximately 7% of the US population knew someone who died of suicide during the past 12 months.

•  In 2006, suicide was the leading cause of death for men 25 to 29 and 40 to 44, and for women 30 to 34 –  Suicide is the 2nd leading cause of death among 15 to 24 y/o

•  14 suicide deaths per 100,000 people •  An estimated 100 attempted suicides occur per every suicide death

Crosby AE, Sacks JJ. Exposure to suicide: Incidence and association with suicidal ideation and behavior – United States, 1994. Suicide and Life-Threatening Behavior 2002:32;321–328.

Canada Safety Council. (2006). Canada s Silent Tragedy. http://www.safety-council.org/info/community/suicide.html

Gender Differences in Suicide

Suicide Demographics •  Historically, suicide rates are highest among those >80 years old •  Starting in 2006 suicide rates have been highest for 45-54 year olds

•  Almost 4X as many males as females die by suicide •  Nearly 5X as many males as females ages 15 to 19 die by suicide

2007 Suicide Rates •  45-54 y/o à 17.6 suicides/ 100,000 •  75-84 y/o à 16.4 suicides/ 100,000 •  35-44 y/o à 16.3 suicides/ 100,000

•  Just under 6X as many males as females ages 20 to 24 die by suicide

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD

Risk Factors for Suicide

Common Myths of Suicide

•  •  •  •

Feelings of hopelessness Impulsive or aggressive tendencies Local epidemics of suicide Isolation, a feeling of being cut off from other people •  Loss (relational, social, work, or financial)

Suicide is None of These Suicide is … •  Impulsive •  Cowardly •  Vengeful •  Controlling •  Selfish

More than 90% of people who die by suicide have these risk factors: •  Depression and/or other mental disorders •  Substance-abuse disorder

Author: Thomas Joiner

Myths of Suicide Myth

Reality

•  Suicide notes are common

•  Suicide notes are rare and studies find rates between 0% and 40%

•  Suicide peaks around the winter holidays

•  Low suicide rates occur around winter holidays

•  •  •  •

6000 patients followed during inpatient treatment 265 died during 30 year follow up Most frequent cause of death suicide (37%) Average age at death was 34 Papadopoulos, The British Journal of Psychiatry (2009) 194, 10–17.

Suicide and Eating Disorders •  23 y/o Grad student; 95% IBW On SSRI •  History of Depression and Bulimia

    

The factors that may contribute to the onset of anorexia nervosa may be unrelated to the physiological dynamics that sustain the illness and cause such emotional turmoil for patients and their families.

Vegetarian

29 y/o; 90% IBW History of Depression, EDNOS Disordered eating since age 9: restricting, purging, compulsive eating

HX SSRI

Anorexia is a nutritional disease. Understanding this points us in a therapeutic direction—anorexia has nutritional solutions.

Vegetarian

      

21 y/o; 95% IBW Depression, OCD, and EDNOS Restrictive eating since high school Supportive family Vegetarian

HX SSRI

Why does your 9 y/o want to be a vegetarian?

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD

Map for a Thorough Approach to Health Problems

Malorexia •  Malorexia is a complicated illness of restrictive eating and self-starvation initiated by multiple factors that contribute to severe malnutrition and consequent biochemical disturbances in the brain.

History, physical exam and tests to make a diagnosis, then with or without a name for the problem, ask . . . Is there a need to get something?

•  Malorexia is the clinical result of any pathway that leads to restriction of essential nutrients.

Is there a need to avoid something?

Nutrients Vitamins Minerals Fatty acids Amino acids Hormones Accessory nutritional factors Light Love

Malorexia is a significant risk factor for suicide

Allergens Food Pollen Dust Dander Chemicals Mold Germs

Toxins Elementary (lead, mercury, etc) Biologic (from plants, germs, etc) Synthetic (mostly petrochemical)

Modified from Sidney Baker Detoxification & Healing 1998

Diagnosis and Treatment General Medical Treatment: Psychiatric Treatment: Symptoms

Symptoms

Measure Physiology

Anti -Symptom treatment given

Anti -physiology treatment

Prevention is Possible

Measure physiology and symptoms

DSM-V: New Diagnoses? •  Olfactory Reference Syndrome •  Temper dysregulation with dysphoria •  Hoarding •  Skin picking

Measure symptoms

Evolution of the DSM: Not the Solution •  Hypersexual disorder •  Paraphilic coercive disorder •  Binge eating disorder •  Restless Legs Syndrome •  Shyness

•  DSM-I

1952 107 diagnoses 132 pages

•  DSM-II 1968 180 diagnoses 119 pages •  DSM-III 1980 226 diagnoses 494 pages •  DSM-IV 1994 365 diagnoses 886 pages

A 340% increase in the number of diseases over 42 years

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD

The Treatment? Antidepressant use doubled from 1996-2005 In 1996, 13 million Americans (6% of the total population) were treated with antidepressants. By 2005, that number soared to 27 million or more than 10% of the population.

Arch Gen Psychiatry, August 2009

Psychiatric drugs & suicide in Sweden 2007 2010

Psychiatric drugs & suicide in Sweden 2007

Janne Larsson www.psychiatricdrugs.jannel.se/

2010

•  1126 suicides committed in 2007 in Sweden (325 women and 801 men) •  724 (64%) filled a prescription for psychiatric drugs within the year before the suicide •  Traces of psychiatric drugs were found in 52% of the suicides

Janne Larsson www.psychiatricdrugs.jannel.se/

1 Year Prior to Suicide

Men

Women

59%

77%

•  Filled a prescription for psychiatric drugs

38%

60%

•  Filled a prescription for antidepressants

;)@A$4($%%")=%&")A&B9C<CA$&

Suicidality with Antidepressants

•  7 year old female with OCD Obsessions Not throwing away garbage Being overweight

FDA Black Box Warning

Compulsions Hoarding garbage in room Hoarding soiled toilet paper

Medication Trials

Oct. 15, 2004

•  Celexa 10 mg – Agitation

The FDA warns about increased risk of suicidal thinking and behavior (suicidality) in young adults ages 18 to 24 during initial treatment (generally the first 1-2 months) with antidepressants

40 lb. weight gain

•  Prozac 10 mg – Aggressive thoughts of self harm attempted suffocation

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD Antidepressants and the risk of suicidal behaviors

Antidepressants and Suicide

Jick H, Kaye JA, Jick SS, JAMA. 2004;292(3):338-43

•  16 y/o of normal weight with history of ED and depression •  Referenced-EEG predicted positive response for antidepressants

•  159,810 users of 4 antidepressant drugs

No history of suicidal ideation •  Cymbalta SI within 1 week •  Wellbutrin SI within 1 month

•  Nonfatal suicidal behavior is 4X more likely to occur within fewer than 10 days and almost 3X more likely to occur within 10-29 days after receiving a first antidepressant prescription than in more than 90 days after the first prescription

•  Risk of nonfatal suicidal behavior is increased in the first month after starting antidepressants, especially during the first 1-9 days

The Problem

•  Depression is one of the most serious and costly health problems in the world today •  Major Depression accounts for the 2nd longest number of days lost to disability in the U.S. •  Approximately 15% of adults will experience severe depressed mood during their lifetime –  Approx. 15% of these adults will commit suicide •  Suicide is the 3rd leading cause of death in youth aged 15 to 24 More teenagers and young adults die from suicide than from cancer, heart disease, AIDS, birth defects, strokes, pneumonia, influenza and chronic lung disease combined.

Suicidality with Anticonvulsants

Suicide-related events in patients treated with antiepileptic drugs

  Dn 200E- the FDA reviewed 1II clinical trials of 11 an@epilep@c drugs

Arana A, et al.; N Engl J Med. 2010;363(6):542-51.

  ?a@ents receiving an@epilep@c drugs had al#ost twice the risk of suicidal behavior or thoughts (0.4N%) co#pared to pa@ents receiving a placebo (0.24%)

The current use of an@epilep@c drugs was not associated with an increased risk of suicide-‐related events a#ong pa@ents with epileps0- but it was associated with an increased risk of suicide-‐related events a4on5 6a7ents with de6ression

  The FDA voted against placing a black box warning on these #edica@ons   The FDA did agree to the distribu@on of #edica@on guides to healthcare providers- outlining the risks of an@epilep@c #edica@ons and suicidal thoughts

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD

Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior

Orthomolecular Risk Factors For Suicide

Andersohn F, et al., Neurology. 2010;75(4):335-40

•  Antidepressants and Anticonvulsants

•  Case-control study of 453 cases and age- and sex-matched controls •  Patients with epilepsy who were treated with antiepileptic drugs (AEDs) •  Current use of newer AEDs with a high potential of causing depression was associated with a 3fold increased risk of self-harm/suicidal behavior as compared with no use of AEDs during the last year

•  100 billion neurons •  20,000 inputs from other neurons

60% of the dry weight of the brain is fat

Incomprehensive complexity regulated by biophysical molecular magic.

Serum cholesterol levels and suicidal tendencies in psychiatric inpatients

Cholesterol levels should be monitored in all patients evaluated for psychological/ psychiatric symptoms

Modai I, et al., J Clin Psychiatry. 1994; 55(6):252-254

  /ata were collected 5rom S84 in4a@ent medical records   Serum cholesterol levels were evaluated 24 to 48 hours aTer admission

Low cholesterol appears to be a significant risk factor for depression and suicide

  ?a@ents who had a,em4ted suicide had si:niUcantl0 lower serum cholesterol than nonsuicidal 4a@ents

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD ;ssocia@on o5 loH seru# total cholesterol Hith #aVor depression and suicide

Low serum cholesterol in suicide attempters Kunugi H, et al., Biol Psychiatry. 1997;41(2):196-200

Partonen, et al., (1999). Br J Psychiatry. 175:259-‐62

•  Lower cholesterol level is associated with an increased risk of suicidal behavior.

•  Association of low serum total cholesterol with major depression and suicide.

•  Cholesterol concentrations in suicide attempters were found to be significantly lower compared with both psychiatric and normal controls, when sex, age, psychiatric diagnosis, and physical conditions (serum total protein and red blood cell count) were adjusted for.

•  29,133 men ages 50-69 years were followed up for 5-8 years •  Finland s Beta Carotene Study •  Self reported depression, DSM IIIR

;ssocia@on o5 loH seru# total cholesterol Hith #aVor depression and suicide

Cholesterol and Suicide Summary

Partonen, et al., (1999). Br J Psychiatry. 175:259-‐62

n

Low serum total cholesterol at baseline is associated with a heightened risk of major depressive disorder. Low serum total cholesterol at baseline is associated with a heightened risk of death from suicide, even after adjusting for risk factors.

Modai I, et al., J Clin Psychiatry. 1994

584 inpatient records

Patients who had attempted suicide had significantly lower serum cholesterol than nonsuicidal patients

Kunugi H, et al., Biol Psychiatry. 1997

99 suicidal pts & 74 nonsuicidal pts

Suicide attempters had significantly lower cholesterol compared with both psychiatric and normal controls

Partonen, et al., Br J Psychiatry. 1999

29,133 Finnish men

Low serum total cholesterol at baseline is associated with a heightened risk of death from suicide, even after adjusting for risk factors.

[oH seru# cholesterol and eQternal-‐cause #ortality: poten@al i#plica@ons 5or research and surGeillance

July 2010

Boscarino, et al., (2009). J Psychiatr Res. 43(9):848-‐54

•  Examined external-cause mortality among a national sample of 4,462 male, US veterans at baseline in 1985 •  Followed subjects until Dec. 31, 2000 •  Study found: –  Men with low serum total cholesterol (<165 mg/dl or <4.27 mmol/L) and depression are at very high risk of premature death from external causes.

Does low cholesterol predispose to depression and suicide, or vice versa?

–  They are 7 times more likely to die prematurely from unnatural causes such as suicide and accidents

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD Association between low plasma levels of cholesterol and relapse in cocaine addicts

Low Cholesterol Low Cholesterol is associated with… •  •  •  •  •  •  •  •

Buydens-Branchey L, & Branchey M, Psychosom Med. 2003;65(1):86-91

Increased cancer rates Increased violent behavior and aggression Increased anxiety Increased depression and bipolar disorder Increased death rate Increased incidence of stroke More difficult recovery from drug addiction Increased rate of school suspensions

•  Total cholesterol levels of 38 non-opiate-dependent and non-alcohol-dependent cocaine addicts were assessed while they were hospitalized. •  Drug use was assessed 3, 6, and 12 months after patients were discharged •  Significantly lower cholesterol values in patients who relapsed at 3, 6, and 12 months after discharge •  Association between a low total cholesterol level and relapse rates in detoxified cocaine addicts

Differential effects of cholesterol and 7-dehydrocholesterol on ligand binding of solubilized hippocampal serotonin1A receptors: implications in SLOS

Low Cholesterol and Memory •  Dr. Duane Graveline, a former astronaut, aerospace medical research scientist, flight surgeon, and family doctor •  Given Lipitor to lower his cholesterol •  This led to temporary shortterm memory loss •  Was finally diagnosed as having transient global amnesia

Chattopadhyay A., et al., Biochem Biophys Res Commun. 2007;363(3):800-5

•  Low cholesterol causes reduced binding of serotonin to the serotonin 1A receptor •  Impairs function of serotonin 1A receptors •  Receptors play an important role in the brain and other organs, regulating temperature control, sleep, aggression, anxiety, and eating

Importance of Cholesterol

Orthomolecular Risk Factors For Suicide

•  The brain is a cholesterol rich organ •  Cholesterol is involved in the synthesis of all steroid hormones •  Required for optimal function of the serotonin 1A receptors •  Activates oxytocin receptors •  Bile salt formation for fat digestion and absorption of fat soluble vitamins •  Synthesis of vitamin D

•  Antidepressants and Anticonvulsants •  Low cholesterol (< 165 mg/dL or < 4.27 mmol/L) ( < 145 mg/dL or < 3.75 mmol/L)

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD

Suicide attempt and n-3 fatty acid levels in red blood cells: a case control study in China Huan, M, et al., Biol Psychiatry. 2004;56(7):490-6

•  100 suicide-attempt cases and another 100 control patients injured by accidents •  Blood was sampled immediately after admission to the hospital for fatty acid levels •  EPA levels in RBC in the case subjects were significantly lower than those of the control subjects •  Low n-3 fatty acid levels in tissues were a risk factor of suicide attempt

In humans, the seasonal variation in poly-unsaturated fatty acids is related to the seasonal variation in violent suicide and serotonergic markers of violent suicide De Vriese SR, Christophe AB, Maes M Prostaglandins Leukot Essent Fatty Acids. 2004;71(1):13-8.

•  23 healthy volunteers •  Analyzed PUFA composition in monthly blood samples during 1 calendar year •  Significant correlation between changes in Arachidonic Acid and EPA and the mean weekly number of violent, but not nonviolent, suicide deaths in Belgium •  Seasonality in PUFAs may be related to the incidence of violent suicide

Elevated CSF CRF in suicide victims

•  •  •  •

Arató M, Bánki CM, Bissette G, Nemeroff CB Biol Psychiatry. 1989 Feb 1;25(3):355-9

33 medication-free depressed subjects Monitored for suicide over 2 year period 7 subjects attempted suicide Low DHA levels and High omega-6: omega-3 ratios predicted suicide

•  19 suicide victims and 19 controls (fatal cardiac arrest) •  CSF samples were analyzed (12 hr after death) •  Significantly higher corticotrophin-releasing factor concentrations (2.5 X higher) found in suicide group than control

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD

Omega-3 status and cerebrospinal fluid corticotrophin releasing hormone in perpetrators of domestic violence

Orthomolecular Risk Factors For Suicide

Hibbeln JR, et al Biol Psychiatry. 2004;56(11):895-7

•  Antidepressants and Anticonvulsants •  Low cholesterol •  Low omega-3 EFAs

•  21 perpetrators of domestic violence •  CSF and plasma were assessed for corticotrophin-releasing hormone and fatty acid compositions •  Lower plasma DHA alone predicted greater CSF corticotrophin-releasing hormone

Side Effects of Lithium Carbonate

Lithium •  •  •  •  •  •

 Metallic element discovered in 1818  In 1949 John Cade, an Australian psychiatrist, found that it was useful for trea@ng ela@on or mania  Toxic in high doses

Drowsiness Hand tremors Frequent urination Thirst Nausea Vomiting

•  Kidney damage •  Muscular weakness •  Interferes with thyroid function •  Poor coordination •  Ringing in the ears •  Blurred vision

Potentially Fatal if OD

Lithium reduces pathological aggression and suicidality: a mini-review

Lithium and Suicide Tondo L, Jamison KR, Baldessarini RJ. Effect of lithium on suicide risk in bipolar disorder patients. Ann NY Acad Sci 1997

Müller-Oerlinghausen B, Lewitzka U; Neuropsychobiology. 2010;62(1):43-9

•  Study examined life-threatening or fatal suicidal acts in over 300 bipolar type I and type II patients before, during, and following long-term lithium treatment •  Patients had been ill for over eight years •  On lithium: rate of suicides and attempts decreased nearly 7-fold •  Lithium discontinuation: suicidal acts increased 14fold above rates found during treatment •  First year off lithium: suicide rate rose 20-fold

Regular lithium long-term treatment reduces the otherwise 2- to 3-fold increased mortality of untreated patients with severe affective disorders down to the level of the general population

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD

Lithium levels in drinking water and risk of suicide

Dietary Sources of Lithium

Ohgami H, Br J Psychiatry. 2009;194(5):464-5

Primary dietary sources of lithium are grains and vegetables, which contribute 66% to 90% of total lithium intake

•  Examined lithium levels in tap water in the 18 municipalities in Japan in relation to the suicide standardised mortality ratio

mcg/ kg

•  •  •  •  •

•  Study found that even very low levels of lithium in drinking water may play a role in reducing suicide risk within the general population

Mushrooms 5788 Cucumbers 5017 Red Cabbage 3579 Cauliflower 3462 Black Tea 3737

mcg/ kg

•  •  •  •  •

Milk 7533 Eggs 7373 Pork 3844 Beef 3428 Tomatoes 6707

Lithium Modifies Brain Arachidonic and Docosahexaenoic Metabolism in Rat Lipopolysaccharide Model of Neuroinflammation

How Does Lithium Work? •  No definitive answer

Basselin, et al. 2010, Journal of Lipid Research, 51:1049-1056.

However, •  Rats on 6 week lithium treatment had reduced levels of arachidonic acid and its product

•  New research supports the theory that lithium may reduce brain inflammation by adjusting the metabolism of the omega-3-fatty acid DHA

•  Lithium treatment increased levels of the metabolite 17-OH-DHA in response to inflammation

•  Excess or unwanted inflammation can damage sensitive brain cells, which can contribute to psychiatric conditions like bipolar disorder or degenerative diseases like Alzheimer s

•  17-OH-DHA is formed from DHA and is the precursor to a wide range of anti-inflammatory compounds known as docosanoids

Lithium Orotate

Use of Nutritional Lithium

Lithium Orotate 5-20 mg

 ^sed to treat condi@ons including

◦  Stress, manic depression, alcoholism, ADHD and ADD, aggression, PTSD, Alzheimer's and to improve memory

Indications Family History

 Increases lithium bioavailability ◦  Able to use lower doses

 Fewer side eaects than prescrip@on lithium  Rarely detected in blood levels

Prevention of

Bipolar disorder, alcoholism, depression, irritability, mood swings, and substance abuse Early cognitive decline, Alzheimer s, suicide and depression

Prevention

Kling MA, et al. (1978). J. Pharm. Pharmacol. 30 (6): 368–70

An Orthomolecular Approach to Suicide Prevention James Greenblatt, MD

Nutrition as Alternative

Orthomolecular Risk Factors For Suicide •  •  •  •

Antidepressants and Anticonvulsants Low cholesterol Low omega-3 EFAs Low lithium levels

Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A)

Neurochemical individuality: genetic diversity among human dopamine and serotonin receptors and transporters

Merikangas KR, et al., J Am Acad Child Adolesc Psychiatry. 2010;49(10):980-9

Cravchik A, Goldman D. Arch Gen Psychiatry. 2000;57(12):1105-14

•  Survey of 10,123 US adolescents aged 13 to 18 yrs

A substantial portion of the variance in

•  1 in 5 children meet criteria for a mental disorder across their lifetime

Personality Psychiatric disease Metabolism and psychotropic drugs

–  31.9% anxiety disorders, 19.1% behavior disorders, 14.3% mood disorders, 11.4% substance use disorders

•  Approx. 40% meet criteria for 2 or more disorders •  22.2% have disorders characterized as with severe impairment and/or distress

is genetically transmitted

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

Vitamin C as Cancer Therapy: What is the Evidence?

Today’s agenda •  Reliable evidence is needed to choose among possible treatments. But what is the meaning of evidence ? –  In government and regulatory agency statements –  In clinical practice guidelines –  In ordinary clinical practice

Orthomolecular Medicine Today 2011

•  How can one make therapeutic recommendations when strong evidence is not available? •  How should we use evidence in our own practice?

April 29, 2011

–  To test our clinical impressions and guard against bias –  To inform the therapeutic community of our findings

•  Where does iv vitamin C therapy fit in this scheme?

L. John Hoffer, MD, PhD FRCPC

The semantics of evidence

Ludwig Wittgenstein: Philosophical problems emerge, not from the real world, but from language itself.

Semantic levels of evidence: government

Our concepts define an experience which we understand only through words.

•  Highly conservative and risk-averse

–  Demand almost incontrovertible evidence from multiple, large randomized clinical trials –  Carefully avoid mistakes or creating embarrassing controversy –  Never make a radical change in recommendations –  Formulate recommendations with a cautious view as to their political implications

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

Semantic levels of evidence: government

Semantic levels of evidence: government •  Agency for Health Care Policy and Research (1989)

•  Food and Nutrition Board, Institute of Medicine Consensus Report: Dietary Reference Intakes for Calcium and Vitamin D 2010

–  Created by US Congress to produce rational evidence-based clinical practice guidelines –  Reported little good evidence to support back surgery as a firstline treatment for low back pain

–  Vitamin D recommendations formulated solely with regard to bone health, discounting 100 s of studies that strongly suggest non-bone benefits of unconventionally high intakes (immunity, muscle, cardiovascular risk, and mental health) as inconclusive

•  Non-surgical approaches should first be tried in most cases

–  –  –  –

–  Yet, the FNB went ahead to recommend increased population intakes that imply the need for most people to use supplements, and increased the upper limit safe intake to 4000 IU/day

Spine surgeons organized, sought court injunctions AHCPR wastes tax dollars and interferes with free market Congress responded by de-funding the AHCPR in 1995 Back fusion for low back pain then sky-rocketed in USA

–  S Brownlee: Washington Monthly, 24 Feb 2011 <http://www.washingtonmonthly.com>

Semantic levels of evidence: clinical practice guidelines

•  Published by non-profit professional organizations •  Clinical review articles in flagship medical journals like the New England Journal of Medicine

•  Non-profit organizations and journal editors are not immune to controversy and political influence

–  Influence of pharmaceutical industry –  Guidelines often differ in some respects among organizations –  Prevailing cultural norms play a large role •  Lynn Payer: Medicine and Culture

–  Very conservative –  Strong recommendations require several large properly designed randomized clinical trials with consistent findings –  Drug recommendations are almost always consistent with approved FDA or TPD label indications –  Weaker recommendations are commonly offered when findings are less convincing or inconsistent, or when sufficient clinical trials are lacking but the treatment is a plausible extension of strongly recommended therapies •  May apply to off-label use of some drugs

Semantic levels of evidence: actual clinical practice

•  US spine surgeons earn $4000 per fusion operation

•  Antidepressant drugs are now known to be no more effective than placebos for most depressed patients

–  Median hospital bill is $45,000

•  A group of spine surgeons took a course to evaluate clinical evidence and discovered for themselves that the procedure is about as helpful as a placebo. What was their response?

•  FDA and TPD approval for this indication was based on deceptive, doctored and selectively censored data provided by the drug industry

–  Sadness, bafflement, disbelief –  I don t have time to read journals and I shouldn t have to be expected to. –  The studies have to be wrong. I know I am relieving my patients pain. –  S Brownlee: Washington Monthly, 24 Feb 2011 <http:// www.washingtonmonthly.com>

•  There is little justification to prescribe SSRIs to any but the most severely depressed patients, unless alternative treatments have failed. Kirsch et al PLoS Medicine 2008;5:e45

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

New York Times, November 29, 2008

Evidence and antidepressants •  US senate committee hearings have revealed enormous, secret payoffs by major drug companies to influential, opinion leader psychiatrists

Semantic levels of evidence: actual clinical practice

What do you believe?

•  When informed that, on average, SSRIs are – at most – little better than placebos, how do psychiatrists and family physicians respond? –  I have countless examples of helping people with these medications. –  My personal experience has been that these pills have been extremely effective… –  Montreal Gazette, September 20, 2008

•  Meta-analysis of RCTs

□

•  Articles drug rep gave you

□

•  Your clinical judgment & experience

□

–  Montreal Gazette, September 20, 2008

Clinical practice and evidence •  In 2009 SCCM and ASPEN recommended high-dose intravenous antioxidant therapy for all critically ill patients –  Evidence level A for surgical patients –  Evidence level B for medical patients –  The systematic review cited studies in which iv vitamin C 1 gram every 8 hours (and other antioxidants) improved clinical outcomes of critically ill patients

•  These recommendations remain universally ignored

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

Evidence-based medicine to the rescue

“New Zealand farmer vitamin C” •  Farmer with swine flu given up for dead by hospital was saved by intravenous vitamin C! •  His physicians initially refused iv vitamin C on the grounds that such therapy was unscientific and irrational. After he recovered, they refused to concede even the possibility vitamin C had played a role •  Presumably they had failed to read the formal international clinical practice guidelines regarding iv vitamin C for critically patients like this one

What is evidence-based medicine?

Use of evidence in clinical practice •  The most reliable general evidence is derived from properly designed, conducted and interpreted randomized clinical trials (level A evidence)

•  EBM is the application of high quality general information and group statistics to the unique situation and preferences of one specific patient

–  RCTs are not the only source of evidence

–  Guyatt GH et al. Chest 2008;133:123S-131S

•  Clinical recommendations are either strong ( we [strongly] recommend…) or weak ( we suggest … )

Guidelines for the practice of evidence-based medicine

Recommendations versus suggestions •  We strongly recommend when the evidence is very good that the treatment has large benefits for most people

Guyatt GH et al. Chest 2008;133:123S-131S

•  Quality of the evidence

•  We suggest when the evidence is uncertain regarding the magnitude of benefit or harm. Suggestions require more judicious application, particularly considering patient values and preferences.

–  A (high), B (moderate), C (low)

•  Strength of the recommendation

–  strong: We [strongly] recommend…for/against… –  weak: We suggest using/not using

•  Suggestions are typically off-label therapies

•  The strength of a recommendation is based on the degree of confidence there is in the balance between overall desirable and undesirable effects of the treatment

–  Patient is so informed and cautioned –  The patient s consent should be documented –  The outcome should be objectively recorded

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

Evidence-based medicine •  The physician s job

–  Know what the evidence is –  Apply what is relevant to this patient s specific situation –  Use treatments for which there is some plausible evidence of benefit without harm –  For off-label treatments – when the balance between benefit and harm is uncertain – respect patients preferences –  Responsibly prescribe EB treatments in partnership with the patient s wishes

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

CMAJ March 28, 2006

Hugh Riordan, Wichita

Mark Levine, NIH, Bethesda

CMAJ March 28, 2006

Canadian Cancer Society Website 2010 Antioxidants are also available as supplements. More research is needed to find out if there are important benefits or harmful effects of using antioxidant supplements during and after treatment. http://www.cancer.ca/Canada-wide/About%20cancer/Coping%20with%20cancer/Nutrition/Nutrition %20concerns%20when%20you%20have%20breast%20cancer.aspx?sc_lang=en

Chen QI et al PNAS 2008

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

Ohno S et al. Anticancer Res 29:809-16, 2009

PEAK PLASMA AA CONCENTRATION CAN BE CALCULATED IN PATIENTS WITH NORMAL RENAL FUNCTION Predicted peak concentration (g/L) = 3.75 D/W D = dose (g) W = body weight (kg)

Example D = 75 g, weight 70 kg Peak concentration = [75/70] X 3.75 = 4.02 g/L Peak concentration = 4020/176 = 23 mmol/L

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

Risks of high-dose iv vitamin C •  Hemolysis in people with G6PDH deficiency •  Oxalate nephropathy •  Adverse effects of osmotic diuretics

Impaired renal function

–  Hyperosmolarity, thirst, volume depletion –  Intravascular volume overload

•  Sodium retention •  Interference with several common lab tests

Normal renal function

Plasma ascorbate concentration - time profile

Clinical protocol in Montreal •  •  •  •  •  •

Current phase I-II clinical trial

G6PDH screen Normal renal function No recent oxalate stone Adequate cardiopulmonary function Encourage water drinking Measure body weight

•  Cytotoxic chemotherapy plus iv vitamin C •  Patients with good functional status for whom chemotherapy is prescribed but with low likelihood of objective response •  Study aim: safety •  Study aim: seek specific promising combination of cancer type and chemotherapy •  See: http://clinicaltrials.gov

Scientific basis of iv vitamin C as anti-cancer therapy •  Biologically plausible •  Unproven •  Off-label Mainstream medicine

Alternative medicine

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

Mainstream medicine

Alternative medicine

IV vitamin C use in USA •  •  •  •  •  •

PLoS ONE www.plosone.org July 2010 Volume 5 Issue 7 e11414

Tens of thousands of patients ~ 800,000 doses (25 g) per year Median administered dose: 50 g 86% of practitioners are licensed MDs Adverse effects claimed to be few Benefits undocumented

IV vitamin C: risks and opportunities

Paddayatty SJ et al (2010) •  IV vitamin C is in wide use •  It has a positive safety profile, favourable pharmacology, evidence for a mechanism of action, and some anti-cancer effects in vitro and in animals •  Its beneficial effects in humans are unproven •  Physicians should be observant of unexpected harm, drug interactions, or benefit

•  •  •  •

Use is unregulated Side effects are undocumented Benefits are almost undocumented Increasing public interest is now drawing attention to all of these problems

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

Safety and benefit

Research opportunities •  Form practical working relationships with mainstream cancer researchers •  Publish well-crafted, plausible case reports and case series •  Which patients respond?

•  Publish safety and ethics guidelines –  Document informed consent –  Protect responsible therapists from the actions of irresponsible ones

•  Establish a large, high-quality patient database

–  survival –  objective tumour arrest or regression –  quality of life

–  Patient and treatment characteristics –  Formally record clinical outcomes

Which patients respond? •  Which cancer type and stage? •  Which dose and dose schedule? •  Which combination of iv vitamin C and cytotoxic or biological drug therapy? Mainstream medicine

EBM, antioxidants and cancer

Alternative medicine

EBM and discovery research

•  Patient values, preferences and unique circumstances are very important

•  Clinics providing iv vitamin C should document cases and outcomes with a view to publication –  Well-documented anecdotes are the seeds for crucial discoveries

•  When chemotherapy is likely to be highly effective and well-tolerated, it would be prudent to avoid antioxidants

•  Form alliances with sympathetic mainstream researchers

•  When chemotherapy is likely to be ineffective/ toxic, the addition of antioxidants would seem to offer the patient the best chance

•  Understand and use the language of evidencebased medicine

Vitamin C as Cancer Therapy: What is the Evidence?

11-03-25

L. John Hoffer, MD, PhD

PLoS Medicine 5:e67, 2008

IV Vitamin CÂ and Quality of Life in Cancer Treatment in Japan Atsuo Yanagisawa, MD

IV Vitamin C & Quality of Life in Cancer Treatment in Japan

Todayâ&#x20AC;&#x2122;s topics (1) IVC & QOL in Japan (2) Doctors choices on their own cancer treatment. (3) What is Japanese College of Intravenous Therapy (JCIT)?

Atsuo Yanagisawa, M.D., Ph.D. Japanese College of IV Therapy 1

Clinical Trial for IV Vitamin C [1]

Clinical Trial for IV Vitamin C [2]

2005 Ovarian, cervical and uterine cancer

2009 Pancreatic cancer

- University of Kansas Medical Center (USA)

- Jefferson Medical College (USA) - Iowa University (USA)

2006 Solid tumor with no effective therapy

2010 Advanced cancer for whom chemo alone is only marginally effective

- Cancer Treatment in America (USA)

2008 Non-Hodgkin lymphoma

- McGill University (Canada)

- Jefferson Medical College (USA) - Tokai University (Japan)

2010 Prostatic cancer - Copenhagen University (Denmark)

2008 IVC phase-I study

2010 IVC and QOL

(published in Annals of Oncology) - McGill University (Canada)

- Japanese College of IV Therapy (Japan) 4

2007 Changes of Terminal Cancer Patients' Health-related Quality of Life after High Dose Vitamin C Administration - Sungkyunkwan University, Korea

- J Korean Med Soc 2007;22:7-11.

*One week treatment of 10g IVC 5

IV Vitamin C and Quality of Life in Cancer Treatment in Japan Atsuo Yanagisawa, MD

Effects of High Dose Intravenous Vitamin C Therapy on Health-related Quality of Life in Cancer Patients.

Methods Organization

Japanese College of IV Therapy

Participants

145 members (140 clinics/5 hospitals)

Subjects

Cancer pts who had no history of IVC

Period of registration

June 1-December 31, 2010

QOL evaluation

EORTC QLQ-C30 at before, end of 2 wks and 4 wks after first-IVC treatment.

Administration of IVC

<Riordan IVC Protocol> Patients were usually administered IVC twice a week.

Riordan IVC Standard Infusion Protocol Developed and Typically Used at Center

The Brightspot for Healthwww.brightspot.org

Vitamin C (A.A.) # Grams (# cc)

Diluent Type

MgCl Infusion Time Added (~0.5 gram/minute)

Osmolality (calculated)

15 grams (30cc)

250cc Ringer's Lactate

1cc

~30 minutes*

827 mOsm/L

25 grams (50cc)

250cc Sterile Water

1cc

~50 minutes

800 mOsm/L

50 grams (100cc)

500cc Sterile Water

2cc

~100 minutes

900 mOsm/L

75 grams (150cc)

1000cc Sterile Water

2cc

~150 minutes

703 mOsm/L

100 grams (200cc)

1000cc Sterile Water

2cc

~200 minutes

893 mOsm/L

The Riordan IVC Protocol dosing schedule depicted above has served as a “safe start” for cancer patients new to IVC. The Center for the Improvement of Human Functioning International in Wichita, Kansas, since 1990, has administered over 30,000 onsite IVC infusions according to this protocol. Zero fatalities and rare side effects a testament to its remarkable safety.

http://www.doctoryourself.com/RiordanIVC.pdf

Effects of High Dose Intravenous Vitamin C Therapy on Health-related Quality of Life in Cancer Patients.

Patients characteristics Sex Age

Male

Female

Previous anticancer therapy

61+12 yrs

Cancer Diagnosis Lung

Pancreas

Breast

Prostate

Stomach

Cervix/ovarian

Colorectal

Lymphoma

Liver

Others

Surgery

Chemotherapy (CTx)

Radiotherapy (RTx)

Surgery+CTX

CTx+RTx

Surgery + CTx+RTx

No standard therapy 0000000000Total 11

9 60 12

IV Vitamin C and Quality of Life in Cancer Treatment in Japan Atsuo Yanagisawa, MD

Effects of High Dose Intravenous Vitamin C Therapy on Health-related Quality of Life in Cancer Patients.

Performance status

48 12

ECOG Grade 0-1 ECOG Grade 2-4

Global health/QOL

ECOG: Eastern Cooperative Oncology Group Grade 0: Fully active. Grade 1: Restricted in physically strenuous activity. Grade 2: Ambulatory and capable of all selfcare. Grade 3: Capable of only limited selfcare.. Grade 4: Completely disabled.

Befor 2 wks 4 wks e 45+ 53+ 27* 61+ 24 ** 28

Values are mean+SD. *p<0.05 and ** p<0.01 from before IVC. (Wilcoxon signed ranks test) 13

Effects of High Dose Intravenous Vitamin C Therapy on Health-related Quality of Life in Cancer Patients.

Symptom scales

Functional scales

Physical Role Emotional Cognitive Social

Before

2 wks

4 wks

74.0+ 27.7 78.3+ 23.7* 79.9+ 24.1* 64.2+ 33.0 71.2+ 31.1* 75.4+ 30.2** 76.4+ 21.1 82.2+ 19.0* 87.4+ 15.3** 74.3+ 26.1 81.6+ 23.9 84.2+ 22.1** 70.9+ 30.4 81.3+ 25.2* 82.4+ 21.7**

Values are mean+SD. *p<0.05 and ** p<0.01 from before IVC. (Wilcoxon signed ranks test)

Effects of High Dose Intravenous Vitamin C Therapy on Health-related Quality of Life in Cancer Patients.

2 wks

4 wks

Markedly improved Moderately improved Mildly improved Unchanged Mildly worsened Moderately worsened Markedly worsened

1 ( 2%) 5 ( 8%) 22 (37%) 30 (50%) 2 ( 3%) 0 ( 0%) 0 ( 0%)

1 ( 2%) 6 (10%) 29 (48%) 21 (35%) 3 ( 5%) 0 ( 0%) 0 ( 0%)

31.8 + 25.3**

4 wks 28.4 + 25.7**

Nausea/vomiting

08.9 + 22.1

0 9.3 + 20.6

Pain

17.8 + 25.7

13.8 + 23.6

10.0 + 13.9*

Dyspnea

27.2 + 29.8

23.2 + 27.2

16.4 + 23.7

07.6 + 17.6

Insomnia

31.1 + 32.1

23.2 + 27.2*

16.4 + 23.7**

Appetite loss

26.1 + 36.4

30.5 + 32.9

20.5 + 28.0

Constipation

21.1 + 31.3

13.6 + 22.4 *

11.7 + 22.3*

Diarrhea

10.7 + 24.3

09.2 + 19.5

10.1 + 20.0

Financial Dificulties

34.5 + 32.1

26.4 + 29.8

26.2 + 28.2*

Conclusions

60%

Physician’s report

2 wks

42.4 + 28.7

Values are mean+SD. *p<0.05 and ** p<0.01 from before IVC. (Wilcoxon signed ranks test)

47%

Before

Fatigue

1 The effects of high-dose IVC on QOL in 60 cancer patients were studied using EORTIC QLQ-30 assessment. 2 In the global health/quality of life scale, health score improved from 45±28 to 61±24 at 4 weeks after IVC (p<0.01). 3 In functional scale, the patients reported significantly higher scores for physical, role, emotional, cognitive, and social function after IVC (p<0.05).

IV Vitamin CÂ and Quality of Life in Cancer Treatment in Japan Atsuo Yanagisawa, MD

Conclusions 4 In symptom scale, the patients reported signifi-cantly lower scores for fatigue, pain, insomnia, constipation and financial difficulties after administration of vitamin C (p<0.05).

5 Physicians reported that 60% of their patients improved QOL after IVC, while 35% was unchanged, and 5% worsened.

6 IVC can be considered as a safe and effective therapy to improve QOL in cancer patients. 19

Age distribution in 222 subjects Specialty Medical Doctor Dental Doctor Total

Sex Male Female

Total Subjects

JCIT Member Non-Member

197 (89 %)

24-29 yrs

1 (0.5%)

1 ( 1%)

0 ( 0%)

25 (11 %)

30-39 yrs

21 (10%)

12 (10%)

9 ( 9%)

40-49 yrs

87 (39%)

50 (40%)

37 (39%)

50-59 yrs

87 (39%)

44 (35%)

43 (45%)

60-69 yrs

19 (8.5%)

13 (10%)

6 ( 6%)

7 ( 3%)

6 ( 5%)

1 ( 1%)

222 (100%)

126 (100%)

96 (100%)

222 (100%) 176 (79 %) 46 (21 %)

70yrs Total 23

IV Vitamin C and Quality of Life in Cancer Treatment in Japan Atsuo Yanagisawa, MD

Q-1: What is the degree of prolongation of survival that you believe is acceptable for choosing a particular agent for chemotherapy? > 3 months 5 % ( 10 )

Style of practice (1) 77 % Private clinic (172) 21 % ( 47 Hospital ) 2% ( 3 ) Others Style of practice (2) Oncologist (standard treatment) (non-standard) Oncologist Non-oncologist

3% ( 6 12 % )( 26%) 85 (190)

> 6 months

15 % ( 33 )

> 12 months

58 % (130)

No chemotherapy

22 % ( 49 )

Q-2: Assuming that you are diagnosed with cancer and have to select anticancer agents for chemotherapy, which of the following items would you give “high priority” to? Please choose 3 items from the following. Severity of adverse reactions 78 % Response rate* 64 % extension of survival period 61 % Probability of complete remission

46 %

Trusting relationship with your doctor

27 %

Opinions of your family

Q-3: Would you undergo chemotherapy if you were diagnosed with "cancer” for which radical surgery is not possible and chemotherapy is the only treatment option? The chemotherapy referred to here is first-line therapy; that is, it has been demonstrated in doubleblind randomized controlled trials to yield a statistically significant prolongation of survival. In this settings, Your general status is ECOG Performance Status 1 : ”Symptomatic but completely ambulatory” (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, 28 office work).

*The response rate is the proportion of patients in whom the tumor has either disappeared (complete remission) or become smaller (partial remission) 27

Q-4: Would you undergo newly proposed chemo-therapy in any of the following cases?

Q-3: Would you undergo chemotherapy if you were diagnosed with "cancer” for which radical surgery is not possible and chemotherapy is the only treatment option?

I would. I probably would.

19 % ( 42 )

62%

I probably would not. I would not.

The first-line chemotherapy you had undergone was ineffective; although it was temporarily effective, it became ineffective or had to be discontinued due to the development of adverse reactions.

38%

43 % ( 97 )

The chemotherapy referred to here is the “socalled second-line therapy,” which has not been shown in double-blind randomized controlled trials to yield any statistically significant prolongation of survival . 30

23 % ( 50 ) 15 % ( 33 ) 29

IV Vitamin C and Quality of Life in Cancer Treatment in Japan Atsuo Yanagisawa, MD

Q-4 was asked to 139 subjects who answered Q-3 as “I would or I probably would undergo first-line chemotherapy”.

Q-5: Would you undergo “non-standard therapy” if you were diagnosed with cancer?

Q-4: Would you undergo newly proposed the secondline chemotherapy in any of the following cases? The first-line chemotherapy you had undergone was ineffective; although it was temporarily effective, it became ineffective or had to be discontinued due to the development of adverse reactions.

I would. I probably would. I probably would not. I would not.

46% 54%

10 % 36 % 47 % 7%

( 14 ) ( 50 ) ( 65 ) ( 10 )

* Standard therapy : surgery, radiotherapy, and chemotherapy.

I would.

65 % ( 146 )

92 I probably would. % I probably would not. 8% I would not.

27 % ( 60 ) 5 % ( 10 ) 3% ( 6 )

List of selected “non-standard therapy (2)

List of selected “non-standard therapy (1)

Stress reduction and healing therapy 19 % ( 43 ) 18 % ( 40 Laughter therapy ) Reduced water, Hydrogen-rich water 18 % ( 39 )

Psychotherapy

18 % ( 38 )

Ozone therapy

16 % ( 35 )

39 % ( 86 )

Physical exercise therapy

15 % ( 34 )

Nutrition Therapy**

31 % ( 68 )

Home medical care

15 % ( 34 )

Low-dose naltrexone (LDN) therapy

29 % ( 65 )

Music therapy

14 % ( 31 )

Intravenous lipoic acid therapy

28 % ( 62 )

Radiation hormesis

11 % ( 25 )

Palliative care

25 % ( 56 )

Yoga

10 % ( 23 )

Gene therapy

22 % ( 49 )

Others: IPT, IV-Ukrain, Hospice, Umbilical Cord Stem Cell Therapy, Pillates, etc.

High-dose IVC therapy

79 % ( 176 )

Immunotherapy*

51 % ( 113 )

Nutritional supplements

46 % ( 102 )

Hyperthermia

44 % ( 98 )

Chinese herb medicine

11 12

* NK-cell, vaccine, Dendritic cell based immunotherapy, T cell based adoptive immunotherapy, Autologous Immune Enhancement Therapy (AIET) **Organic food, Gerson therapy, etc 33

Conclusions

.)* $ # # % %+ .$' &$

1 62% of doctors (MD and DDS) said that they would choose firstline chemotherapy if they were diagnosed with cancer and chemotherapy is the only treatment option: while 38% said they would not.

2006.09.22

2 If their first-line chemotherapy is ineffective or has to be discontinued due to the adverse reactions, 46% would choose second-line chemotherapy, but 54% would not .

3 92% of doctors would undergo non-standard cancer therapy along with or without standard therapy. 4 For the patients, oncologist should show not only treatment with chemotherapy, but also therapeutic option without chemotherapy. Moreover, oncologist also should show patients non-standard therapies such as IVC, Immunotherapy, etc. 35

2007.04.10

IV Vitamin CÂ and Quality of Life in Cancer Treatment in Japan Atsuo Yanagisawa, MD

85 yrs male Prostate ca.

62 yrs. Breast cancer

7/14/2009

11/6/2009 after 19 IVC 2009.07.1 1

2010.01.18 37

54 yrs. female, stomach cancer

55yrs Before IVC BW=48 lb

There is always a key to stop the progression of cancer and it might not be limited to a single key. It could very well be two or more.

58 yrs 3yrs after IVC BW= 90 lbs

&* .* % #,

00 )&' ) ,+) + &% 00 $$,% .*+ $ & # / + &% 00 +) ** % $ %+ 00 ' ) +, # ## %

Each time a key is discovered the progression of a cancer can be curtailed. It is our responsibility to work step-bystep with our patients to discover these keys.

20 + $ % 11 +

IV Vitamin CÂ and Quality of Life in Cancer Treatment in Japan Atsuo Yanagisawa, MD

Japanese College of Intravenous Therapy

* ' .* % &% (, *+ &) + * " .* - $,*+ -&)" - + + $ # * +& $' )+ &,) % &' ,'&% &,) ' + %+* &) + %+ ) +. & + ) #&% % ) ,&,* !&,)% .

â&#x20AC;˘ We are 400 members: 379 physicians 12 dentists 9 veterinarians â&#x20AC;˘ More than 10 educational seminars every year. IV Vitamin C, IV Lipoic acid, IV Chelation, Myersâ&#x20AC;&#x2122; Cocktail, LDN, Nutrition therapy, etc. â&#x20AC;˘ We invite International speakers.

Dr. Ron Hunninghake

Dr. Thomas E. Levy

Dr. John A. Hoffer

Dr. Burton M. Berkson

Dr. Michael Janson

The 1st JCIT Symposium of â&#x20AC;? IVC for Cancer Patientsâ&#x20AC;?

Dr. Bradford S. Weeks 45

Oct 17, 2010, Tokyo, Japan

Thank you!

http://www. iv-therapy.jp 47

Orthomolecular Intervention for Nutrient Depletion from Pharmaceutical Use Hyla Cass, MD Biography: Hyla Cass, M.D.

Orthomolecular Interventions for Drug-Nutrient Depletion

• Integrative medicine and psychiatry: clinical practice, writings, lectures, and nationwide media appearances (CBS News, MSNBC, PBS, The View, etc). • Former Assistant Clinical Professor of Psychiatry at UCLA School of Medicine • Medical Advisory Board of the Health Sciences Institute and Taste for Life Magazine; Associate Editor of Total Health • Board Member American College for Advancement in Medicine • Author of Supplement Your Prescription, Natural Highs and 8 Weeks to Vibrant Health.

HYLA CASS, M.D. 1608 Michael Lane Pacific Palisades, Ca., 90272 (310) 459-9866 • fax (310) 564-0328 e-mail: hyla@drcassmd.com • website: www.drcass.com

Orthomolecular Medicine Today Conference 4/11

• For more information, see www.drcass.com. Drug-Nutrient Depletion/www.drcass.com

Drug-Nutrient Depletion/www.drcass.com

Supplement Your Prescription:

Operating Principles 1. 2. 3.

4. 5.

7. 8.

Healing power of Nature - best pharmacy Identify and treat the root cause, not the symptoms; use best of science/art of medicine Treat as safely and naturally as possible; preferring noninvasive treatments that minimize the risks of harmful side effects when possible Doctor as resource, educator  partnership Treat the whole person: complex interaction of physical, mental, emotional, genetic, dietary, environmental and lifestyle factors Prevention: preventing disease; preventing minor illnesses from developing into more serious or chronic diseases; assessment of risk factors; appropriate interventions Health affected by dietary intake, body chemistry, hormones, environment Specific nutrients essential to function and heal

Find out: 1. How drugs deplete essential nutrients 2. Specific nutrients that can remedy this depletion 3. Natural supplement options to medication 3

Drug-Nutrient Depletion/www.drcass.com

Rx Use Statistics

Drug Dangers

• Targeted for specific effects • Have unwanted ‘side effects’ -- result of the same process • Over 100,000 deaths/year – drugs taken as prescribed!

• Nearly 50% of population taking at least 1 prescription daily • Nearly 20% of population taking 3 or more prescriptions daily • Over 50% of those over 65 taking 3 or more daily • $200 billion industry in 2004

Lazarou J, et al “Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.” JAMA Apr 15, 1998; 279(15): 1200---1205.

• Drug-Nutrient Depletion/www.drcass.com

Drug-Nutrient Depletion/www.drcass.com

Orthomolecular Intervention for Nutrient Depletion from Pharmaceutical Use Hyla Cass, MD Drug Safety?

Recent Drug Danger Issues Removed from market: • Vioxx – heart attacks, GI bleeding • Baycol – rhabdomyolysis - acute & sometimes fatal destructive disease of the skeletal muscle causing renal failure. • Rezulin – liver failure • Avandia – heart attacks (still on market) Black box warning: Paxil – suicide, homicide Cancer warning: Prempro – WHI study

• Conflicts of interest • Increased scrutiny of drug companies by FDA • Marcia Angell’s book: The Truth About the Drug Companies: How They Deceive Us and What To Do About It

Drug-Nutrient Depletion/www.drcass.com

Drug Dangers

Drug Nutrient Depletion

• Excessive dose: ie, too high for the patient or purpose • Interactions: polypharmacy • Depletions: generally ignored

• Most prescription drugs are nutrient robbers • Serious side effects, including fatal muscle wasting, heart failure, and suicide • Most individuals are already depleted in nutrients • Add in a drug- “last straw”

Drug-Nutrient Depletion/www.drcass.com

Mechanisms of nutrient depletion Signs Of Nutrient Depletion

• Decrease appetite - stimulants • Increase appetite – anti-psychotics, antidepressants • Decrease absorption – Bs, vit D with acid blockers • Increase burning of nutrients – antibiotics, steroids • Increase elimination – minerals such as potassium with use of diuretics • Block production eg CoQ10 with statins

• Gradual: fatigue, depression, sore muscles, osteoporosis • Acute: muscle pain, heart attack • Mistaken for “just aging” or part of condition • Drugs prescribed to counter these side effects create more problems Drug-Nutrient Depletion/www.drcass.com

Drug-Nutrient Depletion/www.drcass.com

Orthomolecular Intervention for Nutrient Depletion from Pharmaceutical Use Hyla Cass, MD Antacids

Heartburn/GERD

• Antacids with Aluminum: Maalox, Gaviscon, Mylanta • Action: Neutralize acid: interfere with absorption of nutrients • Depletion/Supplement with:

• May be due to low stomach acid, not high • Poor eating habits • Reduced ability to extract nutrients from food

– – – – – – –

• Worse with medications that block acid

Drug-Nutrient Depletion/www.drcass.com

H2 Blockers

Proton Pump inhibitors • Prilosec, HK-20, Zegerid, Nexium, Prevacid, Zoton, Inhibitol, Protonix, Somac, Pantoloc, Protium, Aciphex, Rabecid • Action: Reduce stomach acid prod’n by 99% • Side effects:

• Tagamet, Pepcid, Axid, Zantac • Actions: Block histamine -> decrease acid secretion • Depletions/Supplement with:

– osteoporosis from Vit D depletion – anemia, fatigue, depression

– Calcium 1000mg

• Depletion/Supplement: Vit D, folic acid, B12, calcium, iron, zinc • Supplement with a multi and extra Vit D, folic, B12

– B12- 200 mcg – Vit D – 1000 -5000 IU

Drug-Nutrient Depletion/www.drcass.com

Vit D 1000-5000 IU (test level) B12 200-800 mcg Folic acid 400-800 mcg Calcium 1000 mg Chromium 500 mcg Iron 20 mg Zinc 25-50 mg, phosphorus

Drug-Nutrient Depletion/www.drcass.com

Natural Solutions

Statins

• Diagnosis: test for H. Pylorii Treat with: • Mastic gum (herb) • Zinc-carnosine • Betaine HCl • Probiotics Drug-Nutrient Depletion/www.drcass.com

Drug-Nutrient Depletion/www.drcass.com

Orthomolecular Intervention for Nutrient Depletion from Pharmaceutical Use Hyla Cass, MD Actions of CoQ10:

Side Effects

• Converts carbohydrate and fat into energy in energy-producing ‘factories’ called mitochondria in all cells • Antioxidant – protects cell membranes against freeradical damage. • Works with vitamin E to prevent oxidation of fats throughout the body, providing improved protection against premature aging and chronic disease. • Blood-thinning effects helps prevent heart attacks and certain types of strokes. Dose: 100–300 mg per day, packaged with oil and vitamin E for best absorption Drug-Nutrient

• Headache, rash, nausea, heartburn, constipation, diarrhea, gas • Irritability, mood swings, and depression • Sexual dysfunction • Heart failure • Muscle pain and weakness; rhabdomyolysis • Cognitive Problems -15% of those on statins have impaired ability to think, reason, remember, and concentrate. See Duane “Doc” Graveline’s Statin Drugs: Side Effects and The Misguided War on Cholesterol Drug-Nutrient Depletion/www.drcass.com

Depletion/www.drcass.com

Diabetes: Oral Hypoglycemics

Nutrients to Lower Cholesterol

Metformin (Glucophage, Glucophage XR, and Glucovance). • enhances the action of insulin • reduces blood sugar • protect against diabetic complications (neuropathy, retinopathy, kidney damage) • lengthen lifespan in overweight people with type 2 diabetes. • Side effects: GI: nausea, vomiting, and diarrhea. • Nutrients depleted/needed: vitamin B12,folic acid; CoQ10

• Omega-3 Oils – reduces inflammation: 2 gms daily • Sterols – prevent absorption of fats: 2 gm daily • Tocotrienols – antioxidant, heart protective, lowers LDL – 100 mg daily • Niacin – vit B3 – raises HDL, lowers LDL; 100 mg- 1500 mg, gradual; monitor liver Drug-Nutrient Depletion/www.drcass.com

Drug-Nutrient Depletion/www.drcass.com

Diabetes: Sulfonylureas

The B Vitamin-Homocysteine Connection

• chlorpropamide (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol), glyburide (DiaBeta, Micronase, or Glynase). - not often used on their own. • Actions: stimulate insulin-producing cells of the pancreas, reduce insulin’s release of fats (such as triglycerides and LDL) into the bloodstream, and reduce production of sugars in the liver. • Side effects: low blood sugar, water weight retention, GI problems, headaches. • Nutrient depleted/needed: CoQ10.

• Metformin depletes B12 and folate • Methionine is converted to homocysteine which increases risk of heart disease, stroke, hypertension, and Alzheimer’s disease • Vitamins B12, B6 and folic acid needed to convert homocysteine into non-toxic amino acids • 3 mmol/l increase in homocysteine raises risk of heart attack by 10%, and raises risk of stroke by 20%, in non-diabetics; the risks are even greater in diabetics. Drug-Nutrient Depletion/www.drcass.com

Drug-Nutrient Depletion/www.drcass.com

Orthomolecular Intervention for Nutrient Depletion from Pharmaceutical Use Hyla Cass, MD Nutrient Solutions to Metabolic Syndrome & Diabetes

Non-Steroidal Anti-inflammatory Drugs

Take daily in divided doses, best with breakfast and dinner, one-half dose each time: • Vitamin B1 320 mg (as benfotiamine) • Vitamin B12 200 mcg • Folic acid 400 mcg • Vitamin B6 10–25 mg • Chromium 200 mcg • Vanadium 2 mg • Magnesium 500–600 mg • Coenzyme Q10 30–200 mg • Alpha-lipoic acid 200– 600 mg • Mixed antioxidant supplement Drug-Nutrient Depletion/www.drcass.com

• Old-guard NSAIDs include aspirin, naproxen, indomethacin, piroxicam, diclofenac, diflunisal, etodolac, fenoprofen, ketoprofen, ketorolac, meclofenamate, nabumetone, tolmetin, and mefenamic acid. • Cause 16,500 death per yr in US alone • COX-2 inhibitors eg Celebrex (Bextra, Vioxx were removed) • Many (if not all) of these medicines can cause GI bleeding and heart problems. Drug-Nutrient Depletion/www.drcass.com

NSAIDs

Warning on Celebrex

• Actions: NSAIDs block the production of hormone-like substances in the body that produce inflammation and pain (prostaglandins) • Side effects: All NSAIDs carry significant risk of GI erosion and bleeding; most also carry cardiac risks. • Nutrients depleted: NSAIDs deplete folic acid and vitamin C • Needed supplements: Take 500–1,000 mg of vitamin C and 400– 800 mcg of folic acid. Drug-Nutrient Depletion/www.drcass.com

•

WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS: Cardiovascular Risk: Celebrex may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All nonsteroidal antiinflammatory drugs (NSAIDs) may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. Celebrex is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

•

Gastrointestinal Risk: NSAIDs, including Celebrex, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. Drug-Nutrient

Depletion/www.drcass.com

Consumer Reports 8/09 Should you still take Celebrex?

• Pfizer spent $54.8 million on ads in 2007 and $58.5 million in 2008 • It's probably harder on the heart • It may not be much easier on the gut • It's no more effective

Depletion/www.drcass.com

Fabricated Efficacy Studies •

• 11 million prescriptions for it are still filled each year, often for arthritis, menstrual cramps, and acute pain

• It's more expensive:$130/mo vs $25 for the generic, over-the-counter versions of acetominophen, ibuprofen, Drug-Nutrient or naproxen

On March 11, 2009, Scott S. Reuben M.D., former chief of acute pain at Baystate Medical Center, Springfield, Mass., & former paid spokesperson for Pfizer revealed that data for 21 studies he had authored for the efficacy of Celebrex (along with other such as Vioxx, Bextra, Effexor) had been fabricated, the analgesic effects of the drugs being exaggerated. The retracted studies were not submitted to either the FDA or the European Union's regulatory agencies prior to the drug's approval. Pfizer issued a public statement declaring, "It is very disappointing to learn about Dr. Scott Reuben's alleged actions. When we decided to support Dr. Reuben's research, he worked for a credible academic medical center and appeared to be a reputable investigator.” The journal Anesthesia & Analgesia retracted 10 of Dr. Reuben's studies and posted a list of the 11 published in other journals on its Web site.

For details: http://en.wikipedia.org/wiki/Celecoxib http://tinyurl.com/d5gamg

Drug-Nutrient Depletion/www.drcass.com

Orthomolecular Intervention for Nutrient Depletion from Pharmaceutical Use Hyla Cass, MD Healthy Joints Supplement Program (cont’d)

Healthy Joints Supplement Program

• Avocado/soybean unsaponifiables (ASU)-plant sterols: 300 mg daily (allow up to two months to see results)

To replace depletions from NSAIDs, as well as addressing the underlying deficiencies and inflammation: • Folic acid 400–800 mcg per day • Vitamin C

• Boswellia: 600 mg daily • Bromelain: 200–400 mg daily, between meals • Devil’s claw: 60 mg daily • Fish oil: 1–2 grams (1,000–2,000 mg) daily • Ginger: Up to 4 grams daily in powdered form, or in foods

500–1,000 mg per day

• Glucosamine/chondroitin 1,500 mg of glucosamine sulfate; if no effect in 3 mos, add 1,200 mg of chondroitin daily • MSM: Up to 6 gm daily

Drug-Nutrient Depletion/www.drcass.com

• Turmeric: 400–600 mg three times daily Drug-Nutrient

Depletion/www.drcass.com

Diuretics

Antihypertensives

• Loop diuretics (Lasix, Bumex) • Thiazide (HCTZ, Diuril, Hygroton) – Both increase kidney’s water and salt elimination & deplete Ca, Mg, Na, K, Zn, CoQ10, B1, B6,

Depletions: • ACE inhibitors- zinc • Catapres, Aldomet – CoQ10, B6, B1, Zn • Beta blockers (Inderal, Corgard, Lopressor) – CoQ10

• Potassium Sparing Diuretics (spironolactone (Aldactone), trimaterene(Dyrenium) : calcium, folic acid, B6, zinc Drug-Nutrient Depletion/www.drcass.com

Drug-Nutrient Depletion/www.drcass.com

Natural Remedies for Hypertension

Misc. Depletions

• Diet, lifestyle, stress reduction • Garlic: 300 mg tid • Grapeseed extract 100-20 mg daily • Hawthorn: 1500 mg daily

• Oral Contraceptives - B6, C; other B vits, Mg, Se, Zn

• Magnesium: 500 mg daily • Calcium 500 – 1000 mg • CoQ10 100 mg daily

• Antibiotics – GI flora, B vits, Vit K • Anticonvulsants – B vits, Vit D, Vit K, Ca, carnitine

• Antidepressants – CoQ10, B6, other B vits

• Thyroid in selected cases (higher incidence of HT in hypothyroid) Drug-Nutrient Depletion/www.drcass.com

Drug-Nutrient Depletion/www.drcass.com

Orthomolecular Intervention for Nutrient Depletion from Pharmaceutical Use Hyla Cass, MD Summary • Drug side effects may be due to nutrient depletion! • A high potency multi + CoQ10 + probiotics will cover most depletions, adding in extra supplements or higher doses (eg Vit D) as needed; EFAs • Treat root cause versus covering symptoms • Use natural supplements when possible instead of drugs Drug-Nutrient Depletion/www.drcass.com

Orthomolecular Therapy for Childhood Asthma Bud Rickhi, PhD

Orthomolecular Treatment as add-on Therapy for Childhood Asthma

Dr. Badri Rickhi, MB, BS, FRCP(C) Research Chair

A Randomized Controlled Trial

CANADIAN INSTITUTE OF NATURAL AND INTEGRATIVE MEDICINE

Trials and Tribulations

Associate Clinical Professor of Medicine University of Calgary

Background – Asthma in Children

What is CINIM? Mission Statement CINIM conducts rigorous scientific research to evaluate natural and integrative therapies for the advancement of medical knowledge CINIM is a registered charitable organization Projects are funded through private donations and project grants from public funding organizations

• Asthma affects about half a million children in Canada • Most common chronic disease involving children

Background – Orthomolecular Therapy and Asthma

Orthomolecular Treatment for Asthma • Asthmatic children commonly present with nutritional deficiencies • Orthomolecular treatment for asthma commonly includes high doses of vitamins and minerals that reduce:

Standard treatment is Inhaled Corticosteroids (ICS) • Compliance issues • Impact of daily doses on growth and bone density of children? • Many concerned parents look to complementary and alternative medicine (CAM) treatments

Oxidative stress Inflammation Allergic responses

Orthomolecular Therapy for Childhood Asthma Bud Rickhi, PhD

Our Trial –Orthomolecular Formula

Our Trial

Trial Intervention Vitamin C Vitamin B6 Magnesium Quercetin

Can taking orthomolecular doses of vitamins and minerals reduce the required dose of Inhaled Corticosteroids in Asthmatic children?

Vitamin E Vitamin B12 Selenium Fish Oil

Chosen Formulation • Supplements are organic • Orange flavored powder that can be dissolved in water or other beverage

Trial Sponsors Lotte & John Hecht Memorial Foundation, Sick Kids Foundation & Private Donors

Our Trial – Eligibility Criteria

Methods • Double blind, randomized, placebo controlled, parallel group study design

• Male or female aged 7 to 18 years • Mild to moderate asthma of at least 1 year's duration diagnosed by a respirologist

• 90 asthmatic children who require ICS will receive orthomolecular doses of vitamins, minerals, and fish oil; or placebo

• use of budesonide at a dose of 200-800 µg/d (or equivalent corticosteroid therapy) for ≥3 months

• All children will have their dose of ICS reduced in a stepwise fashion

Methods

Study Phases

Outcome Measures

• Phase I: 4 week run-in phase. Steroid dose tapered to required levels • Phase 2: 8 week treatment phase. Steroid dose kept constant. Participants begin to take supplements • Phase 3: 8 week treatment phase. Steroid dose tapered. Participants continue supplements

• The lowest tolerated dose of inhaled corticosteroids will be the primary outcome measure • Breathing tests (PEF, FEV1, eNO) • Blood results (CBC, liver panel, serum vitamin levels) • Daily Asthma Symptom Diary • Quality of Life Questionnaire

Orthomolecular Therapy for Childhood Asthma Bud Rickhi, PhD Natural Health Products Directorate (NHPD) of Health Canada

Challenges Encountered

• Process of preparing a Clinical Trial Application (CTA) • Cost of preparing CTA

• Natural Health Products Directorate (NHPD) • Manufacturers

• Process of making amendments to CTA

Process of Preparing a Clinical Trial Application (CTA) for Health Canada

CTA Review by NHPD (5 Months) Acceptance of CTA: 2 weeks  3 Information Request Notes (IRNs) issued: (52 questions)  Issuing and responding to IRNs: 4 months  Final Review: 2 weeks

(New regulations as of Jan. 2004)

• In-house attempt to complete the CTA documents: 4 months • Identify & hire consultant firm to assist with the CTA: 2 months • Find and hire NHPD licensed manufacturer: 7 months • Prepare full CTA: 5 months

Result: NHPD Approval after speedy and helpful review!

Examples of NHPD Review Questions

Cost of Obtaining NHPD Approval In-house work: $13,000 Consultant services: $10,000 NHPD required product testing: $7,000

Question 2: Under “NHP Formulation” of the INTRODUCTION section of the Quality Overall Summary – Natural Health Products (QOS-NHP), Orange juice powder and Evaporate cane juice are indicated as the common name for two of the non-medicinal ingredients. As these common names are not recognized in the Natural Health Products Ingredients Database, please clarify and/or revise the INTRODUCTION section of the QOS-NHP in order to be consistent with the NHPID (i.e., orange juice and sugarcane). Question 25: According to the Certificate of Analysis provided for the medicinal ingredient Vitamin B12, cyanocobalamin is triturated with dibasic calcium phosphate. Consequently, this ingredient should be indicated as a non-medicinal ingredient. Please revise relevant section(s) of the CTAA form and the QOS-NHP accordingly.

Total: $30,000

Orthomolecular Therapy for Childhood Asthma Bud Rickhi, PhD

Process of making amendments to CTA Application

Summary of added time/cost Time spent creating original CTA: Money spent creating original CTA: Time spent amending CTA: Money spent amending CTA:

• Collaboration with manufacturer to make changes to necessary documents: 4 months • 5 Information Request Notices (IRNs) issued: 60 Questions • Issuing and responding to IRNs: 7 months • Final Review: 2 weeks

Total Time: Total Money:

18 months $30, 000 12 months $20, 000 2.5 years $50,000

Challenges Encountered • 7 months just to find a manufacturer. Most large companies turned us down • How is this field going to grow if manufacturing companies are not willing to support research?

Manufacturers

• Do manufacturing companies lack a good understanding of research?

How Can Manufacturers Support Orthomolecular Medicine Research?

Manufacturers are the weak link • Impossible to submit CTA without production info from manufacturers. • Can’t do the trial without a manufacturer producing the product.

• Manufacturers could provide funding for independent research. • Manufacturers and independent researchers could conduct studies together. • Manufacturers could show willingness to produce custom products for research.

• Research as opportunity or threat?

Orthomolecular Therapy for Childhood Asthma Bud Rickhi, PhD

Good News

Summary

• Naturally Nova Scotia (Halifax, NS): Only produces certified organic products. Donated time to help us develop our study supplements • Gelcell Ltd: Donated time and product

Summary 2 •

When scouting out a manufacturer, be persistent but know when to move on

•

Determine your study formula in detail

•

Get help from consultant to communicate with the manufacturer

•

Product and placebo cost: standard is cheaper than custom

•

Budget for Quality Control Testing

•

Investigate the need for an NHPD Application

•

Budget for the cost of preparing the application

•

Due diligence for finding the right consulting firm

•

Set up a pre-CTA conference call with the NHPD

•

Critically evaluate the suitability of the manufacturer

•

Understand NHP production & regulation

Support for Centres • Philanthropy by individuals/groups • Collaboration and support for: – Research – Transfer of Knowledge – Education – Product Quality

“Change will not come if we wait for some other person, or if we wait for some other time. We are the ones we have been waiting for. We are the change that we seek.”

- Barack Obama

3/15/2011 Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy

Aileen Burford Mason, PhD The Immune System • An integrated system of organs, tissues, cells, and cell products

Nutritional Priming and Immunity: An orthomolecular approach to preventing and treating colds, flu and allergies

– Differentiates self from non self – Neutralizes pathogenic organisms/substances

• White blood cells (leucocytes) are major players in fighting infection – Several specialized subtypes, incl. lymphocytes, monocytes, neutrophils, macrophages, NK cells

Aileen Burford-Mason PhD www.aileenburfordmason.ca

• Classified as two main branches

– Innate, inherent or natural immunity – Acquired, induced or adaptive immunity

Orthomolecular Medicine Today, Toronto, April 30, 2011

Innate Immunity

Classification of immune responses

• Natural or non-specific immunity: Ancient set of innate responses – predates bony fish

Natural

(infection/maternal transfer)

Immunity

– Collection of specific cells and effector mechanism that is non-adaptive

Adaptive

• Responsible for the rapid, first response to new, potentially dangerous stresses

Artificial

Innate

(immunization; passive transfer of antibodies)

– Stresses include pathogens, toxins, malignant or injured tissue

• New mechanisms and functions of innate immunity being uncovered all the time

Pattern Recognition and Innate Immunity

Innate Immunity

– Toll-like Receptors –

• Toll-like receptors (TLRs): The principle “sensors” of innate immunity

• Neutrophils, macrophages, NK and other cells recognize limited and unique range of molecules on microbes but not present on host cells

– Recognize patterns of molecules common to many different types of microbes – Activation of TLRs induces inflammation

– Uses pattern recognition receptors (PPRs) to distinguish between self and non-self

• TLRs provide a link between innate and adaptive immunity

• Housekeeping: Also recognize and eliminates “altered self” or “danger” – fragments of extracellular matrix or toxins

– Stimulation of TLR leads to activation of adaptive immunity and future protection

• Response is immediate. No need for prior exposure

(Annu Rev Immunol. 2003;21:335-76)

– No memory and generally no lasting protection

3/15/2011 Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy

Aileen Burford Mason, PhD Adaptive Immunity

Clonal expansion of B-cell repertoire

• More complex than innate immunity. An existing B lymphocyte responds to pathogen fragments (antigens) – Leucocytes then clonally expand to generate an army of similar B-cells that can attack that pathogen

• Slow response (3 -5 days) because of the need for clonal expansion – Provides lasting immunity against future exposure

T and B cells

White cells (leucocytes) WBC count Lymphocytes

• B-cells: Develop and mature in bone marrow



T-cells

Helper Suppressor

B-cells

 

Monocytes Neutrophils

   

– Drive the humoral immune response and the production of (antibodies) when exposed to foreign proteins – bacteria, viruses, pollen, etc.

Eosinophils Basophils Natural killer cells Macrophages

• T-cells: develop in bone marrow but mature in the thymus gland • T-cells and B-cells co-operate T-helper cells facilitate B-cell function T-suppressor cells block it

Note: Although neutrophils and macrophages are the 2 main phagocytic cell types, other cells have phagocytic activity in specialized tissues

T-cell, Immune regulation and the Th1/Th2 balance

The thymus: an overlooked organ

• Immunity to foreign particles is controlled by two types of T-helper cells

• Gland located under the breastbone – –

Grows throughout infancy Large during childhood. Achieves maximum weight in adolescence – Shrinks during adulthood

Th1 cells promote cell mediated immunity – fight pathogens and eliminate cancer cells Th2 cells drive humoral immunity – control the production of antibodies, etc.

• The thymus hormone, thymosin, enables T cells to “mature” • After age 60 thymosin is generally undetectable

• Imbalances of Th1 and Th2 cells contribute to immune dysfunction Excess Th1 is a risk for chronic or acute infection; cancer Excess Th2 linked to the development of allergies and autoimmunity

– This is assumed to mean thymosin is dispensable

3/15/2011 Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy

Aileen Burford Mason, PhD .The role of the thymus in immunosenescence: lessons from the study of thymectomized individuals. Appav V et al. Aging (Albany

The Nutritional Regulation of T Lymphocyte Function. Horrobin DF. 1979 Medical Hypothesis; 5(9):69-85

NY). 2010. 20;2(2):78-81

• Thymus development and T-cell function dependent on key nutrients:

• Background: The natural involution of the thymus

with aging had cast doubts as to its importance for the integrity of immunity in adulthood • Review: Children with congenital heart defects routinely have thymus removed (thymectomy) to facilitate corrective surgery • No immediate evidence of immunodeficiency

– – – –

Essential fats (Omega 3s; omega 6s) B-vitamins (esp. B6) Zinc Vitamin C

• Inadequate intakes of any of these compromises Tcell function – this could increase the incidence of cold and ‘flu

– However, immune system seems prematurely aged – Decrease responses to vaccination, increased risk of autoimmunity and infectious diseases

• Megadoses of single nutrients will only be minimally effective if intakes of other nutrients are inadequate

Prenatal undernutrition and postnatal growth are associated with adolescent thymic function

McDade TW et al. J Nutr. 2001 Apr;131(4):1225-31

• Study: investigated effects of pre- and postnatal nutrition on thymic hormone production in adolescence

– Prospective data collected at birth, year 1 of life, in childhood and in adolescence in an ongoing longitudinal study in the Philippines

• Results: Prenatal undernutrition associated with ↓ thymopoietin production in adolescence

• Conclusion: prenatal and early infant nutrition significantly affects immunity in adolescence

– Growth in length during yr of life was positively associated with adolescent thymopoietin (P = 0.002)

– Growth in length during 1st yr of life was positively associated with adolescent thymopoietin (P = 0.002)

1st

FDA warns GERD drugs may deplete magnesium

The thymus: a barometer of malnutrition Prentice AM. Br J Nutr. 1999,81:345-347

• Invited commentary: • The thymus may not be a vestigial remnant with little bearing on health after childhood

• Warning: Use of proton pump inhibitors (PPIs) for ≥1yr may lead to low levels of circulating Mg – ⁭ risk of leg spasms, arrhythmias, and seizures – ⁭ risk of heart attack or stroke in patients who undergo stenting or other percutaneous CV events

– Function in later life may have been underestimated

• Sensitivity of the human thymus to malnutrition noted as early as 1810 (FJ Menkel)

• Generally reversed with Mg supplements, but in ~25% of cases "magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued.“ • Check serum Mg before starting PPIs

– The term “nutritional thymectomy” was in common usage – Historically this signals the birth of nutritional immunology

• In mice on a magnesium-depleted diet, involution of the thymus is rapid (2 days) – Due to increased sensitivity to oxidative stress – Results in apoptosis of thymocytes

3/15/2011 Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy

Aileen Burford Mason, PhD Nutrition and the Th1/Th2 balance “In general, immune status represents a sensitive indicator of micronutrient supply. Conversely, the activity of the immune system has an effect on the status of and requirements for nutrients.”

• Nutrients shown to beneficially modify Th1/Th2 balance include – Zinc supplements in the elderly to prevent infection and autoimmune disease (Biogerontology. 2006;7(5-6):429-35) – Vegetables, fruit, and antioxidants in pregnancy to prevent wheeze and eczema in infants (Allergy. 2010;65(6):758-65) – Omega-3 fatty acids, Zn and vitamin C for childhood asthma treatment (Acta Paediatr. 2009;98(4):737-42) – Probiotics for allergy (Curr Opin Pediatr. 2010 Oct;22(5):626-34) and URTI prevention (Proc Nutr Soc. 2010;69(3):429-33)

Strohle A et al. Inflamm Allergy Drug Targets. 2011;10(1):64-74

“The Common Cold”

Canadian Community Health Survey Cycle 2.2, Nutrition (2004). ( accessed 14/02/11)

Cochrane Database Syst Rev. 2007 Jul 18;(3): CD000980

www.hc-sc.gc.ca/fn-an/surveill/nutrition/commun/index-eng.php

women

The term ‘the common cold’ does not denote a precisely defined disease, even though the illness is familiar to most of us. It is a complex of conditions caused by a broad range of viruses and occasionally bacteria. There is no unanimously accepted definition. Instead, various different operational definitions have been used, usually defining a minimum set of symptoms.

men

*EAR = the amount of a nutrient estimated to meet the daily requirements for half of all healthy individuals in a given age and gender group

Influenza B in households: virus shedding without symptoms or antibody response

Is it a cold or is it allergy?

Foy HM et al. Am J Epidemiol. 1987;126(3):506-15

http://www.mayoclinic.com/health/common-cold Accessed 27/02/2011

Signs and symptoms of the "common cold" 

     

Sneezing Runny or stuffy nose Cough Sore throat Mild fever (rarely) Usually lasts 3-14 days Contagious

• Study: 53 households tracked (winter/spring) for transmission of seasonal colds and ‘flu

Signs and symptoms of allergy • • • • • • •

– 26 households got influenza type B – Infection was proved by isolation of the virus and/or significant rise in antibodies

Itchy eyes Runny or stuffy nose Cough Sore throat No fever Usually last several weeks Can’t be passed from person to person

• Of the 37 persons shedding virus, 12 had no cold or „flu-like symptoms . Of these – 10 had high titers of antibody – 2 did not develop antibodies

• Conclusion: exposure and infection with a virus does not necessarily result in symptoms

Nutritional Priming and Immunity: An Orthomolecular Approach 3/15/2011 to Colds, Flu and Allergy Aileen Burford Mason, PhD Role of free radicals and antioxidants in health and disease Flora SJ. Cell Mol Biol 2007;53(1):1-2

• Immune cells patrol tissues, seeking out pathogens.

If an influenza virus can be present without causing „flu-like symptoms, what does cause the symptoms?

– NOTE: The recognition of a pathogen by toll-like receptors is vitamin D dependent

• When a pathogen is encountered, the elaborate process of disabling and eliminating it begins – First the pathogen is engulfed and ingested (phagocytosis) – It is then destroyed by rapid bursts of free radicals (ROS)

Free radicals (ROS) and symptoms of colds and „flu

Oxidative Stress and immunity Hydrogen peroxide (H2O2) Neutrophil

• It is the intensity of the ROS response that causes the symptoms of colds and ‘flu – sore throat, aching joints, etc. (Beisel WR. Am J Clin Nutr. 1995 Oct;62(4):813-9) • In turn, excess ROS may damage immune cells

Hydroxy radical (.OH) Hypoclorous acid (HClO) Superoxide anion (O2-) Nitric oxide (NO)

– this results in immune cell death (apoptosis)

• Apoptosis of immune cells compromises the effectiveness of the on-going immune response and

lymphocyte

prolongs symptoms (Grisham MB. Free Radical Biol

kill viruses and bacteria

Med. 2004;36:1479-1480)

damage host tissue

Antioxidant vitamins and minerals and ROS-mediated tissue damage

Oxidative Stress and immunity Hydrogen peroxide (H2O2) Neutrophil

• A, C, E, selenium and manganese work synergistically to neutralize ROS (Lara-Padilla et al. Adv

Hydroxy radical (.OH) Hypoclorous acid (HClO) Superoxide anion (O2-) Nitric oxide (NO)

Ther. 2007; 24(1): 50-9)

• Following activation of the immune response to infection, adequate amounts of all antioxidants are needed to prevent tissue injury (Hughs DA. Proc Nutr Soc 1999;58(1):79-84)

lymphocyte

kill viruses and bacteria

• Antioxidants also protect immune cells from damage (ibid.) and are anti-inflammatory

damage host tissue

3/15/2011 Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy

Aileen Burford Mason, PhD Omega-3 fatty acids, vitamin C and Zn supplementation in asthmatic children: a randomized self-controlled study

Increased antioxidant capacity in healthy volunteers taking a mixture of oral antioxidants versus vitamin C or E supplementation

Biltagi MA et al. Acta Paediatr. 2009 Apr;98(4):737-42.

Lara-Padilla E at al. Adv Ther. 2007;24(1):50-9

• Study: evaluated role of omega-3 EFAs, vitamin C and Zn in children with moderately persistent asthma – 60 children randomized to omega-3s, vitamin C and Zn singly, or in combination separated by washout phases

• Outcome measures: asthma control test (C-ACT), pulmonary function and sputum inflammatory markers

– evaluated at baseline and at end of each therapeutic phase

• Results: all 3 nutrients improved asthma control and inflammatory markers

– greater improvement when all three used together (p < 0.001)

Vitamin C for preventing and treating the common cold. Douglas RM et al. Cochrane Database

Investigating heterogeneity across studies - a review of the systematic reviews in the infectious diseases module of the Cochrane Library

Systematic Review. 2007;(3): CD000980

Hahn S et al. 7th Cochrane Colloquium, Rome 1999; 7: 65

• Cochrane review: Does vitamin C at 200 mg or more reduce the incidence, duration or severity of the common cold when used as prophylaxis or at the onset of a cold?

“In a meta-analysis of a set of trials, an important issue is whether heterogeneity of treatment effect exists between trials. In the presence of heterogeneity, pooling estimates from a series of studies without accounting for such heterogeneity can result in a misleading conclusion.”

– All known publications from 1943 analysed

• Results: High heterogeneity in methodology

– Some trial gave daily vitamin C (various doses) for periods ranging from weeks to months – Others gave vitamin C acutely only after naturally acquired cold symptoms developed – Included trials where volunteers were artificially exposed to cold viruses

Vitamin C for preventing and treating the common cold. Douglas RM et al. Cochrane Database

Vitamin C and Stress

Systematic Review. 2007;(3): CD000980

• Cortisol: released by the adrenal glands in response to stress. Excess cortisol causes

• Conclusions: Prophylaxis studies in adults and children showed a reduction in duration but not incidence • No difference in severity, but outcome measures to evaluate severity differed widely between trials • After short bursts of physical or cold stress (marathon runners, skiers) vitamin C at doses of 200 mg - 2 g/day reduced incidence of the common cold by 50%

–

BP,

blood glucose,

immune function

• Vitamin C supplements reduce cortisol-induced psychological (Psychopharmacology (Berl). 2002; 159(3): 319-24. ) and physical response to stress (Cochrane Database Syst Rev. 2007 Jul 18;(3): CD000980)

• Under stress animals that can synthesize vitamin C rapidly increase their output (5-20 fold) (Milton K. Comp Biochem Physiol A Mol Integr Physiol 2003;36(1): 47-59 )

3/15/2011 Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy

Aileen Burford Mason, PhD Vitamin C provision improves mood in acutely hospitalized patients.

Vitamin D: its role and uses in immunology Deluca HF, Cantorna MT. FASEB J. 2001;15(14):2579-85

M. Zhang, L. Robitaille, S. Eintracht, L. J Hoffer. Nutrition. 2010. Aug 4th

• Background: Vitamin C and vitamin D insufficiency are prevalent in hospitalized patients

• Review: Vitamin D receptor (VDR) is present on mature T-cells, but density is highest on the immature T-cells of thymus • Vitamin D3 can prevent or markedly suppress experimental autoimmune diseases, including

– both vitamins are linked to abnormal mood states

• Study: RCT (n=55) of vitamin C (500mg x 2/d) or vitamin D (1000 IU x 2/d) for 5-7 days • Results: C supplements ⁭increased plasma and white cell vitamin C (P < 0.0001; P = 0.014)

– – – –

– This was associated with a 34% reduction in mood disturbance (P = 0.013)

• Vitamin D increased plasma 25-(OH) D (P = 0.0004), but had no significant effect on mood

Toll-like receptor triggering of a vitamin Dmediated human antimicrobial response.

rheumatoid arthritis multiple sclerosis type I diabetes inflammatory bowel disease (Crohn’s disease, UC)

Sunlight therapy for tuberculosis – Sheffield 1905

Liu PT et al. Science 2006 311 (5768):1770-3

• Antimicrobial peptides (APs)are produced in numerous cells of the human body • APs directly and rapidly destroy cell walls of viruses and bacteria – act as naturally occurring antibiotics

• Vitamin D stimulates production of APs • In this laboratory study vitamin D- stimulated APs killed tuberculosis bacteria

Serum 25-Hydroxyvitamin D and the Incidence of Acute Viral Respiratory Tract Infections in Healthy Adults

Vitamin D and Immunity

Sabetta JR et al. PLoS One. 2010 Jun 14;5(6):e11088

• Prospective cohort study: to determine if serum 25(OH)D correlated with the incidence of acute viral respiratory tract infections

“When a T-cell is exposed to a foreign pathogen, it has an immediate biochemical reaction and extends a signaling device or 'antenna' known as a vitamin D receptor, with which it [searches] for vitamin D. This means that the Tcell must have vitamin D or activation of the cell will cease. If T-cells cannot find enough vitamin D in the blood, they won't even begin to mobilize….”

– 25-(OH)D measured in 198 healthy adults over fall and winter 2009–2010

• Results: 25-(OH)D concentration of 38 ng/ml (95 nmol/L) or more associated with a 2-fold decrease in acute URTIs (p<0.0001). – Marked reduction in % of days ill

Professor Carsten Geisler commenting on the paper Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol. 2010 Apr;11(4):344-9

Nutritional Priming and Immunity: An Orthomolecular Approach 3/15/2011 to Colds, Flu and Allergy Aileen Burford Mason, PhD Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren

Serum 25(OH)D continuum and disease protection

Urashima M et al. Am J Clin Nutr. 2010 May;91(5):1255-60

• Study: evaluated relation between vitamin D and physician-diagnosed seasonal ‘flu

Rickets

– RCT: 334 Japanese children given1200 IU vitamin D3 or placebo from Dec „08 – March ‟09 – Primary outcome: Incidence of influenza A, diagnosed by nasopharyngeal swab

• Results: Influenza A occurred in 18/167 (10.8%) on

Multiple sclerosis

100

125

Breast cancer

150

175

200

Serum 25-hydroxy D (nmol/L)

vitamin D(3) compared with 31/167 (18.6%) on placebo [RR = 0.58; 95% CI: 0.34, 0.99; P = 0.04]

– In children with asthma, attacks occurred in 2 on vitamin D(3) compared with 12 on placebo

Osteoporosis

Type 1 diabetes

Note: to convert values to ng/ml divide by 2.5

Childhood asthma may be a consequence of vitamin D deficiency

New dietary reference intakes for vitamin D Institute of Medicine 30th November 2010

Litoniua AA. Curr Opin Allergy Clin Immunol. 2009 Jun;9(3):202-7

• Reviewed approx 1000 papers on vitamin D

– Approx 28,000 papers currently in the medical literature – New papers currently appearing at the rate of 1750 new publications per year

• Review: Vitamin D plays a role in fetal lung growth and maturation –

prenatal D intake may protect against wheezing illnesses in children

• Blood levels of 25-hydroxy D of 50 nmol/L considered adequate for bone health

• Improving vitamin D status shows promise in primary prevention of asthma and in decreasing exacerbations of disease • However, the appropriate level of circulating vitamin D for optimal immune functioning remains unclear

– Conclusions regarding impact of vitamin D on CVD, cancer, other diseases awaits more “drug-style” RCTs

• No recommendations given on testing blood levels to estimate individual needs – New RDA 600 IU ( ⁭ 300%) from 1 yr – 70 years

– Same recommendations for Florida as the Yukon – New UL 4000 IU ( ⁭ 50%). 10,000 probably safe

Survey: Is IOM Wrong About Vitamin D? MedPage Today Dec 3rd 2010

“The unpredictable relationship between vitamin D intake and blood levels makes it difficult to recommend a standard supplement dose and supports incorporating measurements of blood levels into recommendations.” Goodwin PJ. J Clin Oncol 27(13):2117-9, 2009

3/15/2011 Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy

Aileen Burford Mason, PhD Zinc as Antioxidant

Zinc and Immunity

www.ars.usda.gov/is/pr/2002/021029.htm (accessed 23/05/09)

• Zinc plays numerous critical roles in immune functioning

• Subjects: 8 healthy men (27-47yrs) • Methods: Fragility of red cell membranes (an accepted measure of ROS exposure) checked in volunteers taking a diet providing the RDI for zinc (4.6 mg)

– Required for antibody production – Regulates genes involved in the immune response – Deficiency increases release of inflammatory mediators (TNF- , IL-1 , and IL-8 cytokines)

– Then rechecked after taking an extra 9.1mg for 5 weeks – Capsules then replaced with placebo for 10 weeks – Extra zinc given again for last 5 weeks

• Zinc insufficiency dysregulates intracellular pathogen killing by immune cells (Shankar AH, Prasad AS. Am J Clin Nutr. 1998;68 (2 Suppl): 447S-463S)

A meta-analysis of zinc salts lozenges and the common cold. Jackson JL et al.

Zinc as Antioxidant

www.ars.usda.gov/is/pr/2002/021029.htm (accessed 2/02/08)

Arch Intern Med. 1997;157(20):2373-6. .

• Results: Red cell membranes were significantly

• Background: The common cold is estimated to cost the USA > $3.5 billion annually • Systematic review: Meta-analysis of 10 published RCTs on zinc gluconate lozenges to treat colds

more fragile after the 10-week lower-Zn period (RDA only) – This occurred in the absence of Zn deficiency

– No attempt made to separate low vs. high dose zinc, or form of zinc in supplements

• Conclusion: Zinc protects cell membranes from damage caused by everyday oxidative stress

• Conclusion: despite numerous RCTs, evidence for effectiveness of zinc in reducing duration of colds is still lacking

– In healthy individuals, the RDA for zinc is insufficient to prevent this damage

Zinc for the common cold

Singh M, Das RR Cochrane Database of Systematic Reviews 2011, Issue 2.

Art. No.: CD001364. DOI: 10.1002/14651858.CD001364.pub3

• Cochrane review: searched for double-blind RCTs of zinc or placebo for ≥ 5d at onset of symptoms, or ≥ 5months as preventative

• Results (cont): adverse events included bad taste and nausea – More likely to be caused by zinc lozenges than syrup or tablet form

– 13 therapeutic trials (n = 966) and 2 preventive trials (n = 394) included in the review

• Comment: “more research is needed to

• Results: zinc (syrup or lozenges) reduced

determine the optimal duration of treatment as well as the dosage and formulations of zinc that will produce clinical benefits without increasing adverse effects”

– duration and severity of cold symptoms when used within 24 hours of onset – Regular use >5m reduces cold incidence, school absenteeism and antibiotic use in children

3/15/2011 Nutritional Priming and Immunity: An Orthomolecular Approach to Colds, Flu and Allergy

Aileen Burford Mason, PhD Intranasal zinc and anosmia: the zinc-induced anosmia syndrome

Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elderly adults

Alexander TH, Davidson TM. Laryngoscope. 2006;116(2):217-20

Meydani SN et al. Am J Clin Nutr. 1991;53(5):1275-80

• Study: zinc is associated with the sense of taste and smell but has a narrow therapeutic range

• Eight healthy elderly adults depleted of vitamin B6 over a 1 month period • Vitamin B6 depletion

– intranasal zinc has been used as a treatment for the common cold. Reported to cause anosmia in humans and animals

– Reduced number and % of circulating lymphocytes – Reduced proliferation in response to stimulation – Reduced interleukin 2 production

• Retrospective analysis uncovered 17 patients whose loss of smell followed use of zinc gel to head off UTRIs

• 50mg/day of B6 given for 6 days returned blood levels to baseline and normalized immune responses

– All reported sniffing deeply when applying the gel and immediate burning sensation lasting minutes to hours

• 7/17 reported that no URTI developed

Probiotics during weaning reduce the incidence of eczema. West CE et al. Pediatr Allergy Immunol. 2009 Mar 9

Probiotics in Primary Prevention of Atopic Disease. Marko Kalliomäki et al. The Lancet 2001;357:1076-79



• Probiotics help modify dietary antigens by degradation of protein macromolecules – Process is necessary for children to develop nonresponsiveness to dietary antigens



• To regulate the development of allergy treatment with probiotics must begin in infancy, and preferably at the first encounters with dietary antigens

Study: Evaluated Th1/Th2 balance and eczema incidence in infants given probiotic (Lactobacillus F19) during weaning Methods: infants fed cereals with (n = 89) or without probiotic (n = 90) from 4-3 m At 13m eczema incidence was 11% in probiotic vs. 22% in placebo group (p < 0.05) –

Prevention Protocol

This was associated with a favourable shift in Th1/Th2 balance but no differences in serum IgE between groups

Acute Treatment (colds and flu)

colds, flu and allergy

• Additional vitamin C

• Daily full spectrum multivitamin

– 500mg mid-morning, mid-afternoon and before bed

– Minimum of 25mg of vitamin B6; 15 mg zinc

• Vitamin C (time released)

• Additional B-vitamins

– 1g (1000mg) twice daily

– B-complex 50 with dinner

• Vitamin D (drops or pills)

• Zinc lozenges: low dose (5-8mg)

– Test 25-hydroxy D and supplement to achieve blood levels >150 nmol/L (60 ng/ml)

– Suck one at the first sign of a cold or sore throat – Do not exceed maximum dose (6-8 in 24 hrs or 40mg) – Stop when you begin to hate the taste OR you feel nauseous after taking

• Daily fish oil supplement

– 750mg EPA/500mg DHA

• Magnesium (protein or amino acid bound) – Minimum 100mg (elemental) daily

• Daily probiotics (from food or supplements)

The GABA- Receptors and the Etiology of Anxiety Phyllis Bronson, PhD GABA, The GABAA receptor and the ETIOLOGY of Anxiety

One molecule only

Some people get anxious, some do not • Naturally occurring benzodiazepines in the brain act as regulators at GABAA receptor • BDZ benzodiazepines and barbiturates bind to GABAA receptors at different sites than GABA itself • Principal effect = change in Clconductance

Throughout the brain and nervous system billions of cells communicate with each other through chemical messengers called neurotransmitters. Some carry orders for muscle movement, and some specialize in emotional responses like excitatory and inhibitory feelings.

Transmitters can have two effects at synapses • One is to open or close ionic channels

GABA is the most widely distributed inhibitory neurotransmitter in the brain.

• The other is to trigger a change in rate of chemical reaction

GABA helps keep the brain calm and orderly, but prolonged Stress, Anxiety or Fear can deplete GABA reserves opening the way for a flood of alarm messages.

The GABA- Receptors and the Etiology of Anxiety Phyllis Bronson, PhD

Inhibitory neurons act like reins that keep neuronal “horses” in check

Transmitters such as glutamate, GABA, and acetylcholine trigger changes in electrical potential of receiving cell.

• Coherent behavior depends on the brain not over-firing messages.

This can lead to more excitation or inhibition depending on nature of transmitter.

• This inhibition is obtained by neurons controlled by local GABAergic neurons and projection neurons from neural command posts.

Glutamate w/o enough GABA feels like Too much coffee.

• GABA is synthesized in GABAergic neurons through the decarboxylation of L-glutamic acid by the enzyme glutamic acic decarboxylase. • GABAA receptors are linked to a gated chloride ion channel • Benzodiazepines bind to a specific receptor located on the same macromolecular protein complex as the GABAA receptor and act by increasing chloride ion conduction of endogenous GABA at this receptor.

The GABA- Receptors and the Etiology of Anxiety Phyllis Bronson, PhD

There is no new GABA There is one GABA GABA is not chiral Is not rotatory Synthesized safely from Pyrrolidone

GABA • no asymmetric center • is not chiral

Asymmetric • Having no balance or symmetry • Carbon atom with four different atoms or structural groups Resulting in unbalanced spatial shape so that molecule cannot be superimposed on its mirror image

The GABA- Receptors and the Etiology of Anxiety Phyllis Bronson, PhD Neurosteroid Neurosteroid Effects in the Central in the Effects Nervous System Central Nervous System

Pharmacology Five :

Gabapentin was initially synthesized to mimic the chemical structure of the GABA neurotransmitter, but is not believed to act on the same brain receptors. Its exact mechanism of action was recently discovered by Prof. Ben Barres of Stanford University. The results were published 8 Oct 2009 in The Cell. The study shows that gabapentin halts the formation of new synapses.

Allopregnanolone • Allopregnanolone is potent modulator of GABA receptor • Progesterone breaks down into allopregnanolone - in men and women • Increase in neuronal excitability dependent on upregulation of alpha-4 subunit of GABA S.Smith,Ph.D

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD Vitamin B12 -‐ Cobalamin

•  B12/cobalamin is the only nutrient with a 50 year history of medical use as an established injectable treatment, a treatment equally notable for its absence of nega4ve side-‐eNects.

The Importance of Micronutrients in Au4sm

•  From the 1960’s thru the 1990’s (and to a lesser extent, in the current decade), B12 injec4ons were a well-‐documented ﬁrst line of treatment for many neurological and psychiatric disorders.

Joan Jory, MSc, PhD, RD

•  Today, pharmaceu4cal medica4ons are the ﬁrst line of treatment,

even in children, with signiﬁcant well-‐documented nega4ve sequelae.

B12 Deﬁciency in Adults

•  Professional guide to diseases, 1989. Springhouse Corp, Springhouse, PA. •  MacDonald Holmes, J. BMJ 1956; Dec 15.

Signs and Symptoms of B12 deﬁciency:

•  The cerebral symptoms may be classiﬁed as mental and ophthalmological.

•  Altered or decreased growth of all cells… (pancytopenia), •  poor oxygen-‐carrying capacity

•  The mental symptoms are extremely variable and include mild disorders of mood, mental slowness, memory defect,..

•  decreased myelin forma4on, impairing neurological func4on

•  Confusion, severe agita4on and depression, delusions, paranoid behaviour, visual and auditory hallucina4ons, urinary and faecal incon4nence, .. dysphasia, violent maniacal behaviour and epilepsy.

•  increased suscep4bility to infec4on •  gastric mucosal atrophy, disturbed diges4on, nausea, anorexia, diarrhea, cons4pa4on.

•  In the absence of anemia,… B12 deﬁciency may never be considered un4l the psychosis is far too advanced to respond to treatment.

B12 Deﬁciency in Children

•  B12 (cobalamin) is essen4al to the integrity of the myelin sheath covering every nerve in the body.

•  Dror DK and LH Allen. Nutr Rev 2008; 66(5): 250-‐5.

•  Severe vitamin B12 deﬁciency produces a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia and developmental regression, which respond remarkably rapidly to supplementa4on.

•  Zarly onset infan4le B12 deﬁciency is associated with insuﬃcient myelina4on, impaired neurological development and, occasionally, death.

•  The underlying mechanisms may involve delayed myelina4on or demyelina4on of nerves, altera4on in the S-‐adenoysylmethionine:S-‐ adenosylhomocysteine ra4o, imbalance of neurotrophic and neurotoxic cytokines, and/or accumula4on of lactate in brain cells.

•  Later onset B12 deﬁciency is a pernicious demyelina4on disorder associated with a vast array of neurological symptoms, many of which overlap with the development, neurological and behavioural symptoms associated with the au4s4c spectrum.

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD B12 Deﬁciency in Children

B12 Deﬁciency in Children

•  Hall CA. Am J Hematol 1990; 34(2):121-‐7.

•  Biancheri et al. Neuropediatrics 2001; 32 (1): 14-‐22.

•  The 13 cases of methylcobalamin deﬁciency presen4ng in early infancy have all been developmentally delayed, and the majority have had seizures, hypotonia, lethargy, and microcephaly.

•  Early onset subtype of cobalamin deﬁciency is characterised by feeding di[cul4es, failure to thrive, hypotonia, seizures, microcephaly and developmental delay.

•  A) The slow improvement in psychomotor status ader years of treatment with cobalamin may be related to the eventual myelina4on.

•  In 11E14 pa4ents (`Qa), there was selec4ve white maber atrophy shown by both neuroradiologic and neurophysiological studies. •  Mental retarda4on was present in most pa4ents, possibly mediated through a reduced supply of methyl groups

•  B) However, the hypotonia, lethargy and impaired responsiveness react to treatment with cobalamin within 24-‐48 hours which suggests an eUpression of MeCbl deﬁciency on the CgS dis4nct from the delayed myelina4on.

B12 Deﬁciency in Children

•  Lucke T el al. Z Geburtshilfe Neonatol 2007; 211(4): 157-‐61.

•  Osifo BO et al. J Neurol Sci 1985; 68(2-‐3) 185-‐90

•  Symptoms of vitamin B12 deﬁciency in infancy include growth retarda4on, regression of psychomotor development, muscular hypotonia and brain atrophy.

•  Folate and B12 parameters were studied in the serum and CSF of 40 febrile paediatric pa4ents, compared to controls. •  18 were in convulsion, 22 were non-‐convulsing, at 4me of study.

•  B12 deﬁciency can easily be diagnosed by detec4on of methylmalonic acid.

•  Serum folate was higher in convulsers than controls, highest during seizues

•  The neurological symptoms of vitamin B12 deﬁciency are only par4ally reversible.

•  Serum B12 was lower in convulsers than controls; lowest during ac4ve convulsions.

E4ology of B12 Deﬁciency i Maternal Status

E4ology of B12 Deﬁciency i Maternal Status •  Smolka V et al. Cas Lek Cesk 2001; 140(23): 732-‐5.

•  13 month daughter of B12 deﬁcient mother revealed psychomotor retarda4on, apathy, muscular hypotonia, abnormal movements and failure to thrive, low B12 and high MMA.

•  The e4ology of pediatric B12 deﬁciency is likely mul4factorial (like au4sm), but one of the strongest determinants of childhood B12 status is the B12 status of the mother during pregnancy.

•  MRI of the brain revealed diﬀuse frontotemporoparietal atrophy and retarda4on of myelina4on.

•  Jones et al. J Nutr 2007; 137(5): 1307-‐13.

•  In linear regression, infant plasma B-‐12 concentra4on was strongly and posi4vely associated with maternal plasma vitamin B-‐12 and with maternal B-‐12 intake from complementary foods (Guatemala)

•  8 month son of B12 deﬁcient mother demonstrated psychomotor retarda4on, hypotonia, dyskinesia, failure to thrive and microcephaly, high MMA and tHcy. •  Ader vitamin B12 interven4on, biochemical and metabolic markers of disease were normalized BUT the generalised hypotonia, microcephaly and language delay remained.

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD Z4ology of B12 :eﬁciency i Maternal 8tatus

Z4ology of B12 :eﬁciency i Maternal 8tatus

•  Bhate V et al. Food Nutr Bull 2008; 29(4): 249-‐54.

•  Maternal B12 status will be aﬀected by: -‐ dietary red meat and egg intake -‐ absorp4on or transport disorders of B12 -‐ gene4cs (family history of pernicious anemia), -‐ exposure to medica4ons which deplete B12 status or block %ntrinsic-‐Factor-‐mediated B12 absorp4on (birth control, antacids, etc) .

•  %nves4ga4on of the rela4onship between maternal vitamin B12 status during pregnancy and the child s cogni4ve func4on at Q years of age. •  Children from mothers with the lowest B12, compared to those with the highest B12, performed more slowly in tests of sustained aben4on and short-‐term memory, ader adJustment for confounders. •  Maternal vitamin B12 status in pregnancy inluences cogni4ve func4on in oﬀspring, and these inluences persist beyond infancy.

Z4ology of B12 :eﬁciency i Maternal 8tatus

Z4ology of B12 :eﬁciency -‐ Folate

•  Volkov et al. Ann Nutr Metab 2007; 51(5): 468-‐70.

•  eowever, there is an addi4onal factor in the e4ology of maternal and pediatric B12 deﬁciency: excess folate intake through a decade of intense food for4ﬁca4on combined with high intakes of folate-‐rich-‐ mul4vitamins.

•  3s a result of media informa4on associa4ng meat, cholesterol and cardiovascular disease, consump4on of meat, par4cularly beef, has decreased.

•  Folate for4ﬁca4on and maternal supplementa4on was a public health ini4a4ve aimed at reducing folate-‐deﬁciency neural tube defects at a 4me when popula4ons were ea4ng large amounts of red meat (B12-‐ rich) but few fruits and vegetables (folate-‐rich).

•  %n addi4on to changes in lifestyle among those of high socioeconomic status, the existence of poverty is a second main factor in the decreasing consump4on of animal products •  Together, these factors have contributed to: -‐ a decrease in the level of vitamin B12 in the general popula4on, -‐ an increase in pathology due to vitamin B12 deﬁciency.

•  The ini4a4ve was also an4cipated to have a posi4ve impact on folate-‐ dependent cancers of the colon and cervix.

Z4ology of B12 :eﬁciency -‐ Folate

•  Ray et al. Clin Biochem 2003; 36(5): 387-‐91.

•  Selhub et al. Proc Natl Acad Sci USA 2007; 104(50): 1995-‐20000.

•  Using combined provincial data from Ontario, the mean serum folate concentra4on increased by R_a ader for4ﬁca4on between 1QQR and 2000.

•  3 recent study of older par4cipants in the 1QQQ-‐2002 ge3gZ8 survey demonstrated a combina4on of high serum folate and low vitamin B12 status which was associated with a high pre(alence of cogni/(e impairment and anemia than other combina4ons of vitamin B12 and folate status.

•  The prevalence of combined B12 insuﬃciency with supraphysiological concentra4ons (super-‐high) of serum folate increased ader folate for4ﬁca4on.

•  %n subJects with lower serum vitamin B12, concentra4ons of homocysteine and methylmaloninc acid (associated with B12 deﬁciency) increased as serum folate levels increased, sugges4ng a worsening of B12 status with increasing folate intake.

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD B12 and Folate

B12 and Folate

•  %ni4al response to the folate-‐suppor4ng ini4a4ves was indeed posi4ve, with rates of neural tube defects and several cancers declining.

•  Jory, Joan…. Unpublished data

•  55 children clinically diagnosed with au4sm spectrum disorder

•  eowever, the current environment of massive oversupplementa4on and overfor4ﬁca4on with folate, while intake of red meat and eggs is falling, has precipitated a crisis in the folate-‐B12 equilibrium.

•  RBC folates were > 1000 in 81.8% (45/55)

•  Consequently, there has been a recent resurgence in neural tube defects, caused by acquired B12 deficiency. •  \eading researchers are now promo4ng co-‐for4fica4on with B12 and/ or arguing for lower doses of folate in supplements and for4fied foods

B12 and Neural Tube Defects

•  Ray et al. QJM 2008; 101(6): 475-‐7..

•  Ray JG et al. Epidemiology 2007; 18(3): 362-‐6.

•  Vitamin B12 deﬁciency may be an independent risk factor for neural tube defects (NTD)

•  89 women with NTD and 422 pregnant controls (Ontario) •  There was almost a tripling in the risk for NTD in the presence of low maternal B12 status, as measured by holotranscobalamin.

•  …determined the prevalence of biochemical B12 deﬁciency (<125 pmol/l) among 10,622 Ontarian women 15-‐46 years, 9 years ader implementa4on of Canadian folic acid lour for4ﬁca4on.

•  Molloy AM et al. Pediatrics 2009; 123(3): 917-‐23.

•  Mothers of children with NTD had signiﬁcantly lower B12 status. •  Those in the lowest B12 quar4le, compared with the highest, had between two and threefold higher adJusted odd ra4os for being the mother of a child with NTD. •  9regnancy B12 concentra4ons <250 ng/l were associated with the highest risk. •  We suggest that women have B12 levels >300 ng/l before becoming pregnant.

•  Biochemical B12 deﬁciency was 0.78 for pregnancy <28 days and 1.4 >28 days pregnancy. •  About 1 in 20 women may be deﬁcient in B12 in early pregnancy.

B12 Deﬁciency -‐ Assessment

•  Folate for4ﬁca4on and/or supplementa4on can both mask and exacerbate subclinical B12 deﬁciency, and contribute to progressive nerve demyelina4on.

•  Aaron S et al. Neurol India 2005; 53(1): 55-‐8.

•  Johnson. Nutr Rev 2007; 65(10): 451-‐458. •  There is concern that high intakes of folic acid from for4ﬁed food and dietary supplements might mask the macrocy4c anemia of vitamin B12 deﬁciency, thereby elimina4ng an important diagnos4c sign.

•  63 pa4ents over three years with B12 deﬁciency-‐related neurological syndrome.

•  Normal CBC, MCV and serum B12 levels, in countries with Food Folate For4ﬁca4on, are NOT diagnos4c of normal B12 and do not exclude B12 suﬃciency.

•  A normal hemoglobin or MCV does not exclude B12 deﬁciency.

•  All pa4ents had megaloblas4c changes in the bone marrow but both hemoglobin and mean cell volume were within normal range among 17.5%.

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD B12 Deﬁciency -‐ Assessment

B12 and Hematology

•  J Neurol 2010; Oct 2 (epub)

•  •  •  •

<alida4on study for serum B12 and holotranscobalamin. Standardized against MMA (methylmalonic acid) 12`Q inpa4ents with clinical neuropsychiatric symptoms and B12 defy Neither test (serum B12 or holotranscobalimin) can be recommended to diagnose B12 deﬁciency in subjects with neuropsychiatric disorders

•  Maamar M et al. Rev Med Interne 2006; 27(6): 442-‐7.

•  2R pa4ents with neurological manifesta4ons of B12 deﬁciency. •  Eight had macrocy4c anemia, nine had bi-‐cytopenia, and eight had severe pancytopenia.

•  J Inherit Metabol Dis 2010; May 27 (epub)

•  9a4ents with neurological symptoms had signiﬁcantly higher platelet counts and hemoglobins than those without neurological symptoms.

•  Even moderate B12 deficiency in children may be harmful •  Neurological deteriora4on may persist ader treatment •  B12 deficiency should be considered a differen4al diagnosis in children with subtle symptoms

B12 and Hematology

B12 and Hematology •  Teplitsky V et al. Isr Med Assoc 2003; 5(12): 868-‐72.

•  Simsek OP et al. J Pediatr Hematol Oncol 2004; 26(12): 834-‐6.

•  Four genera4on family (nq2c) with hereditary transcobalamin deﬁciency.

•  1R month infant with nutri4onal vitamin B12 deﬁciency. •  Holotranscobalamin was low in all family members. •  9resen4ng symptoms include developmental regression, severe pancytopenia, excessive skin pigmenta4on and tremor.

•  Neurological symptoms included dyslexia, decreased Ir, ver4go, and personality disorders.

•  Serum B12 levels were low with increased urinary methymalonic acid. •  Aﬀected children and adolescent had normal or slightly decreased serum B12 levels but no anemia.

•  B12 therapy reversed the pancytopenia, tremor and hyperpigmenta4on but the neurological regression did not completely resolve.

•  Decreased B12 levels, anemia and ANS degenera4on did not occur un4l adulthood

B12 and Immunity

B12 and Gastroenterology

•  Takimoto G et al. Int J Tissue React 1982; 4(2): 95-‐101

•  B12 in the in-‐vitro system enhances an4body produc4on •  Of all the B12 homologues, methyl B12 had the strongest effect, nearing the efficacy of Levamisole. •  B12 also exerts an enhancing ac4vity on the induc4on of suppressor ! cells. •  Methyl B12 has a therapeu4c effect against spontaneous incidence of diseases.

•  B12 is the only nutrient which cannot be passively absorbed. •  B12 is the only nutrient known to man which requires a co-‐factor (Intrinsic Factor) for facilitated absorp4on through the GI tract. •  So, B12 for4ﬁca4on and oral supplementa4on will not be eﬀec4ve if there are problems with Intrinsic Factor produc4on, the rate-‐limi4ng step in B12 absorp4on.

•  Sakane T et al. J Clin Immunol 1982; 2(2): 101-‐9

•  Methyl B12 was suﬃcient to enhance the ac4vity of helper ! cells for immunoglobulin synthesis. •  Methyl B12 could modulate lymphocyte func4on through augmen4ng regulatory !-‐cell ac4vi4es.

•  Intrinsic factor produc4on may be adversely aﬀected by gene4cs (pernicious anemia), gastrointes4nal disease or dysfunc4on, pharmaceu4cal medica4ons.

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD B12 and Gastroenterology

B12, Gastroenterology and Au4sm

•  Wakeﬁeld et al. Lancet 1998; 351(9103): 637-‐641.

•  To compound the problem, established B12 deﬁciency causes atrophy of the gastric mucosa, the very site of Intrinsic Factor produc4on.

•  12 children with regressive pervasive developmental disorder (PDD) and chronic enterocoli4s.

•  This effec4vely disables Intrinsic-‐Factor-‐facilitated B12 absorp4on from supplements or for4fied foods, and perpetuates the B12 deficiency ‘in a sea of plenty’.

•  Urinary methylmalonic acid (MMA) signiﬁcantly higher among children with PDD than controls (p<0.003). •  Low haemoglobin among 33% of children with PDD

•  Further, B12-‐deficiency-‐mediated gastric mucosal atrophy lays the groundwork for significant gastrointes4nal abnormali4es which in turn alter the absorp4on of mul4ple micronutrients with resultant effects on immunity, hematology, etc.

B12 in Au4sm

•  Pasca SP et al. Life Sci. 2006; 78(19): 2244-‐8.

•  It is highly likely that B12 supplementa4on, through inJec4on, sublingual and/or transdermal administra4on, should remain a ﬁrst line of treatment in au4sm, in pediatrics and adults, as well as other neurological or psychiatric disorders, where suﬃcient iron stores exist to support the subsequent erythropoeisis.

•  12 children with au4sm and 9 controls (mean age 8.3) •  Homocysteine levels (p<0.01) –  au4sm 9.83 +/-‐ 2.75 mumol/L –  controls 7.51 +/-‐ 0.93 mumol/L •  Homocysteine and subop4mal B12 levels had a strong nega4ve correla4on among children with au4sm.

Iron Deﬁciency

Iron Deﬁciency in Children

•  Iron deﬁciency is therefore synonymous with chronic hypoxia, and is associated with decreased neurological development.

•  Iron is required as a cofactor for many reac4ons in the body.

•  In the pediatric brain, the neurological consequences of low iron status may be only par4ally reversible.

•  Perhaps most notably, heme iron is the carrier molecule for oxygen in the blood. •  Without adequate iron, there is inadequate transport of oxygen to the brain, the lungs, the heart and the muscles.

•  Beard & Connor. Annu Rev Nutr 2003; 23: 41-‐58

•  Iron deﬁciency in early life is associated with delayed de(elo%0ent=. which %ersists== a?er iron thera%y has corrected iron status.

•  8ubop4mal iron status leads to poor oxygena4on of the brain with abendant consequences to neurological func4on and development.

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD Iron Deﬁciency in Children

Iron Deﬁciency -‐ Assessment

•  Beard JL. J Nutr 2008; 138 (12): 2534-‐6

•  Infants who experience iron deﬁciency during the ﬁrst 6-‐12 months are likely to experience persistent eNects …that alter func4oning in adulthood.

•  Diagnos4cally, neither hemoglobin nor hematocrit are speciﬁc for iron deﬁciency.

•  A lack of iron may signiﬁcantly delay the development of the central nervous system as a result of altera4ons in morphology, neurochemistry and bioenerge4cs.

•  Low hemoglobin and hematocrit also reflect folate and B12 deficiencies. •  Only serum ferri4n levels are specific to iron status in the body.

•  ;odent studies show eNects of iron deﬁciency during gesta4on and lacta4on that persist into adulthood despite restora4on of iron status at weaning.

•  Low iron status in children, as measured by serum ferri4n, is indica4ve of a need for increased iron intake through food or supplements (or, rarely, of blood losses).

•  …indica4ng that gesta4on and early lacta4on are cri4cal periods when iron deﬁciency will result in long-‐las4ng damage.

Iron Deﬁciency -‐ Assessment

Iron Deﬁciency and Development

•  However, it is also possible to have adequate or high ferri4n stores in the presence of low transferrin satura4on, because of impaired abachment of iron to the red blood cells – a cobalamin (B12)-‐ dependent mechanism.

•  Shaﬁr T et al. Early Hum Dev 2008; 84 (7): 479-‐85.

•  77 infants: 28 IDA, 28 non-‐anemic ID, 21 iron suﬃcient •  Comprehensive assessment found poorer motor func4on in iron deﬁciency with and without anemia. •  Poorer motor func4on in ID is par4cularly concerning since ID is NOT detected by common screening procedures.

•  Therefore, assessment must include serum ferri4n and transferrin satura4on, as well as a CBC, to fully determine the adequacy of iron-‐ mediated oxygen delivery in the au4s4c child. •  Arch Lacnoam Nutr 1999; 49 (3-‐Supp 2): 11S-‐14S

•  Carter RC et al. Pediatrics 2010; 126 (2): e427-‐434.

•  The op4mal combina4on of laboratory measurements for detec4ng Iron Deﬁciency Anemia is:

•  49 infants at 9 and 12 months: 28 IDA, 28 NA-‐ID, 21 IS •  Poorer object permanence, short term memory encoding and/or retrieval in infants with IDA.

–  Hemoglobin –  Serum ferri4n –  Serum transferrin (transferrin satura4on)

Iron Deﬁciency and Behaviour

•  Sever Y et al. Neuropsychobiology 1997; 35(4): 178-‐80.

•  •  •  •

•  Konofal et al. Arch Pediatr Adolesc Med 2004; 158(12): 1113-‐5

14 non-‐anemic Israeli boys with ADHD (7-‐11 years) Ferrocal @ 5mg/kg/day x 30 days. Ferri4n increase 25.9 +/-‐ 9.2 to 44.6 +/-‐ 18 ng/ml Connor ;a4ng Score decrease 17.6 +/-‐ 4.5 to 12.7 +/-‐5.4.

•  53 Children w ADHD; 27 Controls; 4-‐14 years

•  Konofal E et al. Pediatrics 2005; 116(5): 732-‐4.

•  3 year old French child with hyperac4vity, AD, impulsivity and sleep problems •  Connor Teacher and Parent ;a4ng Scale 30 and 32 resp. •  Ferrous sulfate 80 mg/d x 8 months •  Serum ferri4n increase from 12 to 102 ng/ml •  Connor ;a4ngs decrease to 19 and 13 resp.

•  Children with ADHD

-‐ ferri4n o 30 ng/ml in 84% -‐ mean 23 +/-‐ 13 ng/ml

•  Control Children

-‐ ferri4n o 30 ng/ml in 18% -‐ mean 44 +/-‐ 22 ng/ml

•  Low serum ferri4n significantly correlated with severity of Connor ADHD ra4ng scale (po0.02) and cogni4ve deficits (po0.01). •  Iron deficiency causes abnormal dopaminergic neurotransmission and may contribute to the physiopathology of ADHD.

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD Iron Deﬁciency, Neurofunc4on and Sleep

Iron Deﬁciency and Sleep

•  Bokkala et al. Pediatr Neurol 2008; 39(1): 33-‐39

•  77 children with periodic limb movements of sleep. •  Serum ferri4n was decreased in 96.6%

•  Peirano PD et al. J Pediatr Gastronenterol Nutr 2009; 48 S1: S8-‐S15

•  An es4mated 20-‐25% of the world s infants have IDA with at least as many having iron deﬁciency without anemia.

•  Dosman et al. Pediatr Neurol 2007; 36(3): 152-‐8.

•  Follow-‐up studies point to long-‐las4ng diNerences…despite 1 year of iron therapy…including slower neural transmission in the auditory and visual systems, diNerent motor ac4vity paberning in all sleep-‐waking states, and several diNerences in sleep states organi^a4on.

•  33 children •  8 week open trial of oral iron supplementa4on •  77% had restless sleep at baseline

•  Signiﬁcant increase in serum ferri4n (16 to 29 mcg/L) •  Signiﬁcant improvements in Sleep Disturbance Scale.

Iron in Au4sm

•  Eac9 et al. Cucsm. 2002; 6(1): 103-‐4

•  Jory, Joan….. Unpublished data

•  Children with clinically diagnosed au4sm spectrum disorder, assessed through provincial medical labs.

•  52 children with Au4sm -‐ 12% with anemia -‐ 52% with low ferri4n

•  Serum ferri4n < 20 = 27.6% (21/76) •  Serum ferri4n < 30 = 57.9% (44/76)

•  44 children with Aspergers Syndrome -‐ 5% with anemia -‐ 14% with low ferri4n

•  Serum iron < 11 = 52.6% (10/19) •  Iron Satura4on< 25 = 44% (8/18)

Iron Deﬁciency i E4ology

Decreasing Iron Content of Food Select Summary of Changes in the Mineral Content of Vegetables, Fruit and Meat Between 1940 and 1991

•  Low iron stores are likely related to one of several mechanisms: •  Low maternal iron stores during pregnancy will predispose the developing fetus to subop4mal iron status at birth and thereader. •  Secondly, the self-‐restricted diets of au4s4c children with food adversi4es are very low in dietary iron sources such as red meat and eggs. •  Many families who are restric4ng adult intakes of red meat and eggs for cholesterol reasons, are also restric4ng these foods in their children ….without reali^ing the essen4ality of these dietary iron sources to pediatric health and development.

Year of Analysis Mineral

Vegetables Fruit

Meat

1991

(Na)

Less 49%

Less 29%

Less 30%

1991

(K)

Less 16%

Less 19%

Less 16%

1991

(P)

Plus 9%

Plus 2%

Less 28%

1991

(Mg)

Less 24%

Less 16%

Less 10%

1991

(Ca)

Less 46% Less 16%

Less 41%

1991

(Fe)

Less 27%

Less 24%

Less 54%

1991

(Cu)

Less 76%

Less 20%

Less 24%

•

Data obtained from 'The Chemical Composition of Food' published in 1940 by the Medical Research Council were compared with later updated editions including the 5th edition entitled 'Composition of Food' published in 1991under the auspices of the Royal Society of Chemistry and the Ministry of Agriculture Fisheries and Foods.[McCance and Widdowson 1940 1st Edition The Chemical Composition of Foods published by Medical Research Council: Special Report Series No: 235; McCance and Widdowson 1991 5th Edition The Composition of Foods Published by RSC/MAFF] ( http://www.mineralresourcesint.com/docs/research/caseneed_dthomas.pdf)

•  Finally, the iron content of food has decreased drama4cally:

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD Zinc Deﬁciency in Children

Zinc Deﬁciency -‐ Z4ology

•  Many children on the au4s4c spectrum have impaired appe4te, altered taste percep4on, and very limited dietary preferences. •  The self-‐limited diet of many ASD children precludes intake of zinc-‐ rich foods such as red meat, ﬁsh, organ meats and eggs.

•  Shay & Mangian. J Nutr 2000; 130 (5S): 1493S-‐9S •  Prasad AS 2009; 28(3): 257-‐65

•  Zinc is essen4al to more than 200 reac4ons in the body. •  Zinc is necessary for the immune system, growth, lean 4ssue development, bone and tooth integrity, neurological development, behaviour, appe4te and taste bud integrity, diges4ve enzyme produc4on and release

•  Hence, zinc deﬁciency in au4sm can be secondary to self-‐imposed dietary restric4ons. •  However, family intakes of zinc-‐rich foods may also be limited because of public health recommenda4ons to restrict intake of : –  red meat and eggs for cholesterol reasons –  ﬁsh because of the risk of heavy metals and toxins

•  Children with low zinc status may present with lowered immunity, poor muscle development, altered height development, decreased appe4te, decreased range of foods, predisposi4on for carbohydrate-‐ rich foods, diges4ve disorders esp diarrhea.

Zinc Deﬁciency -‐ Z4ology

Zinc -‐ Assessment

•  Low maternal zinc status prior to concep4on and during pregnancy leads to subop4mal zinc status in the fetus. •  Food Nutr Bull 2007; 28 (3 Supp): S403-‐29

•  If maternal zinc intake from foods is compromised in women preconcep4on and during pregnancy, zinc deﬁciency may be present in the child at birth.

•  Serum zinc can be considered a useful biomarker of a popula4on s risk of zinc deﬁciency and response to zinc interven4ons

•  Further, birth control pills widely used in western socie4es cause secondary zinc deple4on.

•  It may not be a reliable indicator of an individual zinc status.

•  Therefore, many women may be entering pregnancy with depleted zinc stores, regardless of zinc intakes from food. •  A child born with low zinc status will have decreased appe4te and a compromised immune status, crea4ng a vicious cycle loop of poor food intake and ill health.

Zinc -‐ Anorexia, Altered Intake

Zinc – jrowth and =ody Composi4on •  Cesur Y et al. J Pediatr Endocrinol Metab 2009; 22(12): 1137-‐43

•  Rains & Shay. J Nutr 1995; 125(11): 2874-‐9

•  Zinc reple4on increased food intake, and increased protein intake by 50%.

•  •  •  •  •  •

•  Jing et al. Biol Tace Elem Res 2007; 115(2): 187-‐94

•  _annoe LL et al. Am J Clin Nutr 2008; 88(1): 154-‐60

•  It has been known for more than 50 years that zinc deﬁciency regularly and consistently causes anorexia (loss of appe4te)

•  •  •  •

Zinc deple4on decreased food intake but increased carbohydrate

intake among rats.

•  Deﬁciency of zinc also produces several pathological disorders and abnormali4es in its metabolism, such as poor e[ciency of growth and growth retarda4on

29 children (11f; 18m), 11 +/-‐ 3.1 years Idiopathic growth retarda4on IjF and IjF=9 before and ader 50 mg Zn/d x 2 months Low IjF/IjF=9 in 96% prior to Zn supplementa4on Signiﬁcant increase in IjF, IjF=9 ader Zinc Signiﬁcant correla4on with bone age

9renatal zinc supplementa4on of 1295 9eruvian women Supplement: 15 mg Zn/d through pregnancy -‐> 1 month postnatal 546 babies followed for 12 months Signiﬁcantly higher levels of weight, chest circumference, calf circumference and calf muscle area among children of zinc-‐ supplemented mothers.

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD Zinc and Immunity

Zinc and Diges4on in Au4sm

•  Wintergerst ES et al. Ann Nutr Metab 2006; 50(2): 85-‐94 •  Zinc undernutri4on was shown to impair cellular mediators of innate immunity such as phagocytosis, natural killer cell ac4vity, …

•  Zinc is an essen4al component of the enzymes necessary for protein diges4on. (9rasad & Oberleas, 1971) •  The secre4on of the enzymes by the pancreas is also a zinc-‐ dependent process (Mills et al, 1969)

•  Adequate intakes of zinc (up to 30 mg) ameliorate symptoms and shorten the dura4on of respiratory tract infec4ons,… reduce the incidence and improve the outcome of pneumonia, malaria and diarrhea,…..

•  The byproducts of casein and gluten maldiges4on are opioid pep4des know as casomorphine and gliadomorphine •  Elevated levels of these opioids have been documented in the urine of children and adults with au4sm (Reichelt & Knivsberg, 2003, Shabock et al, 1990), and can cross the blood-‐brain barrier (Gao et al, 2000)

•  Bao S et al. Am J Physiol Lung Cell Mol Physiol 2010; 298 (6): L744-‐54

•  Animal model of lung infec4on •  Zinc deﬁciency increased bacterial burden and NF-‐kappaB ac4vity leading to sepsis, inlamma4on, lung inJury and mortality •  Zinc supplementa4on prior to sepsis reversed these ﬁndings.

•  The enzyme necessary for degrading these opioids, dipep4dyl pep4dase (D99 I<), is zinc dependent.

Zinc and Neurotransmibers

Zinc and Behaviour

•  Yorbik O et al. Turk Psikiyatri Derg 2004; 15(4): 276-‐81.

•  •  •  •

Johnson S. Med Hypotheses 2001; 56(5): 641-‐645. Serotonin is an essen4al precursor to melatonin synthesis. Serotonin synthesis requires zinc-‐dependent enzymes. Zinc deﬁciency may therefore limit the produc4on of both serotonin and melatonin.

•  •  •  •

21 boys with opposi4onal deﬁance disorder (ODD) (mean age 8.6) 24 controls (mean age 8.3). 61% of ODD had comorbid ADHD plasma zinc was signiﬁcantly lower in ODD children (p<0.05)

•  Arnold, LE et al. J Child Adolesc Psychopharmacol 2005; 15(4): 628-‐36.

•  Wallwork JC et al. J Nutr. 1982; 112(3): 514-‐519. •  In the rat model, zinc deﬁciency is associated with signiﬁcant increases in brain norepinephrine, an important neurotransmiber.

•  48 children with ADHD, aged 5-‐10 years. •  Serum zinc levels highly correlated with parent-‐teacher ra4ngs of inaben4on (p<0.004).

Zinc and Behaviour

Zinc in Au4sm

•  Bilici M et al. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28(1): 181-‐90.

•  Jory J and WR McGinnis. Am J Biotech and Biochem 2008; 4(2): 101-‐104

•  72 f and 328 m with ADHD; mean age 9.6 years •  Randomized to 150 mg Zn sulfate/d or placebo. •  Zinc group was sta4s4cally superior in reducing hyperac4ve, impulsive and impaired socializa4on symptoms but not reducing aben4on deﬁcits.

•  20 children with au4sm •  RBC Zn = 134±23 p<0.08

15 control children RBC Zn=148±17

•  Xia W et al. Eur J Pediatr 2010; 169 (10): 1201-‐1206.

•  Uckardes Y et al. Acta Pediatr 2009; 98 (4): 731-‐736.

•  111 Chinese children with au4sm, 2-‐9 years. •  3 day dietary recall record •  100% of children had zinc intakes below the DRI.

•  218 children with hyperac4vity •  15 mg zinc/day supplement or placebo syrup •  10 week study, Connor Ra4ng Scale •  Clinically signiﬁcant decrease in aben4on deﬁcit and hyperac4vity scores in zinc supplemented group

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD Selenium and Immunity

Selenium and Detoxiﬁca4on •  Schrauzer GN. Crit Rev Biotechnol 2009; 29(1): 10-‐7

•  Shrimali RK et al. J Biol Chem 2008; 283(29): 20181-‐5.

•  Selenium has an4oxida4ve, an4mutagenic, an4viral and an4carcinogenic proper4es.

•  Selenium is an essen4al dietary element with an4oxidant roles in immune regula4on.

•  An important property of selenium is its interac4on with other elements.

•  Selenium is incorporated into the amino acid selenocysteine, which fuels selenoproteins.

•  The sequestering of toxic elements by selenium represents an e[cient natural detoxiﬁca4on mechanism but also results in the physiological inac4va4on of selenium.

•  Selenoprotein deﬁciency leads to decreased pools of mature T cells, a defect in the T-‐cell-‐dependent an4body responses, and oxidant hyperproduc4on in T cells.

•  The greater the detoxiﬁca4on burden of other elements, the higher the requirements for supplemental selenium.

Selenium Sources

U.S. Department of Agriculture, Agricultural Research Service. 2003. USDA National Nutrient Database for Standard Reference, Release 16. Nutrient Data Laboratory Home Page, http://www.nal.usda.gov/fnic/foodcomp.

•  Ravn-‐Haren G et al. Br J Nutr 2008; 99(4): 883-‐92.

•  Increased selenium intake is associated with important an4oxidant eﬀects but these eﬀects are dependent on selenium source.

Brazil nuts, dried, unblanched, 1 ounce Tuna, light, canned in oil, drained, 3 ounces Beef, cooked, 3½ ounces Cod, cooked, 3 ounces Turkey, light meat, roasted, 3½ ounces Beef chuck roast, lean only, roasted, 3 ounces Chicken Breast, meat only, roasted, 3½ ounces

•  Comparison of organic selenium versus selenate supplements demonstrates increases in serum levels selenium from organic and inorganic supplements but only selenate increased glutathione peroxidase

Selenium in Au4sm

Protein and Development

•  Jory J and WR McGinnis. Am J Biotech Biochem 2008; 4(2): 101-‐4.

•  20 children with au4sm •  RBC Se = 3.12±0.54 p<0.0006

544mcg 63mcg 35mcg 32mcg 32mcg 23mcg 20mcg

•  Morgan J et al. J Pediatr Gastroenterol Nutr 2004; 39(5) 493-‐8. •  144 full-‐term 4 month olds monitored to 24 months. •  Meat intake from 4-‐16 months had a signiﬁcant posi4ve correla4on with psychomotor developmental indices (p<0.013)

15 control children RBC Se=3.67±0.38

•  Whaley SE et al. J Nutr 2003; 133: 3965S-‐71S

•  155 grade 1 Kenyan children. •  Meat, Milk, Energy suppl diet or placebo x 21 months. •  Children receiving supplemental food with meat signiﬁcantly outperformed all other groups on performance tests (p<0.001) •  No diﬀ in performance among milk, energy or placebo .

•  Jory J….unpublished data •  62 children with au4sm, assessed by mntario medical laboratory •  AST > 40 in 22.6% (14/62)

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD Protein and Development

Protein and Amino Acids in Au4sm

•  Neumann CG et al. J Nutr 2007; 137 (4): 1119-‐23 •  Zeisel SH. Adv Pediatr 1986: 33: 23-‐47.

•  12 primary schools in Kenya •  Mid-‐morning snack enriched with a) meat b) milk or c) fat •  Control group with no mid-‐morning snack

•  Tryptophan and tyrosine in the diet are used as precursors for neuronal synthesis of serotonin, dopamine and norepinephrine.

•  Meat group showed the steepest increase in arithme4c tests

•  Deijen DB et al. Brain Res Bull 1999. 48(2): 203-‐9

•  10 cadets undergoing intensive military training •  Tyrosine supplementa4on increased performance on memory and tracking tasks. •  Tyrosine supplementa4on may reduce the eﬀect of physical and psychosocial stress on cogni4ve task performance

•  Meat group showed the greatest increase in levels of physical ac4vity •  Meat group showed the greatest increase in ini4a4ve and leadership •  Meat group showed the greatest increase in height and mid-‐upper arm muscle

•

Protein and Amino Acids in Au4sm

Essen4al Faby Acids in ADHD

•  Chen JR et al. J Nutr Biochem 2004; 15(8): 467-‐72.

•  Naruse et al. No So Hajatsu 1989; 21 (2): 181-‐189.

•  58 with ADHD (mean age 8.5); 52 controls (mean age 7.9) •  RBC linoleic (n-‐6) and DHA (n-‐3) significantly lower in Taiwanese children with ADHD but no significant differences in intake.

•  Among a subgroup of au4s4c infants, there was a marked disturbance in uptake of tryptophan and phenyalanine from the intes4ne into the blood. •  Among a further subgroup, there was a decrease in blood turnover of tyrosine.

•  Ross BM et al. Nutr Neurosci 2003; 6(5): 277-‐81. •  10 children with ADHD and 12 controls •  Signiﬁcantly higher levels of exhaled ethane among children with ADHD. •  High ethane is indica4ve of excessive oxida4ve breakdown of n-‐3 faby acids.

•  Tyrosine and free tryptophan delivery to the au4s4c brain may be reduced, decreasing synthesis of serotonin, dopamine and/or norepinephrine.

Essen4al Faby Acids in ADHD

Essen4al Faby Acids in Au4sm

•  Richardso & Puri. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26(2): 233-‐239.

Jory, Joan….unpublished data

RBC DHA: 2.23 ± 1.42 4.50 ± 1.43

RBC EPA: 0.4 ± 0.52 0.64 ± 0.27

11 children with au4sm   15 controls

•  41 children with ADHD and learning di[cul4es •  Supplemented with HUFAs or placebo x 12 weeks •  Signiﬁcant increases in cogni4ve and behaviour ra4ng scales

Au4sm

Sorgi PJ et al. Nutr J 2007; 6: 16

9 Japanese ADHD children Supplement of 16.2 gm EPA/DHA concentrate/day x 8 weeks Blinded psychiatrist Significant improvements in inaben4on, hyperac4vity, opposi4onal-‐ defiant behaviour and conduct disorder   Significant correla4on between lowered AA:EPA ra4o and global severity of illness scores.

N-‐3/N-‐6: 0.16 ± 0.05

Control

(p=0.0003) (p=0.03) 0.24 ± 0.06 (p=0.001)

•  Xancassel et al. Prostaglandins EeuRot ^ssent Yajy Acids 2001; 65 (1): 1-‐7.

•  23a lower N-‐3 PUFA for au4s4c children than controls •  Normal N-‐6 PUFA levels of au4s4c children compared with controls with mental retarda4on

Autism: an Evidence Base for Orthomolecular Intervention Joan Jory, MSc, PhD Essen4al Pab6 Acids in Au4sm

Essen4al Pab6 Acids in Au4sm

Amminger GP et al. Biol Psychiatry 2007; 61 (4): 551-‐553.

Bent ? et al. / Aucsm $eH $isord 2010 Aug 4 (e@uV)

13 au4s4c children (15-‐17 6rs) with severe tantrums7 aggression or self-‐injurious behaviour   Randomized double-‐blind placebo-‐controlled trial   Supplement of 1.5 gm/d DHA/EPA x 6 weeks   Improvements in h6perac4vit6 as per Aberrant Behavior Ahecklist (p=0.98).

27 children with ASD   1.3 g/da6 mmega 3 supplementa4on x 12 weeks   gon-‐signiWcant decreases in h6perac4vit6 among tmt group   Treatment: 2.7 pt improvement in Aberrant Behaviour Score   Placebo: 0.3 pt improvement in Aberrant Behaviour Score

Meguid NA et al. Clin Biochem 2008; 41(13): 1044-‐1048.

30 au4s4c children (18 /h 12 P) 3-‐11 6rsh 30 controls.   Supplementa4on with Efalex Wsh oil7 _ caps/d x 3 months.   Improved clinical and biochemical indicators in 66% of children.

Treating Mental Disorders with Multiple Nutrients Bonnie Kaplan, PhD

Disclosure Treating Mental Disorders with Multiple Nutrients

• I hold no stock, financial interest, or leadership roles in any company • I receive no grants or research funding from any company, nor any personal gifts (not even travel or meals) • But I stand on the intellectual shoulders of giants….Dr. Hoffer and some of you….and I doubt that I will present a single totally novel idea relative to theirs.

Bonnie J. Kaplan, PhD Faculty of Medicine University of Calgary kaplan@ucalgary.ca ISOM, Toronto, April 30, 2011

Continued…..

Natural health practitioners • Have been using multi-ingredient, individualized treatment approach forever – probably the correct thing to do

• I will be discussing a nutrient formula called EMPowerplus (EMP+), made by Truehope Nutritional Support Ltd. • PLEASE don’t google this stuff or my name; refer instead to legitimate sources (truehope.com)

• Impossible to study individualized approach systematically: b/c of individual differences, it only makes sense to use a single, standardized, shotgun intervention for research

• Some of us … not surprised at Andrew’s return to normal function

CASE PRESENTATION • Even though he had symptoms of psychosis

“ANDREW”

Treating Mental Disorders with Multiple Nutrients Bonnie Kaplan, PhD

Case Report: child with bipolar disorder, psychosis Frazier et al. Multinutrient Supplement as Treatment: Literature Review and Case Report of a 12-year-old Boy with Bipolar Disorder. J Child Adolesc Psychopharmacol 2010, 19:453-60.

• There are now 12 publications on EMP+ (13th is in press; several under review)

• 12 yr –old with bipolar disorder with psychotic features, had no life after 6 years of conventional treatment

• Many designs, samples from 1 to 358

• Transitioned to EMP+ in 19 days

• Children, adults, research & clinical settings

• Virtually all mood and psychotic symptoms resolved, better global functioning, sociability, sleep, cognition

• For example……………..

• Sx severity

Database analysis of 358 adults

– ↓ 41% after 3 m

Gately D, Kaplan BJ. Database analysis of adults with bipolar disorder consuming a micronutrient formula. Clin Med Insights: Psychiatry 2009; 4:3-16.

– ↓ 45% after 6 m (both paired t-tests sig, p <0.001). • Responder status:

• Self-report data from 682 adults who reported a diagnosis of bipolar disorder; 81% were taking psychiatric medications.

– 53% >50% improvement at 6 m • Regression analyses: ↓ sx severity over 6 m sig assoc with

• Excluded

– ↑ micronutrient dosage

– Anyone reporting additional diagnoses

– ↓ medication

– Anyone who provided data <60 times during 180 days

• Sx improvements sustained at 6 months, suggesting not due to placebo/expectancy effects

• Final sample N = 358

• Benefits CANNOT be due to placebo/expectancy effects • Strongest predictor of NOT benefiting: not decreasing psychiatric meds

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Treating Mental Disorders with Multiple Nutrients Bonnie Kaplan, PhD

Database analysis of 120 child & adolescent participants Rucklidge JJ, Gately D, Kaplan BJ. Database analysis of children and adolescents with bipolar disorder consuming a micronutrient formula. BMC Psychiatry, 2010, 10:74.

• Parent-report data for 6 months • N=120 diagnosed with bipolar disorder with or without ADHD

Case study: 18-yr-old boy with OCD

Case study: Natural ABAB

Rucklidge JJ. Successful treatment of OCD with a micronutrient formula following partial response to CBT: A case study. J Anxiety Disord 2009; 23: 836–40. •

Hand washing, religiosity, etc.

•

Cognitive behavior therapy (CBT) for 1 yr with a modest response: OCD had shifted from severe to moderate

•

Within a year, anxiety had back to severe range and he now had major depression

•

Entered an ABAB design trial using EMPowerplus

•

After 8 wks on formula

•

Treatment was then discontinued for 8 wks, during which time his obsessions and anxiety worsened and his mood dropped.

•

Reintroduction of formula again improved symptoms

– Mood was stabilized, anxiety reduced, obsessions in remission

– {Note: he did not believe formula was responsible for improvement.}

Case series: adult ADHD Rucklidge et al. Effect of micronutrients on behaviour and mood in adults with ADHD: Evidence from an 8-week open label trial with natural extension. J Attention Disorders 2010.

• 14 adults with ADHD + mood/anxiety disorders (mean age: 37.53 (9.56))

• Co-occurring current diagnoses: – 10 MDD (75%), 6 Social Phobia (42.9%), 3 GAD (21.4%), 3 BDII (21.4%), 3 drug/alcohol abuse/dependency (21.4%)

• Outcome measures: MADRS, Y-MRS, CAARS, OQ, DASS, NAS-PI, LIFE-RIFT

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Treating Mental Disorders with Multiple Nutrients Bonnie Kaplan, PhD

Depression and quality of life (clinician rated)

ADHD and emotional lability/anger measures (self-rated)

ES=1.96 ***

ES=.98 ES=1.45

ES=1.58 ES=1.29

T scores

***

*** * **

ES=1.88 ***

** ***

+ Of the 12 who entered the trial with clinically elev ated sy mptoms of depression, 10 (83.3%) showed at least 50% sy mptom reduction with 8 (66.7%) now in remission

*based on 7 follow-ups 4 months post baseline **based on 6 individuals who stopped EMP post trial ***p<.001

**p<.01, ***p<.001

Self-report depression/anxiety/stress

ADHD and emotional lability/anger measures (observer rated)

T scores

ES=.66 **

ES=.7

ES=1.45

***

Raw scores

ES=1.08 **

***

ES=1.27 ***

ES=.88 ***

**p<.01, ***p<.001 **p<.01, ***p<.001

Data from

Gesch et al. Micronutrient supplementation in young adult prisoners, Brit J Psychiatr 2002; 181:22-28

• RCT in 231 young offenders • Supplement with a broad array of minerals,

• other multinutrient treatments • other settings

vitamins, and some EFAs (26 ingredients)

Active formula

102

26.3% fewer rule infractions 35.1% fewer violent acts

Treating Mental Disorders with Multiple Nutrients Bonnie Kaplan, PhD Zaalberg et al. Effects of nutritional supplements on aggression, rule-breaking, and psychopathology among young adults prisoners. Aggressive Behavior 2010; 36:117-26.

• • • • •

↓6.7%

↓35%

Since 2000, multi-ingredient research • • • • • • •

221 young adult prisoners 1-3 month intervention Active: vitamins, minerals, EFAs Similar 26-ingredient intervention to Gesch Similar result: reported incidents significantly reduced, but not supported by changes in other measures.

Where should multinutrient treatment matter the most???

In infectious diseases In cardiovascular diseases For prevention of fractures In Alzheimer’s In stroke recovery In cognitive function, generally In mental health…….just beginning

only ~2% of our weight Brain accounts for 50-75% of our metabolic demands

Overall Diet and Mood

After accounting for energy intake, BMI, age, SES, education, alcohol consumption, or smoking

Jacka et al. Association of Western and Traditional diets with depression and anxiety in women. AJP, 2010, 167:1-7

•

Australian cross-sectional epidemiological study of 1,046 adult women

•

Measure of diet was a single 12-mo FFQ categorized from factor analysis (only 14% of variance explained) as:

PRIMARY RESULT: Higher diet quality scores assoc with lower GHQ-12 scores • Traditional Diet: Lower risk of DSM major depression or dysthymia, Lower risk of DSM anxiety disorders.

– Traditional Diet: Vegetables, fruit, beef, lamb/meat, fish, whole grains.

• Junk Food Diet: More psychological symptoms.

– Western (Junk Food) Diet: Processed meats, refined grains, sugary products, fried foods, beer.

• Health Food Diet: Trend for higher risk of major depression or dysthymia; Better than Junk Food Diet, but not much better

– Modern (Health Food) Diet: Fruits, salads, fish, tofu, beans, nuts, yogurt, red wine •

Psychiatric sx defined by a SCID, GHQ-12

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Treating Mental Disorders with Multiple Nutrients Bonnie Kaplan, PhD

Sanchez-Villegas et al. Association of the Mediterranean dietary pattern with the incidence of depression. Arch Gen Psychiatry, 2009, 66:1090-8

• “It is easier to change a man's religion than to change his diet."

Single FFQ, >10,000 people, prospective After a median follow-up of 4.4 years, 480 were identified as having developed depression Protective factors for new-onset depression: • Adherence to a Mediterranean dietary pattern. • More intake of fruits, nuts, and legumes. • Higher intake ratio of mono-unsaturated to saturated fatty acids.

— Margaret Mead

What’s in EMPowerplus?

Interaction with Medications

Broad spectrum vitamin/mineral formulation

• EMP+ is not a ‘supplement’; it is an active intervention

36 ingredients: not exotic All the vitamins (except K)

• Mixing biologically active interventions can be a challenge

Long list of dietary minerals Some are in relatively large (safe) doses

• Cf. Sarris et al., J Psychiatr Res, Sept 2010

Emphasis on dietary minerals www.truehope.com

Mitochondrial dysfunction • Appropriate use of EMP+ is to follow a protocol that transitions people gradually from medication to EMP+ in a cross taper • Dangerous to do otherwise • My H: if the nutrients you are using with your patients do NOT amplify the effect of meds, you may want to look for a better source for your nutrients

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Treating Mental Disorders with Multiple Nutrients Bonnie Kaplan, PhD Shouldn’t shortchange single ingredient effectiveness

• The more complex the intervention, the better the results seem to be.

• Niacin for dementia associated with pellagra • Thiamine for Wernicke's encephalopathy • Iodine for endemic goiter with depressive symptoms.

• EMP is not the only multi-ingredient formula --- but the only one for which there are many peer-reviewed scientific publications in mental health

• Refer to Psych Bulletin article for review: Vitamins, Minerals, and Mood

1950s • Development of psychiatric meds began to make a difference

But we can do better

• Now – 50+ years of drug development, and many success stories • Today’s message is NOT anti-medication

Publications on EMP+

The genes for mental illness are likely

1. Rucklidge, J. J., Johnstone, J., Harrison, R. (in press). Effect of micronutrients on neurocognitive functioning in adults with ADHD and Severe Mood Dysregulation: A pilot study. Journal of Alternative and Complementary Medicine. 2. Rucklidge, J.J., Gately, D., Kaplan, B.J. (2010). Database analysis of children and adolescents with Bipolar Disorder consuming a micronutrient formula, BMC Psychiatry, 10:74. doi:10.1186/1471-244X-10-74 3. Rucklidge, J. J., & Harrison, R. (2010). Successful treatment of Bipolar Disorder II and ADHD with a micronutrient formula: A case study, CNS Spectrums. 15(5):231-237. 4. Mehl-Madrona, L., Leung, B., Kennedy, C., Paul, S., Kaplan, B.J. (2010). Micronutrients versus standard medication management in autism: A naturalistic case-control study, Journal of Child and Adolescent Psychopharmacology. 20(2): 95-103. 5. Rucklidge, JJ, Taylor, MR, Whitehead, KA. (2010). Effect of micronutrients on behaviour and mood in adults with ADHD: Evidence from an 8-week open label trial with natural extension, Journal of Attention Disorders. Published Jan 13, 2010 as doi:10.1177/1087054709356173

the genes that regulate brain metabolism of essential nutrients Pauling (1974)

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Treating Mental Disorders with Multiple Nutrients Bonnie Kaplan, PhD

6. Gately, D., Kaplan, B.J. (2009). Database analysis of adults with bipolar disorder consuming a micronutrient formula. Clinical Medicine Insights: Psychiatry. 4:3-16. 7. Rucklidge, J. J. (2009). Successful treatment of OCD with a micronutrient formula following partial response to CBT: A case study. Journal of Anxiety Disorders, 23: 836â&#x20AC;&#x201C;840. 8. Frazier, E.A., Fristad, M., Arnold, L.E. (2009). Multinutrient Supplement as Treatment: Literature Review and Case Report of a 12-year-old Boy with Bipolar Disorder. Journal of Child and Adolescent Psychopharmacology, 19:453-460. 9. Kaplan, B.J., Fisher, J.E., Crawford, S.G., Field, C.J., Kolb, B. (2004). Improved mood and behavior during treatment with a mineral-vitamin supplement: An open-label case series of children. Journal of Child and Adolescent Psychopharmacology, 14(1), 115-122. 10. Kaplan, B. J., Crawford, S. G., Gardner, B., & Farrelly, G. (2002). Treatment of mood lability and explosive rage with minerals and vitamins: Two case studies in children. Journal of Child and Adolescent Psychopharmacology, 12(3), 203218.

11.Simmons, M. (2003). Nutritional approach to bipolar disorder (Letter). Journal of Clinical Psychiatry, 64, 338. 12. Popper, C. W. (2001). Do vitamins or minerals (apart from lithium) have mood-stabilizing effects? [Commentary]. Journal of Clinical Psychiatry, 62, 933-935. 13. Kaplan, B. J., Simpson, J. S. A., Ferre, R. C., Gorman, C., McMullen, D., & Crawford, S. G. (2001). Effective mood stabilization in bipolar disorder with a chelated mineral supplement. Journal of Clinical Psychiatry, 62, 936-944. Other relevant articles Shaw, I., Rucklidge, J. J., Hughes, R. N. (2010). A possible biological mechanism for the B Vitamins altering behaviour in ADHD. Pharmaceutical Medicine. 24 (5): 1-6. Kaplan, BJ, Crawford, S., Field, C, and Simpson, JSA. (2007). Vitamins, minerals, and mood. Psychological Bulletin, 133(5), 747-760.

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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An Orthomolecular Approach to Alzheimerâ&#x20AC;&#x2122;s Disease Patrick Holford

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The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

11-03-29

Michael Schachter, MD Michael B Schachter MD, CNS Schachter Center for Complementary Medicine 2 ExecuOve Boulevard Suite 202 Suﬀern, New York 10901 Phone: 845-‐368-‐4700; FAX: 845-‐368-‐4727 Website: www.schachtercenter.com E-‐Mail: www.oﬃce@mbschachter.com

The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

5/1/2011

Michael B Schachter MD, CNS ISOM: May 1, 2011 Fairmont Royal York Hotel Toronto, Canada Michael B Schachter MD, CNS (ISOM) Toronto

No relevant ﬁnancial disclosures for this lecture 3ole of minerals in the diet and as supplements 6ill 7e discussed in terms of sugges9ve research For the purpose of this lecture, none of these minerals are intended to diagnose, prevent or treat any disease and the F=> has not approved any of the informa9on that is 7eing presented here ?he informa9on is presented for informa9onal purposes only

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Orthomolecular Treatment & Minerals

Michael B Schachter MD, CNS (ISOM) Toronto

•  NutriOonal minerals are involved in the structure of the body (e.g. bone) and as catalysts (along with vitamins) for virtually all of the biochemical reacOons in the body. •  Toxic minerals primarily interfere with nutriOonal minerals funcOon. Examples are mercury, lead, cadmium and others •  High doses of nutriOonal minerals can be toxic & minute doses of so-‐called toxic minerals can be essenOal. Examples include: aluminum, arsenic

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•  Older observaOonal studies of nutriOonal habits in different cultures do involve the effects of the full range of mulOple minerals •  Newer research involving the effects of diets on various aspects of health also include mulOple minerals •  Examples include: the Ornish diet, PriOkin diet, Atkins diet, Paleolithic diet, raw food diets and others •  ConvenOonal medicine is beginning to do research on diets, rather than just components

•  Most done in vitro showing biochemical reacOons & with various animal models •  Most research done with isolaOon of a single mineral, rather than deal with the complicated interacOon of all of the minerals •  Very lifle moOvaOon to do therapeuOc trials with minerals because they are not patentable •  TherapeuOc trials usually involve one mineral at a Ome (Has limited relevance for clinical work, as all minerals constantly interact with each other) Michael B Schachter MD, CNS (ISOM) Toronto

Michael B Schachter MD, CNS (ISOM) Toronto

Whole Dietary Programs Involve MulOple Minerals Simultaneously

NutriOonal Mineral Research

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Minerals: NutriOonal & Toxic

•  Most orthomolecular research and clinical pracOce focuses on dietary suggesOons & opOmal amounts of vitamins •  NutriOonal minerals not emphasized; a few (Ca, Mg, Zn, Se, Fe, Cr) someOmes menOoned •  This lecture focuses on nutriOonal minerals as a team and also reviews characterisOcs of some selected minerals •  Chronic degeneraOve diseases are associated with depleOon of nutriOonal minerals and/or presence of toxic minerals •  Other factors such as persistent organic pollutants, other nutrient deﬁciencies, lifestyle habits (sleep, exercise, stress management) important, but will not be discussed

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The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

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Michael Schachter, MD Weston Price s Findings

Roots of NutriOonal Medicine

•  DenOst who visited and examined people from mulOple cultures: •  NaOve foods: beauOful teeth, wide dental arches; No degeneraOve diseases •  Western foods: Reﬁned sugar and ﬂour: dental decay, crooked teeth, narrow dental arches, arthriOs and all of the degeneraOve diseases

Weston Price DDS: Wrote Book: Nutri9on and Physical Degenera"#n &'(' See: ,-.://00010e23#na.456e1#47/ and ,-.://0001..n91#47/ 5/1/2011

Michael B Schachter MD, CNS (ISOM) Toronto

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Two Brothers Who Ate at Same Table: Excellent Teeth vs Rampant Caries

PrimiOve food of oatmeal & oatcake & seafood 5/1/2011

They Sat at the Same Table

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Michael B Schachter MD, CNS (ISOM) Toronto

Dr. Alan Gaby s New Textbook

Roots of NutriOonal Medicine: Roger Williams PhD-‐1950 s

Biochemical Individuality (e.g. Pauling 250 to 20,000 mg C) Genetotrophic Theory of Illness Nutrients work as a team

iThe brother on the lej hadk excellent teeth and ion the rightk rampant caries. These boys were brothers eaOng at the same table. The older boy, with excellent teeth, was sOll enjoying primiOve food of oatmeal and oatcake and sea foods with some limited dairy products. The younger boy, seen to the right, had extensive tooth decay. Many teeth were missing including two in the front. He insisted on having white bread, jam, highly sweetened coﬀee and also sweet chocolates. His father told me with deep concern how diﬃcult it was for this boy to get up in the morning and go to work." Read more in :;345"#n and <,=256a> ?e7ene4a"#n by Weston A. Price, DDS

White bread, jam, highly sweetened coﬀee & sweet chocolates

Michael B Schachter MD, CNS (ISOM) Toronto

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• Newly released in Jan 2011 • A clinically-‐oriented, scienOﬁcally-‐based guide to the use of diet, nutriOonal supplements, and other natural substances for the prevenOon and treatment of a wide range of physical and mental disorders • > T00 diﬀerent health condiOons • 61 chapters; >1,300 pages • 15,000 reference citaOons • Discusses many minerals & prevenOve & therapeuOc applicaOons, ciOng primarily human studies Michael B Schachter MD, CNS (ISOM) Toronto

The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

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Michael Schachter, MD Focus on the Whole Diet

Whole Food Diet Protects Against Depression; Processed Food Diet Increases Risk: 2009 Study

•  Much research has focused on components of diet, such as fats or high protein, rather than on the whole diet •  Clear that reducOonisOc approaches are not the most fruipul •  Various authors and researchers have criOcized the reducOonisOc approach & focused on a whole dietary program (Weston Price, Colin Campbell, Dean Ornish, Loren Cordain, others) •  Creeping into convenOonal medical literature

•  Studies of diet and depression previously: focused primarily on individual nutrients •  AIMS: To examine the associaOon between dietary paferns and depression using an overall diet approach prospecOvely •  METHOD: 3,500 parOcipants (26r women; mean age 55.6 years): two dietary paferns idenOfied: 'whole food' (heavily loaded by vegetables, fruits and fish) and 'processed food' (heavily loaded by sweetened desserts, fried food, processed meat, refined grains and high-‐fat dairy products).

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Michael B Schachter MD, CNS (ISOM) Toronto

Akbaraly TN, Brunner EJ, Ferrie JE, Marmot MG, Kivimaki M, Singh-‐Manoux A. Dietary paOern and depressive sy4pt"4s in 4iddle a8e Br J Psychiatry. 2009;195:408– 413; Presented for CME Credit on Medscape on 11-‐23-‐09

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Michael B Schachter MD, CNS (ISOM) Toronto

Mediterranean Diet Pafern (MDP) Protects Against Depression (2009)

Whole Food Diet Protects Against Depression; Processed Food Diet Increases Risk (2009)-‐2 •  Self-‐reported depression was assessed 5 years later using the Center for Epidemiologic Studies -‐ Depression (CES-‐D) scale •  RESULTS: ParOcipants in the highest terOle of the whole food pafern had signiﬁcantly lower odds of CES-‐D depression than those in the lowest terOle. In contrast, high consumpOon of processed food was associated with an increased odds of CES-‐ D depression. •  CONCLUSIONS: In middle-‐aged parOcipants, a processed food dietary pafern is a risk factor for CES-‐D depression 5 years later, whereas a whole food pafern is protecOve.

•  Ar"spec9ve study began 12-‐21-‐99 and is ongoing •  MDP thought to reduce inﬂammatory, vascular and metabolic processes related to development of clinical depression •  Palidated 1R6-‐ite4 1""d 1reUuency Uues9"nnaire to assess adherence to a MDP •  10;000 ini9ally 2ealt2y Spanis2 par9cipants; a dynamic cohort of university graduates

Sánchez-‐Villegas A, Delgado-‐Rodríguez M, Alonso A, Schlafer J, LahorOga F, Majem LS, Marynez-‐González MA. AssociaOon of the Mediterranean dietary pafern with the incidence of depression: the Seguimiento Universidad de Navarra/University of Navarra follow-‐up (SUN) cohort. Arch Gen Psychiatry. 2009 Oct;66(10):1090-‐8. Presented for CME Medscape 10-‐12-‐09

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Michael B Schachter MD, CNS (ISOM) Toronto

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Mediterranean Diet Pafern (MDP) Protects Against Depression-‐2

Michael B Schachter MD, CNS (ISOM) Toronto

Dietary AaOerns and 3isE 1"r Type-‐2 Diabetes Mellitus in U.S. Men (Harvard Study)

•  Incident depression = free of depression and anOdepressant medicaOon at baseline and reported physician-‐made diagnosis of clinical depression and/ or anOdepressant medicaOon use during follow-‐up •  Ajer median of 4.4 years, 480 new cases of depression were idenOﬁed •  MulOple adjusted hazard raOos of depression showed a clear inverse relaOonship between adherence to MDP & incidence of depression (P for trend < 0.001) 5/1/2011

Michael B Schachter MD, CNS (ISOM) Toronto

•  The role of diet in the development of type 2 diabetes mellitus remains unsefled •  OBJECTIVE: To examine the associaOon between major dietary paferns and risk for type 2 diabetes mellitus. •  DESIGN: ProspecOve cohort study van Dam RM, Rimm EB, Willef WC, Stampfer MJ, Hu FB. Ann Intern Med. 2002 Feb 5;136(3):I30.

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The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

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Michael Schachter, MD Dietar< AaOerns and 3isE 1or ?<5eT2 Diabetes Mellitus in U.S. Men (2)

ProspecOve Study of Major Dietary Paferns and Risk of Coronary Heart Disease in Men (Harvard)

on diet and coronary heart •  BACKGROUND: Previous studies disease (CHD) focused primarily on individual nutrients or foods •  OBJECTIeE: We eNamined whether overall dietary paferns derived from a food-‐frequency quesOonnaire (FF}) predict risk of CHD in men. •  DESIGN: This was a prospecOve cohort study of 44875 men aged 40-‐75 y without diagnosed cardiovascular disease or cancer at baseline in 1986

•  MEASUREMENTS: Using factor analysis based on data from food-‐frequency quesOonnaires, two major dietary paferns "prudent" (characterized by higher consumpOon of vegetables, fruit, fish, poultry and whole grains) and "western" (characterized by higher consumpOon of red meat, processed meat, French fries, high-‐fat dairy products, refined grains, and sweets and desserts). •  CONCLUSION: Our findings suggest that a western dietary pafern is associated with a substanOally increased risk for type 2 diabetes in men. 5/1/2011

Michael B Schachter MD, CNS (ISOM) Toronto

Hu FB, Rimm EB, Stampfer MJ, Ascherio A, Spiegelman D, Willef WC. Am J Clin Nutr. 2000 Oct;72(4):912-‐21.

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•  RESULTS: Using factor analysis, we idenOfied 2 major dietary paferns. The first factor, which we labeled the "prudent pafern," was characterized by higher intake of vegetables, fruit, legumes, whole grains, fish, and poultry, whereas the second factor, the "Western pafern," was characterized by higher intake of red meat, processed meat, refined grains, sweets and dessert, French fries, and high-‐fat dairy products. •  CONCLUSIONS: These data suggest that major dietary paferns derived from the FF} predict risk of CHD, independent of other lifestyle variables. •  Prudent diet gave befer results •  Similar study carried out in women at Harvard Michael B Schachter MD, CNS (ISOM) Toronto

Food Supply Has Become Depleted of Minerals

ProspecOve Study of Major Dietary Paferns and Risk of Coronary Heart Disease in Men (2)

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Michael B Schachter MD, CNS (ISOM) Toronto

•  Starts with the soil: concentraOon of minerals in soil has always varied from place to place •  With Ome, food supply has become depleted of minerals •  Agricultural pracOces of syntheOc ferOlizers lacking trace minerals (mainly use phosphorus, nitrogen & potassium) resulOng in minerals lacking from plants •  Made worse by pesOcides, which bind to minerals present •  Made much worse by reﬁning foods and removing minerals (e.g. white bread, sugar, etc…)

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Selenium Levels of Soil in the USA

Michael B Schachter MD, CNS (ISOM) Toronto

Dr. William A. Albrecht (1888-‐1974) • Chairman Dept of Soils-‐Univ of Missouri • Direct link between soil quality, food quality and human health •  The soil is the creaOve material of most of the basic needs of life • Published hundreds of papers and gave numerous lectures • Foremost authority on the relaOonship of soil ferOlity to human health

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The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

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Michael Schachter, MD ReducOon in Average Mineral Content of Fruits & Vegetables Between 1940 & 1991

Mineral DepleOon Worldwide •  1992, the oﬃcial report of the Rio Earth Summit concluded there is deep concern over conOnuing major declines in the mineral values in farm and range soils throughout the world . •  Statement was based on data showing that over the last 100 years, average mineral levels in agricultural soils had fallen worldwide – by 72% in Europe, 76% in Asia and 85% in North America.

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Michael B Schachter MD, CNS (ISOM) Toronto

Mineral Sodium Potassium Magnesium Calcium Iron Copper Zinc

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What Can Be Done?

Michael B Schachter MD, CNS (ISOM) Toronto

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Unreﬁned Salt

Michael B Schachter MD, CNS (ISOM) Toronto

Water & Salt

Michael B Schachter MD, CNS (ISOM) Toronto

Refined vs. Unrefined Salt •  Big difference: trace minerals retained (~ 80) in unrefined salt •  Refined: Contains only NaCl-‐No trace minerals; It depletes the body of minerals •  We need sodium chloride AND the trace minerals found in unrefined salt •  Different salts-‐different minerals-‐different tastes •  CelOc salt, Real, Himalayan z Unrefined •  Less iodine that refined iodized salt; Need to get Iodine from another source •  DemonizaOon of salt refers to REFINED SALT; No studies on unrefined salt; ConvenOonal world does not make the disOncOon

•  In our culture, salt is demonized & low salt diets are promoted •  Historically, in virtually all cultures, salt was considered as valuable as gold •  Salt & salt rich clays were the ﬁrst mineral food supplement consciously used by man •  The term salary comes from the term salt •  Historical records of the importance of salt to the Romans, Chinese & all over the world; Wives & children sold as slaves for salt; many examples •  Salt is absolutely necessary for life •  Orthomolecular pracOOoners generally don t recommend salt; I believe this is a big mistake, but the right kind needs to be used

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Fruit -‐29% -‐19% -‐16% -‐16% -‐24% -‐20% -‐27%

•  Ajer oxygen, the most important substance for life is water •  Most people are dehydrated; they drink the wrong liquids •  Suﬃcient pure water intake is key for opOmal health •  One formula that works well is to drink water at about ½ your body weight in ounces (200 lbs— drink about 100 oz daily) •  Ajer water, the next most important substance is salt

•  Societal level: More awareness of problem; counter the quick buck mentality of large corporaOons like Monsanto with its emphasis on GM foods •  Encourage movement back toward small family farms •  PoliOcal awareness necessary: See: hfp://www.naturalnews.com/ for starters •  Individually & as pracOOoners much can be done

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Vegetables -‐49% -‐16% -‐24% -‐46% -‐27% -‐76% -‐59%

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The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

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Michael Schachter, MD

•  •  •  •  •  •  •

Importance of Salt to the Body

Low Salt Diet for Hypertension-‐Fully Accepted by Medical Profession & Government Agencies

Body can t func9on wit2out salt Every cell-‐requires salt Sodium and potassium need to be in balance Potassium high in cells Sodium high in blood and extracellular ﬂuid Salt & water needed for detoxiﬁcaOon Pa9ents feel beOer wit2 salt; feel lousy on low salt diets

•  1904-‐Ambard & Beugard: Salt deprivaOon associated with low BP in animals •  Various animal studies: High salt (reﬁned & 10 to 20X recommended) associated with high BP; extrapolated to humans •  1979-‐Surgeon general: Salt causes ↑BP & need low salt diets; Repeated in 2009 •  Pushed by Governmental agencies, researchers, medical schools & dieOcians •  Numerous studies on low salt diets-‐-‐no beneﬁts; yet sOll pushed. See Dr. David Brownstein s book (Salt Your Way to Health) and lecture on DVD on salt; www.drbrownstein.com.

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Michael B Schachter MD, CNS (ISOM) Toronto

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Headaches FaOgue Autoimmune Fibromyalgia CFSIDS

Michael B Schachter MD, CNS (ISOM) Toronto

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EssenOal Minerals

Michael B Schachter MD, CNS (ISOM) Toronto

Minerals

•  Macrominerals: calcium, magnesium, sodium, chloride, phosphorus and sulfur •  Micro minerals: zinc, copper, manganese, selenium, chromium, iodine, iron, cobalt, nickel, boron, silica, molybdenum, boron, ﬂuoride (?) •  Some controversial minerals that may be essenOal: stronOum, silver, arsenic, bismuth, cesium, rubidium, germanium, lithium, gold, others •  Rare earth minerals: Many minerals you ve never heard ofÅshown to be essenOal in some species (Wallach) 5/1/2011

Glimpse of the Periodic Table

Cases Responding to Unreﬁned Salt & H2O Seizure disorders Hypertension ArthriOs Adrenal exhausOon Muscle cramps (e.g. MD) Hypotension

Michael B Schachter MD, CNS (ISOM) Toronto

•  Trace Minerals •  Macro-‐minerals

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The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

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Michael Schachter, MD Toxic Minerals

Worldwide Iodine Levels

•  •  •  •

Interfere with funcOoning of nutriOonal minerals Examples: Mercury, lead, cadmium, aluminum, arsenic Some toxic minerals are nutriOonal at low dosages Sources of Mercury: Dental amalgam fillings, vaccines, fish, coal refineries (air), others •  Removed by chelaOon therapy •  New books shed light on AuOsm Epidemic: (1)The .ge o; .u<sm: Mercury, Medicine & a Man-‐Made Epidemic by Olmstead & Blaxill & (2) Vaccine Epidemic: How Corporate Greed, Biased Science, & Coercive Government Threaten Our Human Rights, Our Health & Our Children Edited by Habakus & Holland •  Websites: wwwâgeofauOsm^com; hfp://www^fourteenstudiesôrg; hfp://www^nvicôrg/ ; hfp://www^vaccinaOoncouncilôrg/

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Michael B Schachter MD, CNS (ISOM) Toronto

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Worldwide Iodine Problems

Michael B Schachter MD, CNS (ISOM) Toronto

•  Magor intracellular caOon; serious deficiencies can be present with normal serum K •  Sodium-‐potassium pump requires energy to maintain high intracellular K & high serum Na; requires sufficient Mg for ATP to maintain intracellular K; magnesium deficiency lead to potassium deficiency •  Deficiency associated with hypertension, ASCVD, cardiac arrhythmias, faOgue and muscle cramps •  DiureOcs and other medicaOons cause potassium loss •  Good diet with fresh fruits and vegetables should contain about 3,500 mg of potassium (much lower in highly refined diets)

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Iron (Fe) Atomic Number 26

Michael B Schachter MD, CNS (ISOM) Toronto

Calcium (Ca) Atomic Number 20

•  Hemoglobin molecule carries oxygen to all cells (chelate); deficiency associated with iron deficiency anemia, faOgue •  Common causes are heavy menses, vegan diets, bleeding from colon cancer, occult bleeding (GI system) from drugs like aspirin & NSAIDS •  Involved with cytochrome enbymes and energy producOon; faOgue can occur prior to anemia •  Needed for proper thyroid funcOon •  Overload of iron-‐increase free radical producOon & increased risk of various degeneraOve diseases; reduce with donaOng blood (increases stem cell producOon) •  FerriOn-‐Protein that binds iron in storage-‐-‐ fairly good marker of too much or too lifle iron (but can be elevated in inhammatory states when iron not increased (FerriOn at least 50 for thyroid funcOon) •  Befer absorbed with vitamin C •  Phytates from grains, dairy products & hypochlorhydria & digesOve enbyme deficiency interfere with absorpOon from the gut

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Potassium (K) Atomic Number 19

•  Most people worldwide are taking subopOmal doses of iodine and that this has signiﬁcantly contributed to a vast array of diseases, including: all types of thyroid disorders, breast cancer and other cancers, ﬁbrocysOc breast disease, all kinds of problems with children, autoimmune disorders (such as Hashimoto s disease) and many others •  Iodine needed for much more than making thyroid hormones (Triage Theory as prevented by Bruce Ames for Vitamin K for blood cloÉng and Iodine to make thyroid hormones) •  See my arOcle IntegraOve Oncology for Clinicians & Cancer PaOents in JOM, Vol 25, Number 4 2010 for discussion about iodine; also my lecture at the Fall 2010 ACAM meeOng traces history of how physicians became misinformed about iodine (mulOple references)

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Michael B Schachter MD, CNS (ISOM) Toronto

•  Mainly stored in bone—99%; but involved with nerve impulses, muscular contracOon and cloÉng of blood •  Requires vitamin D and acid in the stomach for opOmal absorpOon in duodenum (so chloride from salt necessary to produce HCl in stomach) •  Amount in blood regulated by PTH & calcitonin •  Soj Ossue calciﬁcaOon & spurs ojen associated with reduced calcium intake and/or reduced Mg intake •  Dietary raOo of Ca/P should be between 1:1 and 2:1 •  Diets high in phosphorus & low in calcium creates acid environment & sOmulates calcium loss from bones •  Calcium deﬁciency associated with: osteopenia, osteoporosis, degeneraOve arthriOs, insomnia, hypertension, kidney stones, cramps & twitches, PMS, calcium deposits, restless leg syndrome •  Supplements should be about 600 to 1000 mg daily

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The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

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Michael Schachter, MD Zinc (Zn) Atomic Number 30

Magnesium (Mg) Atomic Number 12

•  Involved with at least 70 enzymes •  Deficiency can cause problems in wound healing, sexual funcOoning, prostate problems, skin problems (acne, eczema), psychiatric symptoms (e.g. anorexia nervosa), increased suscepObility to infecOons, congenital birth defects and many more •  Improves taste & smell and reduces body odor and likelihood of macular degeneraOon •  Highest concentraOon in men s seminal fluid & frequent sexual acOvity may induce deficiency •  Sufficiency reduces prostate problems •  Dose of zinc varies from 15 mg to 60 mg •  Balance with copper at about 10:1 raOo; too much causes Cu def •  Zinc lost with exercise; needs replacement; hypochlorhydria & excessive phosphorus reduces GI absorpOon;

•  Deficiency extremely common; not easily measured; 60% in bone; RDA 350 mg; 450 mg during pregnancy; higher doses used; intracellular caOon •  Major role in reacOons involving ATP, DNA & RNA •  Hundreds of enzymes require magnesium •  Center of chlorophyll molecule (chelate like hemoglobin is of Iron) •  Has anOspasmodic effects and anO-‐excitaOon effects •  Found in MOM & Epsom salts •  Helpful in hypertension, anxiety, PMS, cardiovascular disease, asthma and many other condiOons; deficiency induces potassium loss •  In balance with calcium, between 2:1 and 1:2 raOo; helps to reduce intracellular calcium and abnormal calcificaOon •  Always balance calcium supplements with magnesium supplement •  Stress, alcohol, many drugs deplete magnesium •  Hard water with calcium & magnesium assoc with reduced CV deaths

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Michael B Schachter MD, CNS (ISOM) Toronto

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Michael B Schachter MD, CNS (ISOM) Toronto

Copper (Cu) Atomic Number 29

Selenium (Se) Atomic Number 34

•  Importance generally underesOmated •  Hard to assess with tesOng-‐stored in liver & serum level increases with inflammaOon; not necessarily reflecOon of excess •  Bound to protein ceruloplasmin, which is usually correlated with copper status (except in Wilson s disease) •  Deficiency related to weak elasOn and aneurysms, high cholesterol, atherosclerosis (work of Dr. Klevay), insomnia, cardiac arrhythmias, depression, anemia & leukopenia, hair turning gray or white •  Has anOfungal & anObacterial qualiOes •  Orthomolecular pracOOoners generally focus on toxicity rather than on nutriOonal importance (Carl Pfeifer s influence) •  Depleted with high doses of zinc, molybdenum and vitamin C •  IntenOonal depleOon used to reduce angiogenesis as a cancer therapy (with high dose zinc &/or Molybdenum) •  Dosage usually between 1 and 4 mg daily; someOmes more •  Balance with Zinc at about 10:1 raOo of Zinc to Copper

•  Not universally distributed worldwide & many areas insufficient, like many other minerals, such as iodine •  Important anOoxidant, works with glutathione peroxidase; helps to prevent lipofuscin or aging spots; works with vitamin E •  Increasing evidence as important in prevenOng and possibly treaOng cardiovascular disease (deficiency may cause cardiomyopathy—Keshan disease in China) & cancer, as well as cysOc fibrosis, SIDS, various neurological diseases & other condiOons •  Extremely important for iodine metabolism & thyroid funcOoning (Reduces anOthyroid anObodies & helps convert T4 to T3) •  Combines with mercury to neutralize mercury s toxic effects •  Dosage is usually between 100 and 1,000 mcg, though maximally tolerated dose set my Govt is set at 400 mcg •  Can be toxic in higher doses

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Michael B Schachter MD, CNS (ISOM) Toronto

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Manganese(Mn)Atomic Number 25

Michael B Schachter MD, CNS (ISOM) Toronto

Chromium (Cr) Atomic Number 24

•  Most manganese is in bone, liver & kidney •  EssenOal part of enzymes involved with energy producOon, bone formaOon, protein & fat metabolism •  Modulates neurotransmifer acOvity (used to help tardive dyskinesia-‐Richard Kunin MD, along with choline and niacin) •  Deﬁciency results in abnormal bone & carOlage formaOon with disk degeneraOon, impaired glucose tolerance, birth defects, seizures, cardiac arrhythmias, weight & hair color loss & dermaOOs •  EssenOal component of mitochondrial superoxide dismutase (SOD), which is a major AOX enzyme; other cytosol SOD uses copper and zinc •  Best sources nuts, grains & legumes

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Michael B Schachter MD, CNS (ISOM) Toronto

•  One of most deficient minerals in USA, as refined foods remove most chromium •  Involved with stabilizing blood glucose & deficiencies associated with metabolic syndrome & diabetes, Type II •  Glucose Tolerance Factor: Associated with niacin and the 3 amino acids glycine, glutamate & cysteine •  SynergisOc with vanadium •  Increase need in pregnancy •  Raises HDL and reduces atherosclerosis & heart disease •  Evidence it funcOons as an anOdepressant •  Trivalent state is nutriOonal; hexavalent state toxic

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The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

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Michael Schachter, MD Vanadium (V) Atomic Number 23

Molybdenum (Mo) Atomic Number 42

•  Proven to be essenOal in 19X1 •  SOmulates glucose oxidaOon & transport into fat cells and glycogen synthesis in liver & muscle, as well as inhibiOng gluconeogenesis •  Lowers blood sugar like insulin by altering cell membrane funcOon for ion transport •  Beneﬁcial for carbohydrate intolerance, bipolar disorder, ADD & ADHD, violent behavior, narcolepsy, diabetes prediabetes •  Inhibits cholesterol synthesis •  Strengthens contracOle force of heart •  AnOcancer ePect •  Works with chromium

Michael B Schachter MD, CNS (ISOM) Toronto

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•  Integral part of three essenOal enzymes: xanthine oxidase (catabolism of purines to uric acid), aldehyde oxidase (metabolizes aldehydes to acids) and sulﬁte oxidase to convert sulﬁtes to sulfates •  RDA for Mo is 250 mcg per day •  Toxicity occurs above 10 mg daily with symptoms of gout-‐like disease and interference with copper metabolism

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Boron (Bo) Atomic Number 5

Michael B Schachter MD, CNS (ISOM) Toronto

•  Symptoms of germanium deﬁciency include: reduced immune status, arthriOs, osteoporosis, low energy, faOgue and cancer •  Recommended maintenance dose is 30 mg daily and therapeuOc dosages are usually 100 to 200 mg daily •  Acts as a semiconductor, accepOng and transmiÉng electrons & is closely related to carbon and silica •  Healing properOes of some herbs may relate to high germanium concentraOons & high in holy waters at Lourdes •  Helps oxygen uOlizaOon and enhances immune funcOoning (sOmulaOng Nt cells & lymphokines such as IFN, macrophages & T-‐ Suppressor Cells •  Ge 132 (carboxyethyl germanium sesquioxide is relaOvely safe as a supplement, but other forms can be toxic

5/1/2011

Joel Wallach & the Role of Minerals in Health & Disease: Unusual Training & ExperOse

Joel Wallach BS, DVM, ND

5/1/2011

Michael B Schachter MD, CNS (ISOM) Toronto

Rare Earths: Forbidden Cures Joel Wallach & Ma Lan (1994)

• B.S. Agriculture with major in animal husbandry (nutriOon); DVM; Three-‐year post doctoral in comparaOve pathology • Involved in pathology research and did many animal autopsies-‐several species • Naturopathic degree from NCNP-‐Portland • Worked as Vet & Naturopathic Physician • X0 peer-‐reviewed publicaOons • Involved in markeOng nutriOonal supplements for many years; apparently quite successfully • Highly criOcal of medical profession • Controversial book & tape: Dead Doctors Don t Lie ; Extremely controversial, but worth checking out Michael B Schachter MD, CNS (ISOM) Toronto

Germanium (Ge) Atomic Number 32

•  Shown to be essenOal in chicks in 1981 and in humans in 1990 •  Needed for maintenance of bone density; helps to retain Ca, Mg & P in bones •  Needed for normal levels of sex hormones in men and women •  Component of boric acid to treat eyes •  Supplement dose usually 3 to 6 mg daily 5/1/2011

Michael B Schachter MD, CNS (ISOM) Toronto

• Chronic degeneraOve diseases primarily caused by mineral deficiencies • Soil is depleted of minerals related to agricultural pracOces • Pica and other cravings of abnormal substances due to mineral deficiencies • CombinaOon of scienOfic studies & popular news arOcles

5/1/2011

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Michael B Schachter MD, CNS (ISOM) Toronto

The Role of a Comprehensive Mineral Program in Orthomolecular Treatment

11-03-29

Michael Schachter, MD Wallach s Thesis

The Agebeaters & their Universal Currency for Immortality

•  Farmlands depleted of essenOal minerals •  Deﬁciency of any one mineral can cause several deﬁciency diseases •  In his books, Wallach examines the habits & diet of several long-‐lived cultures •  Long healthy life based on calorie restricOon while supplemenOng with plant minerals (because wood ash no longer available to ferOlize gardens) & high |uality anOoxidants; •  Dr. Roy Walford did major research in calorie restricOon including on himself, but did not supplement with minerals & died at age 79 of ALS

• Joel D Wallach BS, DVM, ND & wife Ma Lan MD, MS, Lac • Amazing amount of informaOon about minerals, including role in health & disease (including many not covered in this lecture) • Advocates supplementaOon with full range of plant minerals to prevent and treat a variety of degeneraOve diseases in animals with possible applicaOon to humans Michael B Schachter MD, CNS (ISOM) Toronto

5/1/2011

•  Exercise suicidal without supplementaOon (examples: James Fixx, Dr. George Sheehan & many other athletes die because exercise depletes minerals through sweaOng causing mineral deﬁciencies if not repleted ); average professional athlete lives to 62 while average couch potato lives to 78 years old •  Many major diseases have been eliminated in the livestock industry years ago by simple inexpensive nutriOonal supplementaOon (e.g. cardiomyopathy with selenium and aneurysms with copper). •  Stresses the importance of covering all bases in any treatment program (Suggests that there are 90 essenOal nutrients, including 60 minerals)

Michael B Schachter MD, CNS (ISOM) Toronto

•  Story of supplement developed for managing bipolar disorder and other psychiatric disorders (Bonnie Kaplan s lecture) •  MulOvitamin-‐mineral formula with an emphasis on high doses of minerals in proper relaOonship to each other—well absorbed; called EMPowerplus •  High doses of magnesium, copper, chromium and others •  Highly ePecOve, allowing paOents to drasOcally reduce or get oP medicaOons •  Resistance by pharmaceuOcal companies & Canadian Govt •  Court case—Company won •  See: www.truehope.com; get video and check out literature

5/1/2011

Dosage of Minerals in Supplement Used for Bipolar Disorder-‐15 caps/day

5/1/2011

Mineral

Dosage

Calcium

1,320 mg

Phosphorus

840 mg

Magnesium

600 mg

Zinc

48 mg

Copper

7.1 mg

Chromium

623 mcg

Manganese

8.75 mg

Selenium

204 mcg

Molybdenum

144 mcg

Iron

13.9 mg

Iodine

204 mcg

Boron, Vanadium Germanium Proprietary Michael B Schachter MD, CNS (ISOM) Nickel Toronto

Remember: Nutrients & Supplements Best Work as a Team

Wallach s Thesis-‐2

5/1/2011

Michael B Schachter MD, CNS (ISOM) Toronto

Strategies for Obtaining Necessary Minerals •  Show paOents the relaOonship between what they eat, how they feel and diseases they develop •  Emphasize whole food diet, organic when possible, a significant percentage should be raw vegan foods •  Stop refined, processed foods, fried foods, overcooked meats, sugar & white flour products, etc… •  Drink pure water and use unrefined salt •  Look to the sea, uOlizing seaweed and sea vegetables •  Take supplements: Full range of minerals supplements, including the rare minerals, in absorbable form •  Grow your own garden: the soil is likely to be much richer in minerals than agricultural land. 59

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Michael B Schachter MD, CNS (ISOM) Toronto

Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers Joe Pizzorno, ND

Mercury Burden in Canada:

Aca

Example Awards and Recogni5ons

Assessment and Interven5on for Oil Field Workers

–  Juror for Roger’s Prize – 2009, 2011 –  Ins5tute for Func5onal Medicine – Zinus Pauling Award, 2004 –  American Holis5c Medical Associa5on: ?ioneer in Holis(c Medicine, 2003

–  –  –  –

Dr. Joseph Pizzorno, ND

Policy

Natural Health demic Founding president (1978) of Bastyr University, ﬁrst accredited, natural medicine university Editor-‐in-‐Chief: !ntegra()e Medicine/ 0 1linician3s 5ournal Textbook of Natural Medicine, 3nd ed. 2004; 4th edi5on now in process

–  Member Medicare Coverage Advisory Commicee, 2003-‐2005 –  Member White House Commission on CAM Policy, 2000-‐2002

Dr. Joseph E. Pizzorno, N.D.

–  Encyclopedia of Natural Medicine, 1998 (1,000,000 copies in six languages) –  Encyclopedia of Healing Foods, 2005

PublicMagazine: Leading health educator in the past 30 years. 2001

–  Alterna5ve Healthcare Management: I of the J Kost inLuen(al 10M leaders, 2000 –  MeaNle Magazine: I of the top O0 na(onal intellectual leaders froK MeaNle, 1996

Overview •  •  •  •  •  •  •  •

Sources •  Average exposure in non-‐industrial popula5ons

Mercury toxicity, the hidden epidemic Forms Sources Excre5on/Detoxiﬁca5on Toxicity Assessment Interven5on What we found in Canada

–  Amalgams: 10 ug/d –  Fish: 2.3 ug/d –  Water: 0.3 ug/d –  Air –  gaccina5ons

•  Industrial Vimy, M.J., and Lorscheider, F.L (1990) Dental amalgam mercury daily dose estimated from intra-oral vapor measurements: A predictor of mercury accumulation in human tissues.]. Trace Elem. Exp. Med 3, 111-123

Amalgams

Forms

•  Typical amalgam is 55% Hg

•  Elemental •  Inorganic •  Organic

–  = 400 mg/ﬁlling

•  Release 10 ug/d •  Hg excre5on propor5onal to surface area (poorer correla5on with count) •  Release elemental Hg which is methylated by bacteria in gut and absorbed

–  Methyl from ﬁsh –  Ethyl from vaccina5ons –  Most toxic form –  90% absorbed –  Readily crosses blood-‐brain-‐barrier

Lorscheider FL, Vimy MJ, Summer O. Mercury exposure from “silver” tooth fillings: emerging evidence questions a traditional dental paradigm. FASEBJ. 9,504-508(1995) Apostoli P, ICortesi I, Mangili A, et al. Assessment of reference values for mercury in urine: the results of an Italian polycentric study. The Science of the Total Environment 289 (2002)13-24 5

127

Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers Joe Pizzorno, ND Amalgams in Children

What Autopsies Tell Us

•  517 children •  Randomized to composite/amalgam •  Age 8-‐10 when inserted •  Followed 7 years •  Strong correla5on between surfaces and urinary excre5on

•  Mercury accumulates in the brain in propor5on to surface area •  Study of 18 cadavers –  Hg in brain, thyroid and kidneys propor5onal to the number of amalgam surfaces –  For those with more than 12, Hg in brain dispropor5onately higher –  Suggests that at higher levels of exposure the brain’s mercury excre5on pathways become overloaded.

–  6% increase/surface

•  Iirls poorer excre5on

J.W. Reinhardt. Side-Effects: Mercury Contribution to Body Burden From Dental Amalgam. Adv. Dent. Res. 1992; 6; 110 Guzzi G, et al. Dental amalgam and mercury levels in autopsy tissues. Am J Forensic Med Pathol. 2006 Mar;27(1):42-58

Woods JS, et al. The contribution of dental amalgam to urinary mercury excretion in children. Environ Health Perspect. 7 2007 Oct;115(10):1527-31

What Live Tissues Tell Us

Hg From Fish

•  Donated kidneys for transplant •  R = 0.62 correla5on with number of amalgam surfaces •  6% increase in kidney Hg per amalgam surface

•  Total Hg urinary excre5on propor5onal to amount of ﬁsh eaten •  Impaired psychomotor performance –  R = 0.38 blood –  R = 0.77 urine

Barregard L, et al. Cadmium, mercury, and lead in kidney cortex of living kidney donors: Impact of different exposure sources. Environ Res. 2010 Jan;110(1):47-54

Apostoli P, ICortesi I, Mangili A, et al. Assessment of reference values for mercury in urine: the results of an Italian polycentric study. The Science of the Total Environment 289 (2002)13-24 Carta P, et al. Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through fish 10 consumption. NeuroToxicology 24 (2003) 617–623

Mercury in the Air

Mercury In Fish

http://kitchenscoop.com/blog/concerned-aboutmercury-in-fish-heres-an-update/

EPA-452/R-97-003 December 1997

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Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers Joe Pizzorno, ND Hg Concentrates in Fetus

Mercury Distribu5on 3n the Body

•  Both MeHg and elemental Hg •  MeHg 100% higher in cord blood •  Cord blood Hg correlates with # of maternal amalgams, r = 0.46 •  Fetal brain 40% higher than maternal brain AND more sensi5ve to damage

•  Except immediately aker exposure, mercury in the 5ssues is at a higher concentra5on than in the blood. •  Methyl mercury easily crosses blood-‐brain-‐barrier •  Typical issue distribu5on ra5os. –  Blood = 1 (~5% of body burden) –  Brain = 2-‐13 –  Liver = 5 –  Kidney = 33 –  Bone = 100

Palkovicova L, et aI. Maternal amalgam dental fillings as the source of mercury exposure in developing fetus and newborn. J Expo Sci Environ Epidemiol. 2008 May;18(3):326-31 Björnberg KA, et al. Transport of methylmercury and inorganic mercury to the fetus and breast-fed infant. Environ Health Perspect. 2005 Oct;113(10):1381-5

•  Most is bound to sulfur compounds

Excre5on

Body Distribu5on •  Hair

•  Study of radioac5ve Hg distribu5on in a monkey •  16 ﬁllings •  28 days aker ﬁlling implanted •  Note especially high concentra5on in pituitary

–  Primary route for methyl mercury (Me Hg)

•  Liver/Bile

–  Primary route of excre5on 80-‐P0% –  Bound to glutathione –  Enterohepa5c recircula5on. reabsorp5on substan5al –  Dependent on ﬁber, bacteria, pH, etc.

•  Kidneys/Urine

–  ~10% daily excre5on

Hahn, LJ; et al. Whole-Body Imaging of the Distribution of Mercury Released from Dental Fillings into Monkey Tissues. FASEB 15 J. 4:3256-609 1990

Toxicity

Mercury

•  Enzyme poisoning •  8xida5ve stress •  Tissue damage

•  Children born to women with blood mercury >5.8 ppb have a "higher risk of adverse health eﬀects." –  8% of women of child-‐bearing age tested had "at least" that level of Hg –  >300,000 born every year in US at increased risk due to mercury toxicity

–  Neurological especially suscep5ble –  3nhibits forma5on of myelin –  Signiﬁcant lag 5me (weeks to months) before symptoms occur

•  Women may have levels 7x higher if frequent consump5on of ﬁsh/shellﬁsh

•  8rgan dysfunc5on

–  Brain, kidneys especially suscep5ble –  Fetus and infants especially suscep5ble

Schober SE, et al. Blood mercury levels in US children and women of childbearing age, 1999-2000. JAMA. 2003 Mahaffey KR,et al. Blood organic mercury and dietary mercury intake: National Health and Nutrition Examination Survey, 1999 and 2000. Environ Health Perspect. 2004 17

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Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers Joe Pizzorno, ND No Gold Standard For Body Load

Assessment •  •  •  •  •  •  •

•  •  •

Serum RBC Whole blood Hair Nails Urine Urine challenge

•

Poor correla5on between the measures Huge inter-‐person and inter-‐test varia5ons Best measure of Hg from ﬁsh is whole blood/plasma methyl mercury/hair (only excretes organic) Best measure of mercury from amalgams is whole blood/plasma inorganic mercury and urinary inorganic Hg.

Berglund M, et al. Inter-individual variations of human mercury exposure biomarkers: a cross-sectional assessment. Environ Health. 2005 Oct 3;4:20

Evalua5on of Mercury Exposure

Poor Inter-‐Test Correla5on

•  Hair Hg >5 ppm indica5ve of toxicity

–  However, poor detoxiﬁers will have false nega5ve –  Not good es5mate of inorganic mercury, becer for methylmercury –  Decrease in IQ of 0.18 points/ppm increase in maternal hair Hg

•  Poor correla5on between blood and urine , r = 0.30 •  Becer correla5on between blood and hair, r = 0.56

•  Fecal Hg

–  80-‐90% of Hg is excreted via bile (enterohepa5c recircula5on) –  Fecal Hg correlates with # amalgams –  No pharmaceu5cal provoca5on agent required

•  Urine

–  Unprovo<ed urine has reference range established for US popula5on, represents acute exposure –  Provo<ed (DMPS) urine probably becer measure of body load

Katz SA, et al. Use of hair analysis for evaluating mercury intoxication of the human body: a review. J Appl Toxicol. 1992 Axelrad DA, et al. Dose-response relationship of prenatal mercury exposure and IQ: an integrative analysis of epidemiologic data. Environ Health Perspect. 2007 Marques RC, Dórea JG, Fonseca MF, et al. Hair mercury in breast-fed infants exposed to thimerosal-preserved vaccines. Eur J Pediatr. 2007 Berglund M, Lind B, Björnberg KA, et al. Inter-individual variations of human mercury exposure biomarkers: a cross-sectional assessment. Environ Health. 2005 Risher JF, De Rosa CT. Inorganic: the other mercury. J Environ Health. 2007

Zimmera H, et al. Determination of mercury in blood, urine and saliva for the biological monitoring of an exposure from amalgam fillings in a group with self-reported adverse health effects. Int. J. Hyg. Environ. Health 2002;205(3):205-211 Berglund M, et al. Inter-individual variations of human mercury exposure biomarkers: a cross-sectional assessment. Environ 22 Health. 2005 Oct 3;4:20

Assessment Recommenda5on

Mercury Neurological Symptoms

•  First morning urine –  Acute exposure

•  300 mg DMPS –  6 hour collec5on –  Body load

S Langworth, O Almkvist, E Söderman, and B O Wikström. Effects of occupational exposure to mercury vapour on the central 24 nervous system. Br J Ind Med. 1992 August; 49(8): 545–555

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Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers

Most common Symptoms of Hg

Joe Pizzorno, ND Symptom

Depression Memory loss Anxiety Unintentionally dropping things Headache Moody Shakiness in hands Stomach problems Fatigue Confusion Change in sense smell or taste Parasthesia Sleep disturbance Coordination problems Muscle weakness

Frequency

Interven5on

73% 70% 69% 60% 56% 45% 44% 43% 39% 35% 29% 26% 25% 20% 16%

•  Avoidance

–  Choose lower Hg ﬁsh –  Amalgam removal

•  •  •  •  •  •

IV DMPS Oral DMSA Natural agents Fiber Diet Sauna 26

Pizzorno J. The mercury epidemic. IMCJ 2009; 8:1

What We Found In Canada

Assessment Correla5ons •  Extensive measurements in 65

60.0

–  Whole blood Hg –  Oral DMPS challenge –  Amalgam surfaces –  –  –  –  –  –

•  Devia5ons from the mean of 14h, 2Ph and P1h respec5vely •  DMPS is spreading distribu5on, sugges5ng that it is becer at diﬀeren5a5ng mercury body load 27 •  Some VERY high

Whole blood w pre urine: r = 0.40 Whole blood w post urine: r = 0.57 Pre urine w post urine: r = 0.68 Amalgams w pre urine: r = 0.26 Amalgams w whole blood: r = 0.36 Amalgams with post urine: 0.44

50.0

Post Urine Hg ug/g

•  Correla5ons

40.0

30.0

20.0

10.0

0.0

Number of Amalgams

Interven5ons We Gsed

DMPS Brain Fog

•  Removal of amalgamstmust use ecological den5stuu •  IV DMPS

•  Asserted to be due to:

•  DMSA

•  My opinion:

–  Trace mineral loss –  Hypoglycemia

–  Stopped because of excessive adverse events –  “Brain fog” –  250 mg x 3 days, 11 days oﬀ

–  Transient increase in mercury (and lead) blood levels –  Neurotoxicity of DMPS

•  NAC

–  600 mg bid

•  Does not cross intact blood-‐brain-‐barrier? •  BBB more permeable than we were taught in medical school:

•  Fiber

–  PGX: 2.25 g 5d

–  Hyperinsulinism –  Mercury toxicity –  Food allergies (likely anything that increases gut permeability)

•  Suppor5ve nutrients

–  Mul5vitamin designed to promote glutathione produc5on –  CaeMgeyn un5l custom mul5vitamin available 29

131

Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers Joe Pizzorno, ND Neurotoxicity of Chela5ng Agents

(lood Levels Aker IV DMPS •  Single dose IV DMPS 2 mg/kg •  Higher blood levels in those with amalgams •  Rebound •  Some experience eleva5on due to binding of Hg in kidneys and release into blood •  Concluded DMPS not clinically eﬀec5veuu

•  In vitro cor5cal culture: –  * Much higher dosages than achieved clinically –  Increase metal toxicity –  Increase toxicity of iron •  High Fe levels common in men

Vamnes JS, et al. Blood mercury following DMPS administration to subjects with and without dental amalgam. Sci Total Environ. 2003 Jun 1;308(1-3):63-71

Clear is metal alone, gray is metal + chelate Rush T, et al. Effects of chelators on mercury, iron, and lead neurotoxicity in cortical culture. Neurotoxicology. 2009;30(1):47-51 31

DMSA

•  2,3-‐Dimercaptosuccinic acid •  SH-‐containing, water-‐soluble, low-‐toxicity, oral (IV toxic) •  Developed in 1P50s as alterna5ve to more toxic chela5ng agents •  10-‐20% of oral dose absorbed •  Chelates all forms of mercury (more eﬀec5ve for Pb) •  ½ through urine, ½ through bile •  Amount of Hg bound: ~7.5 ug/g of oral DMSA •  Increases glutathione produc5on •  ½ life in blood 2-‐3 hours

•  Nutrients to improve eﬃcacy –  Alpha lipoic acid –  NAC –  Probio5cs –  Fiber

•  Research studies use 30 mg/kg/day –  7 days on, 7 oﬀ –  Not recommended

•  Protocol we used:

–  50 mg trial dosea if no reac5on within 2 hours:

•  250 mg qd for 3 days then oﬀ for 11 days, or •  250 mg every 3rd day before bed

Ruha AM, Curry SC, Gerkin RD, et al. Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters. Arch Pathol Lab Med. 2009 Jan;133(1):87-92 Roels HA, Boeckx M, Ceulemans E, Lauwerys RR. Urinary excretion of mercury after occupational exposure to mercury vapour and influence of the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA). Br J Ind Med. 1991 Apr;48(4): 247-53 33

Graziano JH, et al. 2,3-Dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther. 1985;37(4):431-8

DMSA

NAC •  Most research animal and human cell lines •  Mul5ple bene_ts: –  Increases produc5on of glutathione –  Protects human neurological cells from Hg toxicity –  Reverses damage to human pancrea5c cells from Hg –  Directly binds to Hg, esp. MeHg, and excrete through kidneys

•  At high dosage (30 mg/kg/day):

–  14% elevated ALT –  Mucosi5s –  50% increased loss of Zn

•  At low dose

–  Primary adverse event is allergy, typically skin rash –  No apparent drug interac5ons •  Not recommended in pregnant women (no research)

–  Animal research: removes MeHg in blood, brain and kidneys of fetus

Bradberry S, et al. Use of oral dimercaptosuccinic acid (succimer) in adult patients with inorganic lead poisoning. QJM. 2009 Oct;102(10):721-32 C.C. Bridges, L. Joshee, R.K. Zalups. Effect of DMPS and DMSA on the placental and fetal disposition of methylmercury. Placenta 30 (2009) 800–805 35

Aremu DA, et al. N-acetylcysteine as a potential antidote and biomonitoring agent of methylmercury exposure. Environ Health Perspect. 2008 Jan;116:26-31 Ballatori N, et al. N-acetylcysteine as an antidote in methylmercury poisoning. Environ Health Perspect. 1998 May;106:267-71 36

132

Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers Joe Pizzorno, ND Fiber

NAC

•  Decrease enterohepa5c recircula5on •  No signiﬁcant research on ﬁber •  PGX

•  IV

–  Treatment of acute acetaminophen poisoning –  150 mg/kg body weight given over 15-‐60 minutes –  Epec5ve but high incidence of adverse eventstEW only!!

–  Wesearch support for improving insulin sensi5vity and weight loss –  2.25 g 5d

•  Oral

–  Safe: No serious adverse events in review of 4,000 pa5ents –  500 mg: 1-‐2 5mes a day 37

Atkuri KR, et al. N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007 Aug;7(4):355-9

Selenium

Glutathione: Cri5cal

•  Dietary selenium (Se) status is inversely related to vulnerability to methylmercury (MeHg) toxicity

•  Diﬃcult to overstate its importance •  Most important intracellular and intra-‐ mitochondrial an5oxidant •  Binds and transports mercury out of cells •  Binds and transports mercury out of the brain •  Irreversibly(?) binds to mercury in the brain •  Neutralizes oxida5ve damage from mercury •  Depleted by oxida5ve stress, metals, alcohol •  Even predictor of healthy aging!

–  Directly binds MeHg –  Prevents oxida5ve damage –  Helps protect selenoenzymes which are par5cularly suscep5ble to MeHg –  High Hg ﬁsh also rich in Se are less toxic to fetal brain (probably due to maintenance of thyroid func5on) –  Wequired for glutathione produc5on Ralston NV, Raymond LJ. Dietary selenium's protective effects against methylmercury toxicity. Toxicology. 2010 Nov 28;278(1):112-23

Baker, SM. The Metaphor of Oceanic Disease. IMCJ February, 2008;7:1

Glutathione: Decrease Deple5on

Glutathione: Direct Administra5on

•  Decrease u5liza5on

–  Decrease toxic exposure, esp alcohol

•  Oral glutathione

–  Decrease oxida5ve markers, increase GSH –  Alpha lipoic acid for mitochondria –  Vitamin D for brain –  Melatonin for brain

•  Oral liposomal glutathione

–  Inconsistent research; 3 g did not work in humans

•  Decrease oxida5ve stress

–  Early promising research

•  IV glutathione

–  Very epec5ve, but may increase Hg transport into brain

•  Intranasal glutathione

–  Intriguing, does not transport Hg from blood –  Only lung absorp5on documented (very epec5ve)

Addolorato G, et al. Effects of short-term moderate alcohol administration on oxidative stress and nutritional status in healthy males. Appetite. 2008 Jan;50(1):50-6 Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: overview. Neurochem Res 2008;33:194-203 Garcion E, et al. New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab. 2002 Apr;13(3):100-5 Herrera J,. Melatonin prevents oxidative stress resulting from iron and erythropoietin administration. Am J Kidney Dis. 2001 Apr;37(4):750-7 41

Witschi A, et al. The systemic availability of oral glutathione. Eur. J. Clin. Pharmacol 1992;43(6): 667–9 Cooke RW, Drury JA. Reduction of oxidative stress marker in lung fluid of preterm infants after administration of intratracheal liposomal glutathione. Biol Neonate. 2005;87(3):178-80 Buhl R, et al. Augmentation of glutathione in the fluid lining the epithelium of the lower respiratory tract by directly administering glutathione aerosol. Proc Natl Acad Sci USA 1990;87:4063–7 42

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Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers Joe Pizzorno, ND

134

Mercury Burden in Canada: Assesment and Intervention for 1,500 Oil Field Workers Joe Pizzorno, ND Summary •  Mercury toxicity is real and contributes to a wide range of overt and subtle health problems •  Decrease exposure –  Remove amalgams –  Chose low Hg ﬁsh

•  •  •  •  •

Increase ﬁber to decrease enterohepa5c recircula5on Oral DMSA protocol NAC daily Glutathione support Ba5enceu

135

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

Introduc1on

Orthomolecular Detoxi0ca1on

•  300+ Lunch and Lectures •  The Most Important Nutrient –  The one you are lowest in –  The one I just lectured on

Ron Hunninghake, M.D.

•  The Most Overlooked Cause of Illness –  Toxicity…both exogenous and endogenous –  Detoxi0ca1on Overload

Chief Medical Oﬃcer

Riordan Clinic

Second Disclaimer

First Disclaimer

•  In this presenta1on, I will not be addressing tradi1onal detoxi0ca1on: Fas1ng Exercise Herbs Homeopathy Mind/body

Detox Diets Yoga Enemas Massage Liver Flush

Other relevant topics I won t get to: – Environmental Toxins – EDCs: Endocrine Disruptor Compounds – Sources of EDCs – Classes of EDCs – Common EDCs – Health Eﬀects UVributed to EDCs – Wiomagni0ca1on

Sauna Chela1on Colonics Medita1on Spas & more…

•  These are important methods of detox, but beyond the scope of this presenta1on

EDCs: Endocrine Disruptor Compounds

Environmental Toxins •  Since WWII – 85,000 new chemicals have been introduced to the modern environment •  15 of the 20 most toxic pollutants are known nervous system poisons •  80% of these new chemicals have never been screened for their eﬀects on human health •  Many of these adversely aﬀect endocrine metabolism and energy produc1on in the body and have been labeled Endocrine Disruptors

•  EDCs are exogenous (from outside the body) •  EDCs act like hormones in the endocrine system •  EDCs disrupt the func1on of endogenous hormones

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Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

Sources of EDCs •  •  •  •  •  •  •

Classes of EDCs •  •  •  •  •  •  •

Industry and agriculture Mood contamina1on Xater pollu1on Air pollu1on Household chemicals Plas1cs Natural sources

Common EDCs •  •  •  •  •  •

Pes1cides Plas1cs Pharmaceu1cals (such as an1bio1cs) Heavy metals Industrial pollutants Hormones Plant cons1tuents (such as genestein from soy)

Health ETects AVributed to EDCs

PCB s and PBDE s Bisphenol A Phthalates DDT Dioxin Heavy metals – Mercury

•  3eproduc1ve problems –  reduced fer1lity –  male and female reproduc1ve tract abnormali1es –  skewed maleRfemale sex ra1os –  loss of fetus, menstrual problems •  Hormonal dysfunc1on •  blandular dysfunc1on (especially the thyroid) •  Early puberty •  Brain and behavior problems •  Impaired immunity •  Various cancers

–  Lead –  Arsenic

Biomagniﬁca1on

Lake !ntario Biomagniﬁca1on of PCBs

•  Ini1ally, the EDC s concentra1on in the environment may be miniscule •  Accumula1on occurs in the faVy 1ssues of organisms low in the food chain •  Larger animals eat smaller animals •  As each successive rung on the ladder of the chain is climbed, an exponen1al increase in the concentra1on of the toxin occurs •  The top food chain animals may harbor many million 1mes the toxin s original concentra1on

•  •  •  •  •  •

137

Phytoplankton – 250x Zooplankton – 500x Mysid (shrimp) – 45,000x Smelt (small ﬁsh) – 835,000x Lake trout – 2,800,000x Herring gull – 25,000,000x

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

O.M.D. Premise #1

Third Disclaimer

The right molecules are needed to get rid of the wrong molecules

•  My topic turned out to be bigger than I originally suspected…and more complex

•  Ortho Molecular Detoxi0ca1on Premises –  I have included 10 O.M.D. PREMISES to guide your understanding of this complex topic –  I apologize if these premises appear overly simplis1c

A Cellular Model of Health and Healing

Pathologic Model of Disease

•  Health – balanced redox •  Injury – d,sru/0on •  Signal – ox,da0on •  Repair – ,n1a22a0on •  Healing – restora0on

•  Health – balanced redox à MalnutriEon •  Injury – d,sru/0on à Injury (Persistent) •  Signal – ox,da0on à Distress •  Repair – ,n1a22a0on à Dis-‐ease •  Healing – restora0on à Toxicity

Eustress

Distress

Distress 9/02,:a0on

Malnutri1on

Toxicity

Nutrients

Pathos Imbalance

Injury

7etox,8ca0on

Toxins Orthos Pathos

6da/ta0on

Disease

Injury

138

4e5enera0on

Disease

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

Toxi vs. Ortho Molecular

Orthos is Health & Healing •  •  •  •

•  Toxi – poisonous

Nutrients well-‐chosen to sa1sfy redox need Injuries well-‐aMended to restore func1on Distress signals well-‐heeded to direct ac1on Diseases well-‐treated to promote healing

•  Greek – toxikon •  (poison) for use on arrows"

•  Ortho – correct •  Greek – orthos

•  right, true, straight, leading to the desired result

•  Toxins well-‐processed to restore health

Ortho vs Toxi-‐Molecular

Health Hunter –1996 •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •

Nutrients

Essen1al to life Feed biochemical pathways Non-‐specific, global effects Synergis1c interac1ons Wide range of effec1ve dose Excess rarely toxic Found in nature Tested for millions of years Work slowly, gently Side benefits Non-‐addic1ve Less expensive Non-‐patentable Consumer oriented Promotes health User friendly Chronic care No fatali1es in 20 years

•  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •

O.M.D. Premise #2

Drugs

Generally non-‐essen1al Block or alter pathways Organ-‐targeted Adverse interac1ons Narrow range of eﬀec1ve dose Excess commonly toxic Found in the lab Tested for millions of dollars Work rapidly, forcefully Side eﬀects Can be addic1ve More expensive Patented Doctor oriented Treats disease Dangerous Acute care j.k million reac1ons per year

Toxins occur both

outside and inside the body

Toxin Sources Exogenous Lungs Skin

Exogenous Toxins

Umbilical cord

•  A huge modern experiment is underway, involving this and the last few genera1ons •  There are no controls for this experiment •  Every living organism on earth is now carrying Persistent Organic Pollutants (POPs)

Microﬂora

•  Cord blood tested + for 287 of 413 chemicals

Endogenous

Total Environment Metabolism Food Water Air

Gut

–  180 were known carcinogens –  217 were known to be neurotoxic –  208 were known to cause birth defects in animals

139

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

What is the Body s

O.M.D. Premise #3 The body uses energy to make molecules to remove toxic molecules

Major Mo4ecu4e-‐Ma!ing @cEvity? •  In adults à Detoxiﬁca1on (for children it is growth)

•  Detoxiﬁca1on involves mostly

synthesis as opposed to degrada1on

•  New molecules are made for the sake of safe disposal of toxic molecules •  Detoxiﬁca1on is an energy-‐costly process

Body as a Municipality: The Energy Budget*

Cytochrome P450 – Phase I Detox The ﬁrst detox enzyme was discovered in 70 s –  Contained iron –  High levels found in the liver

•  Sanita1on – 79% Detox systems •  Police – 5% Immune system •  School – 10% Nervous system •  Public Works – 6% InTammaEon \ repair

–  EmiVed absorbed Uc radia1on at 450-‐nm Cytochrome 450 bio-‐transforms lipophilic substances into more hydrophilic (soluble) substances via hydroxyla1on reac1ons 61 cytochrome enzymes discovered to date

*Detoxification & Healing – Sidney Baker

Phase II Conjugases

ConjugaEon – Phase II Detox •  Phase I intermediates are further biotransformed by conjugases

•  •  •  •  •  •

•  These are enzymes that aMach mo4ecu4es: sulfates à sulfa1on glucuronic acid à glucuronida1on methyl groups à methyla1on

•  Drugs7 xenobio1cs7 hormones7 and endogenous metabolites compete for these conjugases •  Over 58 diﬀerent human genes regulate a whole family of phase I and II detoxiﬁca1on enzymes

140

Glutathione-‐S-‐transferase (various iso-‐forms) N-‐acetyl transferase ( fast & slow acetylators ) Sulfo transferase Catechol-‐methyl transferase UDP-‐glucurono-‐syltransferase These enzymes ooen work in parallel with one another

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

Lipid Soluble

Phase I

Nutrient Cofactors: B vitamins, glutathione, flavonoids

Protective Antioxidants: C & E vitamins carotenoids

Reactive Intermediate Metabolites

O.M.D. Premise #4 Phytochemicals that induce:

Phase II

Stress unmasks 5ene1c varia1ons that can adversely aﬀect detoxi0ca1on

onions garlic broccoli cauliﬂower Brussels sprouts

Water Soluble

(excreted in urine/bile)

Ppi5ene1cs

Biochemical Individuality Genomic Variability •  4undreds of ONas _sin5le nucleo1de polymorphisms) typos exist in humans •  ONas modify the structure and func1on of phase I & II detox pathways in individuals •  KCere is wi0e 'ariaEon in in0i'i0ual suscepEbility to en'ironmental toLins •  Ppi5ene1c and nutri1onal factors further complicate delinea1on of ris6 of illness

s ne

vir

Phenotypic Expression of Health or Disease

O.M.D. Premise #5

Lipid Soluble

Phase I SNPs causing up-regulation

Reactive Intermediate Metabolites

Nutrients at orthomolecular doses can help to compensate for adverse 5ene1c varia1ons

SNPs causing down-regulation Phase II

Water Soluble

Cancer

(excreted in urine/bile)

Oxidation & Inflammation

141

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

Orthomolecular Strategies

Example:Glutathione S-‐transferase

(to Compensate for a GST P1 Polymorphism)

•  The pi-‐1 iso-‐form located primarily in the brain and lungs •  If both parent contribute a SNP leading to down-‐regula1on à lo$ers RQK acE'ity •  Increases toxic burden which could lead to higher risk of developing various cancers

Categories GSH Precursors

•  Orthomolecular DetoLi`caEon can compensate for this occurrence

Fnter'enEons NAC, B6, Magnesium, L-‐glutamine, glycine, methionine-‐rich foods

An1oxidants

Colorful, phytonutrient-‐rich foods, vitamins C, E, A, D3, etc.

Limit GSH Loss

Limit GSH deple1on with ALA, milk thistle, taurine, no Fructose Corn SS

Dietary

Emphasize cruciferous veggies and alliums (garlic) to reduce cancer risk

Lifestyle

Minimize exposure to xenobio1cs, toxic metals, charcoaled foods

Methyla1on Chemistry

O.M.D. Premise #6 Disrup1on of the methylaEon cycle by the NO/ONOO-‐ cycle* explains MANY chronic diseases *www.thetenthparadigm.org

•  Methyla1on is adding and subtrac1ng a methyl group in a cyclic fashion •  Over 1[@ reac1ons in the body repuire methyla1on •  A blockage in methyla1on chemistry profoundly inﬂuences ALL of the downstream products of methyla1on

Glutathione Deple1on Y 1

Dr. Richard A Van Konynenburg s sketch of Methylation Cycles

•  Glutathione can be depleted by disrup1on of basic methyla1on chemistry •  Individuals with a gene1c predisposi1on (based upon 12-‐14 SNPs) are suscepE3le when they experience major STRESSORS •  These stressors increase the body s demand upon ﬁnite glutathione reserves

142

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

Glutathione -eple1on Y 2

Dr. Richard A Van Konynenburg s sketch of Methylation Cycles

•  Glutathione levels are rapidly deplete as sulfur metabolites drain down the transsulfura1on pathway •  àoxida1ve stress mounts _see ONOO-‐) •  àB12 protec1on diminishes •  à toxins accumulate •  à immune response is aVenuated

Glutathione -eple1on Y ? •  Toxins interfere with B12 metabolism and a reduc1on in the rate of methyl B12 forma1on ensues •  ONOO-‐ inhibits methionine synthase (MT) which places a par1al bloc6 in the methyla1on cycle •  Then sulfur metabolites drain through the transulfura1on pathway excessively

.NO

.OO-

à

See Dr. Martin Pall s amazing web site: www.thetenthparadigm.org

ONOO-

Glutathione -eple1on Y e

Nitric Oxide + Superoxide à Peroxynitrite

Self-propagating vicious cycles

•  Un ever-‐growing interac1on _vicious cycle) is established between – the methyla1on cycle bloc6 –  glutathione deple1on – and ON/ONOO-‐ cycling •  This interacEon becomes chronic and the organism doesn t know how to ﬁx itself!

NO/ONOO Cycle

143

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

O.M.D. Premise #7

The NO/ONOO-‐ Cycle Can Explain 1.  Chronic Fa1gue Syndrome 2.  Mul1ple Chem. Sensi1vity 3.  Fibromyalgia 4.  Gulf War Syndrome (PTSD) 5.  Tinnitus 6.  Post-‐Radia1on Syndrome 7.  Mul1ple Sclerosis 8.  Au1sm 9.  Overtraining Syndrome 10.  Silicone Implant Syndrome

Many chronic illnesses can be explained by the vicious cycling of d+s-‐meth+laEo" a"d NO/ONOO-‐

The Methyla1on Cycle Block

11. Sudeck s atrophy 12. Post-‐4erpe1c Neuralgia 13. Chronic Whiplash 14. ALS 15. Parkinson s Disease 16. Alzheimer s Disease 17. Asthma 18. Irritable Bowel Syndrome 19. Epilepsy 20. Spinal Cord Injury

Methyla1on DisordersK or Detox Overload?

•  Glutathione and SAM deficiencies can be documented by laboratory tes1ng •  These deficiencies can be treated with an orthomolecular protocol •  Nathan & Van Konynenburg studied 50 fibromyalgia pa1ents using a simple methyla1on protocol and 75^ got beVer

MS Asthma Dysbiosis Wrinkles CFIDS Gall stones

O.M.D. Premise #8

ALS Parkinson s Demen1a Schizophrenia Gastri1s Depression Obesity Neuropathy Diabetes Fibromyalgia Cancer Chem. Sensi1vi1es

Detoxi`caEo" Overload? CFIDS

Most modern diseases arise out of OVERLOAD STRESS on detoxiﬁca1on systems

HypoCrohn s thyroidism

BOSI

IC DM2

Malabsorption

Restless Leg

144

IBS

•  Bacterial Overgrowth of the Small F"tesE"e •  Chronic Fa1gue Syn. •  Fibromyalgia •  IBS / Malabsorp1on •  Osteoporosis •  Autoimmune Disease •  Thyroid disorders •  Candidiasis •  Inters11al Cys11s •  Restless Leg Syndrome •  Crohn s Disease •  Diabetes Mellitus 2

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

Load vs. Capacity

Sick?…or… Intoxicated? Disease •  •  •  •  •  •  •  •  •  •  •

Toxicant

Alcoholism-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐ Alcohol Schizophrenia-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐ Adrenochrome Parkinson s-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐ Pes1cide residues Pain med addic1on-‐-‐-‐-‐-‐-‐ Narco1cs (street or prescribed) Hepa1c Steatosis-‐-‐-‐-‐-‐-‐-‐-‐ Fructose (corn syrup solids) Diabetes-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐ Processed sugars Obesity-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐ Non-‐whole foods Food Sensi1vi1es-‐-‐-‐-‐-‐-‐-‐-‐-‐ indigested pep1des PCOS-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐ Testosterone Celiac-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐ Gluten Au1sm-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐ Mercury?… BOSI?...gluten?

Nutri1onal status Glutathione reserves Hepa1c func1on Gastrointes1nal inqamma1on Heavy metal load (Mercury from ﬁllings)

O.M.D. Premise #9

Four Proposed Mechanisms of Detox Overload Diseases

Disease Pn11es are a modern conceptual device that names the imbalance but ignores the underlying causa1ve factors

1.  Pxcessive exposure or intake of xenobio1cs or environmental carcinogens 2.  Gene1cally lower detox capacity (SNPs) 3.  Decrease capacity to handle short-‐term, high-‐ load stress! 4.  Insuﬃcient nutrient support for detox à Compromised ability to detox toxicants

An Outdated Paradigm

7onvenEonal PerspecEve •  •  •  •  •  •  •

•  People are normal unless they have a disease •  People get sick because they have a disease •  People are vic1ms of diseases that just happen to them or aVack them

145

Industrial taxonomy model of disease Low-‐level toxicity ignored Chemical sensi1vity syndrome dismissed Principle of Parsimony ooen myopic Mul1ple-‐factor-‐causa1on ignored Tendency is to label symptoms: diseases Outcome: the disease en1ty is treated with a pharmaceu1cal toxin

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

Ortho vs. Toxi-‐Molecular

Naming a Problem vs. Finding its Cause •  Disease as an en1ty ooen does not exist •  Giving a diagnosis ooen meansN Thinking can stop and prescribing can start.

•  Group treatments ooen do not meet the real needs of the suﬀering individual •  Please…do not dignify the symptom as a discrete en1ty separate from unipue gene1c predisposi1ons and imbalances

•  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •

Nutrients

•  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •

Drugs

Most Detox Goes On At Night

O.M.D. Premise #10

•  Faulty detoxiﬁca1on is a common cause for poor sleep •  Insomniacs commonly don t need seda1ves, their livers need detox help!

A few prac1cal DetoLi`caEon Pearls to keep in mind

Reduced Glutathione

Dr. Leon Rosenberg

•  Lost from the body when a foreign chemical is detoxiﬁed •  Reco'ered from detoLi`caEon .rocesses when the toxins are generated from our own endogenous chemistry

We have proof that for some persons in par1cular circumstances, pharmacologic doses of vitamins are essen1al. _Dr. Rosenberg an1cipated the great work of Dr. Bruce Ames)

146

Orthomolecular Treatment for Heavy Metal Toxicity

11-04-05

Ron Hunninghake, MD

Intravenous Vitamin C •  •  •  •  •

High Dose Vitamin B3

Irwin Stone Linus Pauling and Ewan Cameron Hugh Riordan Thomas Levy 8ar1n Pall

A''$!B'C')D!E,F'!E*%5')!G,3=!H,3#2,%!BI! Nutrient Deficiency and Dependency Dr. Abram Hoffer and Dr. Harold Foster Scavenging and Synthesizing Niacin Deficiency Pandemic

10 Major Disease Paradigms

In Conclusion…

1. Infec1ous diseases ]. bene1c diseases 3. Nutri1onal deﬁciency diseases e. Hormone dysfunc1on diseases 5. Allergies 6. Autoimmune diseases 7. Soma1c muta1on/selec1on (cancer) 8. Ischemic cardiovascular diseases 9. Amyloid (including prion) diseases 10. NO/ONOO-‐ cycle diseases

•  For the last 70 years, the dominant theory in medicine is that people get sick because they are vic1ms of disease en11es •  People get sick because of a disrup1on of the dynamic balance that exists between them and their environment –  bene1c factors –  Environmental factors –  Nutri1onal factors

147

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Level of IL-4 and IL-5 in mice sera on day 7th of treatment 60

LUCKY MOUSE

DAY 1

DAY 7

DAY 13

Injection of 1 mg of egg-albumin + 5 mg Al(OH)3 in PBS (IP)

Aerosol of 1 mg of egg-albumin + 5 mg Al(OH)3 in PBS

TREATMENT WITH IL-12+IFN-γ from DAY 18 until DAY 38 Blood drawing

Treatment plan of allergic mouse with the 2 anti-allergic interleukines in association (IL-12+IFN-γ)

IL-4 pg/ml

EXPERIMENTAL PROTOCOL

Legenda •1-Untr=healthy mouse (control) •2-OVA=allergic mouse (untreated) •3-OVA+ALLO=IL-12+IFN-γ in pharmacological concentration (mouse died) •4-OVA+4CH=IL-12+IFN-γ in physiological concentration (4CH) diluted and dynamized (no side effects) •5-OVA+4CHn=IL-12+IFN-γ in physiological concentration (4CH) only diluted but not dynamized (no reaction)

Levels of IL-4

The study brought a healthy mouse into an allergic state, at which point Th2 became upregulated. To bring back the balance IL-12 and Interferon gamma was used. These Th1 molecules up-regulated Th1 to re-balance in TH1 & Th2 ratios.

DAY 38 Bronchoalveolar lavage fluid

DAY 30 5% egg-albumin in PBS 0,5. (Aerosol)

ALLERGIC MOUSE DAY 27 Injection of 1 mg of egg-albumin + 5 mg Al(OH)3 in PBS (IP)

30 20

Levels of IL-5

180

160

Untr

OVA

140

OVA+Allo OVA+4CH OVA+4CHn OVA+30CH

120

IL-5 pg/ml

100 80 60 40 20 0

Untr

OVA

OVA+Allo OVA+4CH OVA+4CHn OVA+30CH

The results with the GUNA prepared method are amazing: Column 1- control with the healthy mouse interleukin level Column 2- qty of Interleukin in allergic mouse Column 3- pharma dose of balancing interleukin, mouse died Column 4- Guna physiological dose, no side effects Column 5 – physiological dose, dilution only, not dynamized

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