41st Orthomolecular Medicine Today Conference by Journal of Orthomolecular Medicine

2012

Annual International Conference

vancouver

Orthomolecular Medicine Today

April 27â&#x20AC;&#x201C;29

Fairmont Hotel Vancouver Experience the best education in many areas of Orthomolecular Medicine at our 41st Annual International Conference. Fourteen internationally known physicians and researchers will present five sessions over three days on current advances in orthomolecular medicine, endocrinology, cardiology, psychiatry, pediatrics, and evidence-based medicine.

International Society for Orthomolecular Medicine April 27, 2012 Dear Delegates, Welcome to our 41st Annual International Orthomolecular Medicine Today Conference. We hope these next three days will provide fresh insight and clinical evidence for the advancement of your study and practice in the field of Orthomolecular Medicine. This year we are pleased to bring together 14 speakers, 22 exhibitors and over 180 delegates and guests from 17 countries worldwide, including Australia, Austria, Brazil, Canada, England, Finland, Japan, Mexico, Norway, the Philippines, South Korea, Spain, Sweden, Switzerland, Taiwan, The Netherlands, and the United States of America. We extend a special warm welcome to our large delegation of attendees from Japan; their presence is particularly fitting as we introduce the new President of the International Society for Orthomolecular Medicine, Dr. Atsuo Yanagisawa. In 2011 Dr. Yanagisawa presented at the OMT Conference on the use of intravenous vitamin C to treat the effects of radiation exposure in Japan and he was inducted into the Orthomolecular Medicine Hall of Fame. Dr. Yanagisawa’s demonstrated leadership in founding the Japanese College of IV Therapy and his committed promotion of Orthomolecular Medicine will serve the ISOM well. We thank you for your continued dedication to Orthomolecular Medicine and wish you a most memorable Conference. With best regards,

Director, ISOM

ISOM Meeting Sunday, April 29 9:00 am – 10:00 am Please join us to hear reports on activities in education, communication and advocacy from Japan, Canada, Europe, the Linus Pauling Institute and others from among the 17 countries in attendance at the Orthomolecular Medicine Today Conference Don’t miss this opportunity to gain an international perspective on Orthomolecular Medicine.

Contents

Conference Schedule...................................................................................................................................3 Exhibitors.........................................................................................................................................................4 Exhibitor Floor Plan......................................................................................................................................5 Conference Schedule...................................................................................................................................6

Presentation Notes Session One - General Orthomolecular Medicine Alan Gaby, MD Inaugural Evan Shute Memorial Lecture Controversies in Nutrition..........................................................................................................................7 Aristo Vojdani, PhD Beyond the Gluten-Free Diet for Optimal Healing......................................................................... 24

Aileen Burford-Mason, PhD Extending Health Span: an Orthomolecular Approach...............................................................34

Session Two - Orthomolecular Endocrinology Kent MacLeod, BPharm Hormones and Dysregulation Spectrum Syndrome.....................................................................44

George Gillson, MD, PhD Is there a Holy Grail for Hormone Testing?........................................................................................ 53

Jonathan Wright, MD Treating Childhood Asthma; Potent, Natural Anti-Cancer Agents........................................... 62

Session Three - Orthomolecular Cardiology Thomas Levy, PhD The Reversal of Coronary Atherosclerosis: Theory and Practice............................................... 75

Thomas Alexander, MD Stress, the Autonomic Nervous System and Cardiovascular Disease..................................... 82

James Greenblatt, MD Inflammation and Neuropsychiatric Illness: Treatment and Testing Protocols...................88

Session Four - Orthomolecular Pediatrics Ron Hunninghake, MD Common Denominators of Childhood Mental Illness................................................................102

Mary Braud, MD Why Integrative Psychiatry is Vital Now........................................................................................... 114

Jonathan Prousky, ND, MSc Treating the Hyperactive Child without Drugs............................................................................. 121

Session Five - Examining Evidence-Based Medicine Marja Verhoef Dr. Rogers Prize Lecture Evidence Based Medicine: Beyond Classical RCTs........................................................................ 131

Steve Hickey Annual Abram Hoffer Memorial Lecture The Sickness of Evidence-based Medicine ....................................................................................139

Badge colour code: Red=Speaker; Blue=Full Delegate; 3 Yellow=Sessional Delegate; Green=Exhibitor

FRIDAY APRIL 27

11:30 am James Greenblatt, MD Inflammation and Neuropsychiatric Illness: Treatment and Testing Protocols

8:00 am Registration 8:30 am Exhibit Area Opens

12:30 pm Lunch - Mindful Launch - Visit Exhibitors

Session One - General Orthomolecular Medicine

Session Four - Orthomolecular Pediatrics

9:00 am Welcome - Introduction

2:00 pm Ron Hunninghake, MD Common Denominators of Childhood Mental Illness

9:15 am Alan Gaby, MD Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

2:45 pm Mary Braud, MD Why Integrative Psychiatry is Vital Now

10:15 am Break - Visit Exhibitors 10:45 am Aristo Vojdani, PhD Beyond the Gluten-Free Diet for Optimal Healing

3:30 pm Break - Visit Exhibitors

11:45 am Aileen Burford-Mason, PhD Extending Health Span: an Orthomolecular Approach

6:30 pm Reception 7:00 pm Dinner and Induction

Session Two - Orthomolecular Endocrinology 2:00 pm Kent MacLeod, BPharm Hormones and Dysregulation Spectrum Syndrome

SUNDAY APRIL 29

3:00 pm George Gillson, MD, PhD Is there a Holy Grail for Hormone Testing?

8:30 am Exhibit Area Opens

4:00 pm Break - Visit Exhibitors

Award-winning 2010 Documentary

“Feed Your Head”

The life and work of Abram Hoffer 7:30 pm

SATURDAY APRIL 28 8:30 am Exhibit Area Opens Session Three - Orthomolecular Cardiology 9:00 am Thomas Levy, PhD The Reversal of Coronary Atherosclerosis: Theory and Practice 10:00 am Break - Visit Exhibitors 10:30 am Thomas Alexander, MD Stress, the Autonomic Nervous System and Cardiovascular Disease

9th Annual

Orthomolecular Medicine Hall of Fame

12:45 pm Lunch - Doctor of the Year - Visit Exhibitors

4:30 pm Jonathan Wright, MD (A) Treating Childhood Asthma (B) Potent, Natural Anti-Cancer Agents

4:00 pm Jonathan Prousky, ND, MSc Treating the Hyperactive Child without Drugs

9:00 am International Society for Orthomolecular Medicine meeting

10:00 am Break - Visit Exhibitors Session Five - Examining Evidence-Based Medicine 10:30 am Marja Verhoef Dr. Rogers Prize Lecture Evidence Based Medicine: Beyond Classical RCTs 11:30 am Steve Hickey Abram Hoffer Memorial Lecture The Sickness of Evidence-based Medicine 1:00 pm Exhibits Close

Public Workshop

Mental Health Regained

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

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41st Orthomolecular Medicine Today Conference Please Visit Our Exhibitors Acquired Intelligence, Inc. Suite 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 / 905 336 8075 bdrint@gmail.com www.nanovitaminc.ca Boucher Institute of Naturopathic Medicine 200 - 435 Columbia Street New Westminster, BC V3L 5N8 Canada 604 777 9981 info@binm.org www.binm.org Canada RNA Biochemical Inc. 680 - 4400 Hazelbridge Way Richmond, BC V6X 3R8 Canada 866 287 4986 / 604 207 0167 info@CanadaRNA.com www.canadarna.com 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, Suite 101 Colorado Springs, CO 80918 USA 800 888 9358 / 719 262 0022 info@collegepharmacy.com www.collegepharmacy.com Cyrex Laboratories, LLC 5040 N. 15th Avenue, Suite 107 Phoenix, AZ 85015 USA 602 759 1245 support@cyrexlabs.com www.cyrexlabs.com

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Cyto–Matrix Inc. 300 March Road, Suite 103 Ottawa, ON K2K 2E2 Canada 866 783 7504 / 613 599 1653 info@cyto-matrix.com www.cyto-matrix.com Doctor’s Data, Inc. 3755 Illinois Avenue St. Charles, IL 60174-2420 USA 800 323 2784 / 630 377 8139 inquiries@doctorsdata.com www.doctorsdata.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 Finlandia Natural Pharmacy & Health Centre 1111 West Broadway Vancouver, BC V6H 1G1 Canada 800 363 4372 / 604 733 5323 pharmacy@finlandiahealth.com www.finlandiahealth.com The Great Plains Laboratory, Inc. 11813 W. 77th Street Lenexa, KS 66214 USA 800 288 0383 / 913 341 8949 customerservice@gpl4u.com www.greatplainslaboratory.com Health Action Network Society (HANS) 202 - 5262 Rumble Street Burnaby, BC V5J 2B6 Canada 604 435 0512 hans@hans.org www.hans.org Immunosciences Lab., Inc. 822 S. Robertson Blvd., Suite 312 Los Angeles, CA 90035 USA 310 657 1053 immunosci@ix.netcom.com www.immunoscienceslab.com

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Integrated Health Practitioners 60 Bloor Street West, Suite 1106 Toronto, ON M4W 3B8 Canada 888 358 8186 / 416 203 7900 editorial@gorgmgo.com www.ihpmagazine.com Metagenics Canada, Inc. 851 Rangeview Road Mississauga, ON L5E 1H1 Canada 800 268 6200 www.metagenics.com NutriChem Compounding Pharmacy and Clinic 1303 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 Protocol for Life 5 - 5068 Whitelaw Road Guelph, ON N1H 6J3 Canada 519 827 5010 debra.greene@protocolforlife.com www.protocolforlife.com Rocky Mountain Analytical Unit A, 253147 Bearspaw Road NW Calgary, AB T3L 2P5 Canada 866 370 5227 / 403 241 4514 info@rmalab.com www.rmalab.com Seroyal International Inc. 490 Elgin Mills Road East Richmond Hill, ON L4C 0L8 Canada 800 263 5861 / 905 508 2050 sales@seroyal.com www.seroyal.com 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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41st Orthomolecular Medicine Today Conference Exhibitor Floor Plan Convention Floor Pacific Ballroom

Registration

Literature

Entrance

EXHIBITORS

1. CanPrev Premium Natural Health Products 2. York Downs Chemists 3. Acquired Intelligence Inc. 4. Protocol for Life Balance 5. Cyrex Laboratories LLC 6. Immunosciences Lab Inc. 7. Metagenics 8. The Great Plains Laboratory Inc. 9. Cyto-Matrix Inc. 10. Doctor’s Data Inc.

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11. Douglas Laboratories / Pure Encapsulations 12. BDR INT Inc. 13. Rocky Mountain Analytical 14. College Pharmacy 15. Finlandia Natural Pharmacy 16. Canada RNA Biochemical Inc. 17. Integrated Healthcare Practitioners 18. NutriChem Compounding Pharmacy 19. Nutritional Fundamentals for Health 20. Seroyal International Inc.

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Speaker Biographies Thomas Alexander, MD, graduated from the University of Missouri, Kansas City in 1998. He joined a medical practice in Butler, Missouri and held various posts at Bates County Hospital including Chief of Staff, Medical Director of Respiratory Care, and of Hospice. Desiring to consider integrative approaches to patient care, Dr. Alexander joined the clinic of Dr. Jonathan Wright in Seattle in 2004. He moved to Phoenix in 2007 where he opened a private practice. He has lectured on HPA dysfunction, Insulin Resistance and diabetes and has particular interests in the prevention and treatment of cardiovascular disease, diabetes, adrenal dysfunction, hormonal imbalance, and gastrointestinal disorders.

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

Mary Braud, MD, graduated from Louisiana State University Medical School in 1989. She completed residency training in pediatrics and later in psychiatry, including a fellowship in child and adolescent psychiatry. After working at a community mental health center for several years, Dr. Braud began her private practice in Denver, Colorado. She works with children, adolescents and adults utilizing an integrative approach combining both traditional and alternative modalities. Dr. Braud has studied alternative mental health treatments since 2005. This includes training with the Center for Mind-Body Medicine, the Institute for Functional Medicine and the Autism Research Institute. She was a consultant for the Riordan Clinic of Wichita, Kansas from 2007 to 2010.

Thomas E. Levy, MD, JD, is a board-certified cardiologist and a bar-certified attorney. As an author, he has addressed the critical role of oxidative stress and how best to remedy this condition. He has written books on nutrition, the role of vitamin C in heart disease, and the documented capacity of vitamin C as an antibiotic and universal antidote. His most recent book, Primal Panacea, further examines the many clinical applications of vitamin C and some of the political and legal issues preventing its widespread acceptance. Currently, he is researching and writing, Putting Cancer Into Permanent Remission: Vitamin C as Optimal Chemotherapy.

Aileen Burford-Mason, PhD, is an immunologist, cell biologist and former cancer researcher. She regularly gives seminars on orthomolecular nutrition to both professional and lay audiences and teaches a popular Continuing Medical Education course on the evidence-based use of diet and nutritional supplements at the University of Toronto. Formerly Assistant Professor in the Department of Pathology in the Faculty of Medicine, University of Toronto, and Director of the Conacher Head and Neck Cancer Research Laboratory at The Toronto Hospital, she now has a private practice in orthomolecular nutrition in down-town Toronto.

Kent MacLeod is a Clinical Pharmacist and Director of NutriChem Compounding Pharmacy and Clinic. He is a specialist in women’s health issues, bio-identical hormones and transdermal pain management. Named the 2009 Canadian Compounding Pharmacist of the Year, Kent is a published author and has lectured throughout North America. Profiled in New Pharmacist, Pharmacy Post and Drugstore Canada magazines, Kent has received the Outstanding Award for Service Innovation, the Distinguished Practice Award and the Canadian Innovation Award. Jonathan Prousky, ND, MSc, graduated from Bastyr University (Kenmore, WA) with a Doctorate in Naturopathic Medicine. He is the Chief Naturopathic Medical Officer at the Canadian College of Naturopathic Medicine and also supervises at the Robert Schad Naturopathic Clinic. He is a passionate advocate for patients diagnosed with psychiatric disorders and focuses his clinical practice on optimizing mental and neurological health with nutrition and botanical (plant-based) medicines. He has lectured extensively on various health-related topics throughout North America and is the current editor of the Journal of Orthomolecular Medicine. His clinician-based research primarily involves the neuropsychiatric applications of vitamin B3.

Alan R. Gaby, MD, a past-president of the American Holistic Medical Association, gave expert testimony to the White House Commission on Complementary and Alternative Medicine on the cost-effectiveness of nutritional supplements. He is the author of Preventing and Reversing Osteoporosis (1994), and The Doctor’s Guide to Vitamin B6 (1984). He has been the contributing medical editor for the Townsend Letter for Doctors since 1985. Over the past 30 years, he has developed a database of more than 26,000 medical journal articles in the field of natural medicine. He was professor of nutrition and a faculty member at Bastyr University from 1995 to 2002. In 2010, Dr. Gaby completed a 30-year project, the textbook of Nutritional Medicine.

Marja J. Verhoef, PhD, is a Professor in the Department of Community Health Sciences at the University of Calgary. She received her PhD in social epidemiology from the University of Calgary and holds a Canada Research Chair in Complementary Medicine. Her research focuses on a wide range of factors related to complementary and alternative medicine. She is very interested in methodological issues such as identifying and developing appropriate designs to evaluate whole systems of treatment and care. She is Co-Chair of the Canadian Interdisciplinary Network for CAM Research and was the founder and first President of the International Society of Complementary Medicine Research.

George Gillson, MD, PhD, is the CEO and Medical Director of Rocky Mountain Analytical. Since 1997, he has spent many hours puzzling over hormone testing. When he is not puzzling over hormone testing, he develops rulebased expert systems for the automated interpretation of laboratory tests (hormones, elemental analysis, food allergies, organic acids). When he is not building expert systems, he gives lectures to health practitioners across North America, on a variety of topics including Metabolic Syndrome and Hormone Replacement. When he is in Calgary, he is humiliated on a regular basis by his oldest son, at a local indoor climbing gym. James Greenblatt, MD, is the Medical Director of Comprehensive Psychiatric Resources, an integrative, orthomolecular outpatient treatment center in Waltham, Massachusetts. Dr. Greenblatt 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. Dr. Greenblatt is also an Assistant Clinical Professor at Tufts University Medical School, Department of Psychiatry, and lectures to professionals and families throughout the USA and Canada on integrative medicine for mental health. Steve Hickey holds a PhD in Medical Biophysics from the University of Manchester, England. His PhD was on the development, aging, function and failure of the intervertebral disk. His later research included pattern recognition, artificial intelligence, computer science, and decision science. He has published hundreds of scientific articles in a variety of disciplines. Dr Hickey is the author of books on science, health, vitamins, and cancer. He is co-author, with Hilary Roberts, of Ascorbate: The Science of Vitamin C; Cancer: Nutrition and Survival; Ridiculous Dietary Allowance; The Cancer Breakthrough; and Tarnished Gold: The Sickness of Evidence-based Medicine.

Aristo Vojdani obtained his PhD in the field of microbiology and clinical immunology with postdoctoral studies in tumor immunology. He is CEO and Technical Director of Immunosciences Lab., Inc. in Beverly Hills, CA and has published more than 100 articles in scientific journals. Dr. Vojdani has been the recipient of the Herbert J. Rinkel Award from the American Academy of Environmental Medicine (AAEM) for excellence in teaching the techniques of environmental medicine, and the Linus Pauling, PhD Award from the American College for Advancement in Medicine. Jonathan V. Wright, a Harvard and University of Michigan graduate, is a pioneer in the application of natural remedies. Since 1983, he has taught his methods to thousands of physicians. In 1982, he was the first to develop comprehensive patterns of bio-identical hormone applications and testing for safety. He discovered the effect of cobalt and iodine on estrogen and other steroid detoxification. Dr. Wright has authored 14 books, with two texts achieving best selling status, and numerous medical articles. Since 1994 he has authored Nutrition and Healing‚ a monthly newsletter emphasizing nutritional medicine that reaches over 190,000 6 readers. He is Medical Director of Tahoma Clinic in Renton, Washington.

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD

Do vitamins kill people?

Controversies in Nutrition

22-year prospective study of 38,772 women (mean age, 62 years). In multivariate analysis, the death rate was 6% higher in women who took a multivitamin than in women who did not (p = 0.05).

By Alan R. Gaby, M.D.

Arch Intern Med 2011;171:1625-1633

Do vitamins kill people?

In an analysis that adjusted only for age and energy intake, there was no significant difference in mortality rate between supplement users and nonusers. Crude (unadjusted) mortality data were not presented.

The multivariate analysis adjusted for education, diabetes, hypertension, BMI, use of HRT, smoking, physical activity, and energy intake. For each of these variables, supplement users were in the healthier category (e.g., less diabetes, lower BMI, more physical activity, fewer smokers). Did the multivariate analysis over-adjust?

Arch Intern Med 2011;171:1625-1633

Do vitamins kill people?

Does vitamin E cause prostate cancer?

In addition, the possibility of confounding by indication was not taken into account in the analysis (i.e., why were people taking nutritional supplements?).

Randomized controlled trial: 400 IU/day of alpha-tocopherol for 5.5 years, with a total follow-up period of 7 years. The incidence of prostate cancer was 17% higher with vitamin E than with placebo (p = 0.008).

Arch Intern Med 2011;171:1625-1633

JAMA 2011;306:1549-1556

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Vitamin E and heart failure: possible explanation

Does vitamin E cause prostate cancer?

The study used pure alpha-tocopherol, whereas vitamin E as it occurs naturally in food consists of 4 isomers: alpha-, beta-, gamma-, and delta-tocopherol. Supplementation with large doses of alpha-tocopherol (AT) can deplete gamma-tocopherol (GT).

Alpha- and gamma-tocopherol each inhibited the growth of human prostate cancer cells in vitro, but gamma-tocopherol was the more potent of the two.

J Nutr 2003;133:3137-40

Nutr Res 25:877-889

Does vitamin E cause prostate cancer?

Does vitamin E cause prostate cancer? Dose-response relationship with alphatocopherol in randomized controlled trials:

In a 7-year nested case-control study, higher blood levels of alpha- and gammatocopherol were each associated with a lower risk of developing prostate cancer, but the risk reduction was greater with gammathan with alpha-tocopherol.

50 IU/day: protective effect 400 IU every other day: no effect 400 IU/day: adverse effect J Natl Cancer Inst 1998;90:440-446; JAMA 2009;301:52-62; JAMA 2011;306:1549-1556

J Natl Cancer Inst 2000;92:2018-2023

Does vitamin E cause prostate cancer?

High-dose vitamin D:

It would be reasonable to postulate that mixed tocopherols (which contain both alpha- and gamma-tocopherol) would not increase the risk of prostate cancer, and might even have a protective effect.

Is it safe and effective?

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Vitamin D deficiency

Potential benefits of supplementation Fewer falls & fractures, better bone density

Rickets

Prevention of influenza & asthma attacks Increased insulin sensitivity?

Osteomalacia, osteoporosis

Improvement of hypertension?

Myopathy

Prevention of some cancers, autoimmune diseases, tooth decay? (circumstantial)

Vitamin D: new definition of deficiency

Vitamin D: effective dosages 800-1,200 IU/day generally effective

Traditional definition: deficiency = serum 25(OH) < 10-15 ng/ml (< 25-37.5 nmol/L)

400 IU/day generally ineffective New RDA (2010): 600 IU/day for ages 1-70; 800 IU/day for ages â&#x2030;Ľ 71

New definition: deficiency = serum 25(OH)D < 20 ng/ml (< 50 nmol/L)

2,000 IU/day was used for prostate cancer: slowed disease progression, decreased pain.

insufficiency = < 30 ng/ml (< 75 nmol/L)

Vitamin D: new definition of optimal

Dosage requirements for new adequate and optimal

A review article concluded that a protective effect with respect to various outcomes (i.e., bone health, falls, fractures, dental health, and cancer) began at a serum 25(OH)D level of 30 ng/ml (75 nmol/L) and that the best outcomes were seen in people with levels of 36-40 ng/ml (90-100 nmol/L).

Only 50% of people will achieve adequacy (â&#x2030;Ľ 30 ng/ ml) with 1,000 IU/day. 1,600-3,400 IU/day (depending on the study) will achieve adequacy in nearly all healthy adults. Even larger doses (4,000-10,000 IU/day?) may be needed to achieve optimal levels. Tolerable Upper Intake Level = 4,000 IU/day (recently increased from 2,000 IU/day)

Am J Clin Nutr 2006;84:18-28

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD

Examining the evidence

My conclusions Serum 25(OH)D may not be a reliable indicator of vitamin D status.

Is routine use of vitamin D in dosages greater than 2,000 IU per day beneficial?

The new definitions of vitamin D deficiency and insufficiency may not be valid.

Is it safe?

Evidence supporting the benefit of pushing 25(OH)D to an optimal level is weak.

My conclusions

Why 25-hydroxyvitamin D? Serum vitamin D: unreliable; serum half-life is only 24 hours.

Evidence supporting the long-term safety of dosages > 2,000/day is weak.

Serum 1,25-dihydroxyvitamin D: unreliable; may be normal or elevated in people with vitamin D deficiency. Am J Clin Nutr 2004;79:362-371

The safety and efficacy of vitamin D supplementation cannot be inferred from data regarding the safety and efficacy of sunlight exposure.

Serum 25-hydroxyvitamin D: serum half-life is 3 weeks; more reliable than vitamin D itself.

Serum 25-hydroxyvitamin D: how reliable?

Serum 25(OH)D: quality control issues

Serum 25-hydroxyvitamin D

Substantial variations from one lab to another and with different assay methods

â&#x2020;&#x201C;

With nearly identical serum samples, one lab found that 90% were below 32 ng/ml; another lab found that only 17% were below 32 ng/ml.

Serum 25-hydroxyvitamin D

Am J Clin Nutr 2008;87:1087S-91S

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Vit D requirement: racial differences?

Serum 25(OH)D: E pluribus unum 25(OH)D is only one of more than 50 vitamin D metabolites identified.

Nested case-control study within the Women's Health Initiative Observational Study: Among white women, compared with 25(OH)D levels < 20 ng/ml, 25(OH)D levels of 20 to < 30 ng/ml were associated with an 18% reduction in fracture risk, and levels â&#x2030;Ľ 30 ng/ml were associated with a 44% reduction in fracture risk (p for trend = 0.02).

Vitamin D nutritional status may be a function of complex interactions between many different vitamin D metabolites. Different people may have different serum 25 (OH)D set points for adequate or optimal vitamin D nutritional status.

J Bone Miner Res 2011;26:2378-2388

Vit D requirement: racial differences?

In black women, 25(OH)D levels â&#x2030;Ľ 20 ng/ml, as compared with levels < 20 ng/ml, were associated with a 45% higher risk of fracture (p for trend < 0.05).

In Asian women, 25(OH)D levels â&#x2030;Ľ 30 ng/ ml, as compared with levels < 20 ng/ml, were associated with a 178% higher fracture risk, after adjusting for vitamin D-binding protein (p for trend = 0.04).

J Bone Miner Res 2011;26:2378-2388

25(OH)D level altered by inflammation

Serum 25(OH)D at high vitamin D doses

Serum 25(OH)D levels decline in response to inflammation. Therefore, 25(OH)D may be an unreliable indicator of vitamin D status in people with inflammatory diseases.

Serum 25(OH)D may be even less reliable as an indicator of vitamin D status when vitamin D doses are greater than 2,000 IU/day, because 25-hydroxylases become saturated at those dosages. Storage of large amounts of unmetabolized vitamin D may not be reflected in serum 25(OH)D measurements.

Am J Clin Nutr 2011;93:1006-1011 Am J Clin Nutr 2008;87:1738-42

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD New definition of deficiency: is it valid?

New definition of deficiency: is it valid? Vitamin D sufficiency is inferred when a further increase in serum 25(OH) does not further increase fractional calcium absorption or further depress parathyroid hormone levels. In population studies, the average 25(OH)D level at which vitamin D sufficiency occurred was around 30 ng/ml (75 nmol/L).

Definition is based on biochemical markers: As 25(OH)D levels go up, fractional calcium absorption tends to increase and parathyroid levels tend to go down.

N Engl J Med 2007;357:266-81

New definition of deficiency: is it valid?

Recent studies have questioned whether 25(OH) D levels above those associated with rickets or osteomalacia influence calcium absorption. Earlier studies that showed such an association may have used inappropriate methods for measuring fractional calcium absorption.

In the absence of severe vitamin D deficiency, the association between serum 25(OH) and parathyroid hormone is weak. Variations in 25(OH)D levels explain, at most, 13% of the variation in parathyroid hormone levels.

Am J Clin Nutr 2010;92:835-840

Nutr Res 2009;29:671-5; J Bone Miner Res 2001;16:2066-73

New definition of deficiency: is it valid?

Of 93 young adults living in Hawaii who had sun exposure a mean of 29 hours a week, 25-51% had a 25(OH)D level < 30 ng/ml and 3-8% had a level < 20 ng/ml. There was no correlation between 25(OH) D and parathyroid hormone levels.

Those findings suggest either that the cut-off level for 25(OH)D used to define vitamin D sufficiency is either inappropriately high for some groups or that 25(OH)D is not always a reliable indicator of vitamin D nutritional status.

J Clin Endocrinol Metab 207;92:2130-5

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD

New definition of deficiency: is it valid?

New definition of optimal : is it valid?

In the late 1990s, the standard RIA for 25 (OH)D was changed. The new method decreased measured values by 4 ng/ml (10 nmol/L). Am J Clin Nutr 2008;88:1519-27

To answer the question: Randomize people to receive high-dose (e.g., 5,000-10,000 IU/day) or moderate-dose (e.g., 800-2,000 IU/day) vitamin D, or individualize dosages to achieve prespecified 25(OH)D levels, and compare outcomes.

The new cut-off points for deficiency and insufficiency were based in part on studies done prior to the late 1990s.

Only one such study has been done (discussed later).

New definition of optimal : is it valid?

Limitations of observational studies

Evidence is derived mainly from observational studies in which serum 25(OH)D was correlated with health outcomes. Findings conflicting.

Failure to control for confounders such as age, BMI, co-morbidities, inflammation, hepatic 25-hydroxylase activity, and gonadal function.

Evidence is also derived from controlled trials in which vitamin D-supplemented patients who achieved higher 25(OH) levels had better outcomes than did supplemented patients whose 25(OH)D levels were lower.

High 25(OH)D levels result mainly from sunlight exposure. People who spend time in the sun differ from those who do not. If sun exposure is beneficial, the effect may not be due entirely (or even primarily) to vitamin D.

Hepatic hydroxylase enzymes

Extra-hepatic 25-hydroxylase enzymes

Four different cytochrome P450 enzymes are thought to be capable of 25-hydroxylating vitamin D.

Human testis (androgen-producing Leydig cells) and possibly ovary are also capable of 25-hydroxylating vitamin D.

Trends Biochem Sci 2004;29:664-73

25(OH)D levels were 60% lower in young men with h/o orchiectomy for bilateral testicular cancer than in matched controls.

Cytochrome P450 enzymes also help detoxify xenobiotic chemicals.

Lancet 2010;376:1301

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Limitations of controlled trials

Extra-hepatic 25-hydroxylase enzymes Observational studies on 25(OH)D levels and health outcomes may be confounded by differences in gonadal function, and therefore, differences in levels of testosterone and DHEA. Both of these hormones may have positive influences on health.

Studies that assessed health outcomes as a function of the serum 25(OH)D response to vitamin D supplementation might simply be identifying differences in body chemistry, rather than an effect of vitamin D supplementation per se.

Limitations of controlled trials

Is high-dose vitamin D safe?

A higher serum 25(OH)D response to supplementation might reflect:

Tolerable Upper Intake Level for adults is 4,000 IU per day (recently increased from 2,000 IU/day).

More efficient nutrient absorption in general

Some investigators have argued that up to 10,000 IU per day is safe for most adults.

More efficient 25-hydroxylation of vitamin D

Basis of the argument that long-term use of 10,000 IU/day of vitamin D safe

Weaknesses of the safety argument 1. High-dose supplementation studies were of short duration.

Hypercalcemia uncommon with 10,000 IU/ day

2. Absence of hypercalcemia is not proof of safety. 3. Unclear whether human skin really can produce 10,000 IU/day of vitamin D

Whole-body sun exposure results in the production of at least 10,000 IU/day without causing vitamin D toxicity.

4. Physiological effects of sunlight exposure differ from those of vitamin D supplementation.

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD High-dose supplementation studies were of short duration

Absence of hypercalcemia is not proof of safety An increase in urinary calcium excretion (even within the normal range) might increase the risk of developing kidney stones.

10,000 IU/day was given for a maximum of 20 weeks. As a fat-soluble nutrient, vitamin D can accumulate with continued administration.

3 of 45 elderly individuals who received 5,000 IU/ day of vitamin D for 12 months showed evidence of hypercalciuria. Am J Clin Nutr 2009;89:1132-7

Absence of hypercalcemia is not proof of safety

Can human skin can produce 10,000 IU/ day?

Swine fed human equivalent of 11,500 IU/day of vitamin D3 developed pathological changes in the aorta that were indistinguishable from human atherosclerosis. Am J Clin Nutr 1979;32:58-83

This claim is based in part on a study in which UV irradiation of 5% of body surface area was equivalent to oral administration of 400 IU/day. J Bone Miner Res 1998;13:1238-42

Increasing vitamin D3 intake only modestly (equivalent to a total of 917 IU/day for humans) exacerbated atherosclerosis in swine induced by a diet high in butterfat. Nutr Rep Int 1983;28:1111-8

No evidence that it is appropriate to extrapolate this finding to full-body irradiation

Can human skin can produce 10,000 IU/ day?

One-time exposure to 1 minimal erythemal dose of UV irradiation was equivalent to oral administration of 10,000-25,000 IU of vitamin D2.

Repeated sun exposure results in photodegradation of vitamin D that has not yet entered the circulation. Am J Clin Nutr 1995;61(Suppl):638S-45S

This finding is of doubtful relevance to long-term vitamin D homeostasis.

Therefore, net vitamin D production may be substantially lower on subsequent days than on the first day.

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD UV light and oral vitamin D are not the same

UV light and oral vitamin D are not the same

One photodegradation product of vitamin D (5,6-trans-vitamin D) has effects similar to 1,25dihdroxyvitamin D, but is 20-40 times less potent.

Sunlight (but not vitamin D):

Biochemistry 1972;11:2715-9

Produces corticotropin-releasing hormone

5,6-trans-Vitamin D might compete with 1,25(OH) 2D and thereby function as a regulator of vitamin D activity.

May directly influence hypothalamic and pituitary function through the retina

Produces photodegradation products

Vitamin D and cancer: controlled trial

Women s Health Initiative, double-blind trial: 36,282 postmenopausal women received vitamin D (400 IU/day) and calcium (1 g/day) or placebo for 7 years.

Among women not taking personal calcium or vitamin D supplements at randomization, vitamin D/calcium treatment significantly decreased the incidence of breast cancer and total cancer, and nonsignificantly decreased colorectal cancer incidence.

Overall, vitamin D/calcium had no effect on incidence of colorectal or breast cancer. Am J Clin Nutr 2011;94:1144-1149

Am J Clin Nutr 2011;94:1144-1149

Vitamin D and cancer: controlled trial

Among women taking personal calcium or vitamin D supplements at randomization (maximum permitted personal vitamin D dose, 600-1,000 IU/ day), vitamin D/calcium treatment nonsignificantly increased total cancer, breast cancer, and colorectal cancer incidence by 6-26%.

These data are consistent with the possibility that modest doses of vitamin D reduce the risk of cancer, but that slightly higher than modest doses provide no additional benefit and could even negate the benefit of lower doses or increase the risk of cancer.

Am J Clin Nutr 2011;94:1144-1149

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Vitamin D and bone: controlled trial

Vitamin D and influenza: controlled trial Double-blind trial among Japanese children (mean age, 10 years): 1,200 IU/day of vitamin D for 4 months in the winter. Compared with placebo, 42% reduction in incidence of influenza A with vitamin D.

Postmenopausal women received 6,500 IU (high dose) or 800 IU (standard dose) of vitamin D daily for 1 year. Mean increases in BMD of the total hip, femoral neck, lumbar spine, and total body were each nonsignificantly greater with the standard dose than with the high dose. Osteoporos Int 2012;23:201-211

Am J Clin Nutr 2010;91:1255-1260

Vitamin D and influenza: controlled trial

Vitamin D and COPD: controlled trial

Among children not taking other vitamin D supplements, vitamin D treatment reduced flu incidence by 64% compared with placebo.

Double-blind trial: COPD patients; 100,000 IU of vitamin D3 every 4 weeks for 1 year Among patients with severe vitamin D deficiency (< 10 ng/ml; 16% of all patients) vitamin D supplementation decreased the exacerbation rate by 43% compared with placebo (p < 0.05).

Among children taking other vitamin D supplements (average, 1,000-1,200 IU/week), vitamin D treatment nonsignificantly increased flu incidence by 11% compared with placebo.

Ann Intern Med 2012;156:105-114

Am J Clin Nutr 2010;91:1255-1260

Vitamin D and COPD: controlled trial

Among patients who did not have severe vitamin D deficiency at baseline (â&#x2030;Ľ 10 ng/ml; 84% of all patients) vitamin D supplementation increased the exacerbation rate by 8% compared with placebo (p value not stated).

Among patients who were not taking vitamin D supplements at baseline, the exacerbation rate was nonsignificantly lower by 10% in those assigned to receive vitamin D than in those assigned to receive placebo (p = 0.3).

Ann Intern Med 2012;156:105-114

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD

Vitamin D: what to make of it all

Vitamin D and COPD: controlled trial Among patients who were taking 400-880 IU/day of vitamin D at baseline for osteoporosis, the exacerbation rate was 41% higher in those assigned to receive vitamin D than in those assigned to receive placebo (p value not stated).

The RDAs of 400-600 IU/day may not be sufficient to promote optimal health. 800-1,200 IU/ day is more effective than 400 IU/day. Preliminary evidence suggests that, for the average person, dosages substantially above 800-1,200 IU/ day may be less effective than 800-1,200 IU/day.

Ann Intern Med 2012;156:105-114

Vitamin D: what to make of it all

Doses > 800-1,200 IU/day may be considered for patients with risk factors for deficiency, such as obesity, advanced age, malabsorption, dark skin, lack of sun exposure, or distance from the equator.

Sunlight exposure of 5-15 minutes 2-3 times a week between 10 a.m. and 3 p.m. in spring, summer, and autumn is frequently sufficient for skin types II and III.

The safety and efficacy of using high doses (such as > 2,000 IU/day) for the sole purpose of achieving a target 25(OH)D level have not been established.

Am J Clin Nutr 2004;80(Suppl):1678S-88S

Orthoiodosupplementation

Should we all take high-dose iodine? Adult RDA (Âľg/day)

150

Median urinary [I] in US adults

168

Tolerable Upper Intake Level

1,100

(Guy Abraham, M.D.)

According to Abraham, the optimal dietary iodine intake is 13,800 Âľg/day, which is 92 times the RDA and more than 12 times the Tolerable Upper Intake Level. http://www.optimox.com/pics/Iodine/IOD-02/IOD_02.htm

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Do Japanese people consume 13.8 mg/day?

Basis of the claim

Claim based on a misinterpretation of a 1967 paper. Average seaweed consumption in Japan was 4.6 g/day. Seaweed contains average of 0.3% iodine.

Japanese people consume an average of 13.8 mg/day of iodine, and are among the healthiest people in the world.

4,600 mg x 0.003 = 13.8 mg

High-doses are needed to fully saturate the tissues, as demonstrated by an iodine-load test.

However, 4.6 g/day of seaweed was wet weight, whereas 0.3% iodine was based on dry weight. J Clin Endocrinol Metab 1967;27:638-47

Amount of iodine consumed in Japan

Amount of iodine consumed in Japan According to a 2008 study, average iodine intake in Japan from seaweed was 1.2 mg/ day in 2006 and 1.7 mg/day in 1986, which is 88-93% less than 13.8 mg/day.

In studies in the 1990s that specifically looked at iodine intake in Japan, mean dietary iodine (estimated from urinary iodine excretion) was 330-500 Âľg/day, which is 25-fold lower than 13.8 mg/day. Nippon Naibunpi Gakkai Zasshi 1994;70:1093-1100; Nippon Naibunpi Gakkai Zasshi 1992;68:550-6

Thyroid 2008;18:667

Abraham s iodine load test

Abraham s iodine load test The validity of the test depends on the assumption that the average person can absorb at least 90% of a 50-mg dose.

Patient ingests 50 mg of iodine/iodide. Patient are considered iodine-deficient if less than 90% is excreted in the urine over the next 24 hours.

No research in humans; proponents have not measured fecal iodine levels. In cows fed supraphysiological doses of iodine, 50% appeared in the feces. J Dairy Sci 1996;79:254-9

92-98% of patients taking the test have been found to be deficient.

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Iodine: adverse effects

Iodine: adverse effects

Very high doses (700-4,500 mg/day)

Moderately high doses (3-6 mg/day)

Thyroid dysfunction (mainly hypothyroidism), burning mouth, increased salivation, parotid and submandibular swelling, severe headache, acneiform eruptions, pulmonary edema, angioedema, heart failure, and death.

10.9% of 1,365 women treated for fibrocystic breast changes experienced side effects including acne, nausea, diarrhea, thinning hair, skin rash, headache, hypothyroidism (0.3%), and hyperthyroidism (0.1%). Can J Surg 1993;36:453-60

Adverse effects of orthoiodosupplementation

Iodine: adverse effects Modestly high doses (> 500 Âľg/day?)

Toxic multinodular goiter Graves disease Autoimmune thyroiditis Hypothyroidism Severe headaches Deep acne Hair loss, agitation, sweating Esophagitis

Autoimmune thyroiditis Hypothyroidism Goiter or increased thyroid volume N Engl J Med 2006;354:2783-93; Thyroid 2003;13:561-7; Clin Endocrinol 1991;34:413-6; Lancet 1987;2:257-9; Am J Clin Nutr 2005;81:840-4

Megadose iodine: conclusion

3-6 mg/day may be considered for fibrocystic breast changes that do not improve with methylxanthine avoidance, vitamin E, etc.

Iodine is not indicated as a treatment for hypothyroidism except in cases of dietary iodine deficiency. High iodine intake can make hypothyroidism worse.

As an antimicrobial agent, iodine may benefit selected patients by killing intestinal pathogens. Possibly beneficial for some types of cysts; may favorably influence steroid metabolism; may have certain other clinical benefits.

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Megadose iodine: conclusion

Megadose iodine: conclusion

Routinely giving high-dose iodine based on an iodine load test or on a misunderstanding of human iodine requirements has not been proven to be safe or beneficial.

Some practitioners report beneficial effects and few adverse effects from routine use of high-dose iodine. Please remember that this is drug therapy, not nutritional therapy, and monitor patients closely.

Side effects of high-dose iodine are common, and in a small proportion of cases side effects are severe and/or persistent.

Vitamin E and heart failure: possible explanation

Does vitamin E cause heart failure? In a double-blind study of patients with vascular disease or diabetes, treatment with 400 IU/day of alpha-tocopherol for 7 years resulted in a significant 19% increase in the incidence of heart failure compared with placebo.

JAMA 2005;293:1338-47

J Nutr 2003;133:3137-40

Importance of gamma-tocopherol (GT)

GT is metabolized largely to 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), which may function as a natriuretic hormone, since it is involved in the body s response to sodiuminduced plasma-volume expansion.

GT depletion might therefore lead to impaired regulation of sodium and water balance, potentially increasing the risk for heart failure.

J Pharmacol Exp Ther 1997;282:657-62; Proc Natl Acad Sci 1996;93:6002-7; J Nutr Sci Vitaminol 2004;50:277-82

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Importance of gamma-tocopherol (GT)

Importance of gamma-tocopherol (GT)

GT was more effective than AT as a scavenger of peroxynitrite (a mutagenic nitrating and oxidizing agent formed during the activation of phagocytes). Peroxynitrite is believed to play a role in the pathogenesis of cardiovascular disease, cancer, and neurodegenerative diseases.

GT depletion might lead to increased peroxynitrite formation, potentially promoting the development of cardiovascular disease.

Proc Natl Acad Sci 1997;94:3217-22

Strontium and bone: to dose or to megadose?

Potential benefit of mixed tocopherols If high-dose AT does adversely affect heart function in some people, one might reasonably expect that mixed tocopherols (which contain both AT and GT) would not have the same negative effect, and might actually improve cardiovascular health.

Typical diet provides 1-3 mg/day of strontium Significant amounts lost in refining of flour Strontium has high affinity for bone; promotes mineralization of bones and teeth Stimulates bone formation, inhibits bone resorption

Three-year strontium clinical trial

Distribution of strontium in bone At high doses, most strontium is incorporated by exchange onto the crystal surface. This strontium, which may promote bone formation and inhibit bone resorption, is rapidly lost from bone and excreted in the urine when supplementation is stopped. A few strontium atoms are incorporated into the crystal lattice; this strontium may enhance bone quality, and appears to persist in bone after supplementation is stopped. This effect may occur with nutritional doses.

1,649 postmenopausal women, 680 mg/day of strontium for 3 years. Top half: % increase in BMD. Bottom half: % reduction in fracture risk.

Bone 2001;28:446-453

Adapted from N Engl J Med 2004;350:459-68.

Inaugural Evan Shute Memorial Lecture Controversies in Nutrition

12-03-26

Alan Gaby, MD Potential adverse effects of high-dose strontium on bone

Other potential adverse effects of high-dose strontium

•  Syndrome resembling rickets in animals fed 1.5-3.0% strontium

•  Increased thyroid weight in rats fed 395 ppm of strontium

•  Bone mineralization defects in young rats at diet concentrations of 0.19% or greater in (equivalent to approximately 800 mg/day for humans). Rat diet contained 0.5% calcium. Bone 1990;11:313-9.

•  Decreased pituitary weight in rats fed 98.7 ppm or 1,580 ppm, but not 395 ppm. •  Estimated no-observed-adverse-effect level = 98.7 ppm, equivalent to 41.1 mg/day for humans (calculation based on 2,000 kcal/day, 30% fat = 417 g/day of food, dry weight)

•  High soil strontium concentrations associated with increased prevalence of rickets in Turkish children

Toxicology 1977;7:11-21.

Arch Dis Child 1996;75:524-6.

Adverse effects of strontium in 3-year clinical trial

Three-year strontium clinical trial

Elevated CPK in 3.4% of patients receiving strontium, 1.8% of those receiving placebo. Elevations usually transient. No mineralization defects found, but only mature (lamellar) bone was biopsied, whereas adverse effects would presumably be most pronounced in new bone.

1,649 postmenopausal women, 680 mg/day of strontium for 3 years. Top half: % increase in BMD. Bottom half: % reduction in fracture risk.

N Engl J Med 2004;350:459-468.

Adapted from N Engl J Med 2004;350:459-68.

Strontium and bone: my opinion

Two-year strontium clinical trial Strontium dose

% change in lumbar BMD

Incidence of new vertebral fractures

Placebo

+0.50

54.7%

170 mg/day

+1.35%

38.8%

340 mg/day

+1.65%

56.7%

680 mg/day

+2.97%

42.0%

For established osteoporosis, high-dose strontium (170-680 mg/day) appears to be appropriate for 1-3 years. Thereafter, consider nutritional doses (such as 2-6 mg/day) for long-term use. Results of long-term trials (> 3-5 years) with high doses suggest a reduction in efficacy with respect to fracture prevention.

Study of 353 postmenopausal women with osteoporosis and a history of at least one vertebral fracture. J Clin Endocrinol Metab 2002;87:2060-2066.

Bone 2009;45:1059-1064

Beyond the Gluten-Free Diet for Optimal Healing

12-‐03-‐26

Aristo Vojdani, PhD Increase Sensitivity by Assessing Multiple Wheat Antigens Beyond the Gluten-Free Diet for Optimal Healing Aristo Vojdani, PhD

International Scholarly Research Network, Allergy, Volume 2011, Article ID 950104, doi: 10.5402/2011/950104

Intestinal T cells from gluten sensitivity/celiac disease patients respond to a heterogeneous array of peptides. Our study extended this heterogeneity to humoral immune response to various wheat proteins and peptides in patients with gluten sensitivity or Crohn’s disease. IgG and IgA antibodies in sera from those patients and healthy control subjects were measured against an array of wheat antigens and peptides. In gluten-sensitive patients, IgG Measurements of IgG and IgA antibodies against such an reacted most against transglutaminase, prodynorphin, wheat extract, and α-, γ-, and ωarray IgA of wheat peptides andthen antigens can enhance gliadin; reacted most against wheat transglutaminase, glutenin, andthe other peptides. In the and sera ofspecificity Crohn’s disease IgG reacted most against wheat and wheat sensitivity ofpatients, serological assays for gluten germ agglutinin then transglutaminase, prodynorphin, α-, and γ-gliadin; IgA reacted sensitivity and celiac disease and may also detect silent celiac foremost against prodynorphin then transglutaminase and α-gliadin. These results showed its overlap inflammatory adisease substantial or heterogeneity in thewith magnitude of IgG and IgAbowel responsedisease. against various wheat antigens and peptides. Measurements of IgG and IgA antibodies against such an array of wheat peptides and antigens can enhance the sensitivity and specificity of serological assays for gluten sensitivity and celiac disease and may also detect silent celiac disease or its overlap with inflammatory bowel disease.

Diagnosis: GlutenReactive •  Implement GFD •  Why do anything else?

Beyond the Gluten-Free Diet for Optimal Healing Aristo Vojdani, PhD

Beyond the Gluten-Free Diet for Optimal Healing

12-‐03-‐26

Aristo Vojdani, PhD

CONCLUDING REMARKS

Gral tolerance refers to the observaFon that prior feeding of an anFgen induces local and systemic immune tolerance to that anFgen. Jhysiologically, this process is probably of central importance for prevenFng inLammatory responses to the numerous dietary and microbial anFgens present in the gut. DefecFve oral tolerance can lead to gut inLammatory disease, food allergies, celiac disease, and autoimmuniFes.

• Immune responses induced in early life to environmental and dietary anFgens will be decisive for children and their adult response to these anFgens, and they will condiFon development of immune-‐mediated diseases such as allergies and autoimmunity. • Maternal inLuence on neonatal tolerance inducFon through breast-‐ feeding is probably of great importance because of dietary and environmental anFgen transfer through breast milk and the pleiotropic eOects of breast-‐feeding on gut and immune system maturaFon. • In addiFon, maternal history and maternal sensiFPaFon to common environmental and food anFgens will probably aOect anFgen transfer to the breasQed child along with tolerance inducFon.

Verhasselt V, Nature, 2010, 3(4): 326-‐333

Possible maternal inﬂuence on neonatal tolerance in)uc:on t@rouA@ breast83ee)inAK The presence of IgA will trap anFgens and prevent their transfer to the child, whereas anFgen bound to IgG will be very eﬃciently transferred across the gut barrier using the FcRn. Gut epithelium maturaFon will be accelerated by the presence of growth factors such as epidermal growth factor (EGF) and transforming growth factor (TGF) in maternal milk. The presence of immunomodulaFng factors in milk such as TGF-‐ will favor tolerance inducFon to the transferred anFgens.

Possible maternal inﬂuence on neonatal tolerance in)uc:on t@rouA@ breast83ee)inAK Before reaching the milk, ingested airborne and dietary anFgens are handled by the maternal digesFve system, which could contribute to the generaFon of tolerogenic pepFdes. Depending on the maternal anFgen exposure and mammary gland permeability, various amounts of anFgen will be found in breast milk. Maternal sensiFPaFon to the ingested allergens will dictate whether the transferred anFgens will be found in the milk free or complexed to anFgen-‐ speciﬁc IgA and IgG.

Verhasselt V, Nature, 2010, 3(4): 326-‐333

Mec@anisms o3 oral tolerance in)uc:onK • Gral anFgen crosses from the intesFne into the GALT in a number of ways. It can enter via M cells, be sampled by DC processes that penetrate the lumen, or be taken up by intesFnal epithelial cells. • DCs in the gut are unique in that they can drive Treg diOerenFaFon from Foxp3]cells. These properFes of DCs relate to their being condiFoned by commensal bacteria, TGFβ and IL-‐10 from gut epithelial cells, and their expression of reFnoic acid. • CD11b monocytes may also play a role in the inducFon of Tregs. • Macrophages are sFmulated to produce TGF-‐β a_er uptaking apoptoFc

Possible maternal inﬂuence on neonatal tolerance in)uc:on t@rouA@ breast83ee)inAK Finally, prebioFcs, such as oligosaccharides, that are present in breast milk will lead to the development of a microbiota promoFng immune tolerance inducFon.

epithelial cells or apoptoFc T cells following high dose tolerance. Lower doses of anFgen favor the inducFon of Tregs, whereas higher doses of anFgen favor anergy>deleFon as a mechanism of tolerance inducFon.

• The liver may also play a role in oral tolerance inducFon and anFgen (high dose) may be rapidly taken up by the liver, where it is processed by plasmacytoid DCs that induce anergy and deleFon. Modiﬁed from Weiner et al. Immunol Rev. 2005, 206: 232-‐59.

Beyond the Gluten-Free Diet for Optimal Healing

12-‐03-‐26

Aristo Vojdani, PhD

Weiner et al. Immunol Rev. 2005, 206: 232-‐59.

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BARRIERS TO MACROMOLECULAR ABSORPTION

Increased intestinal permeability is an early biological change that often precedes the onset of autoimmune diseases. Musocal Immunol, 2010; 3(3):247-259 Modified from Mucosal Immunology (Vol 1) 3rd edition, Elsevier academic Press, Burlington, MA; 2005:page 6

An intact intestinal barrier is, therefore, critical to normal physiological function and prevention of disease.

The autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing intestinal barrier function.

Nat Clin Pract Gastroenterol Hepatol, 2005, 2(9):416-422

Beyond the Gluten-Free Diet for Optimal Healing

12-‐03-‐26

Aristo Vojdani, PhD

To this extent, experimental studies involving the in vivo assessment of intestinal permeability using small inert molecules do not necessarily correlate with the uptake of larger dietary antigens.

The exaggerated entrance of antigenic macromolecules across the gut epithelium might initiate and/or perpetuate chronic inflammation as well as the respective contribution of paracellular and transcellular permeability.

Musocal Immunol, 2010; 3(3):247-259

Menard et al. Mucosal Immunol, 2010; 3(3):247-259

Musocal Immunol, 2010; 3(3):247-259

The paracellular pathway relates to structures joining adjacent intestinal epithelial cells. Paracellular diffusion of molecules is mainly restricted by tight junctions. Tight junctions are a network of transmembrane proteins (claudins, occludin, junctional adhesion molecule A (JAM-A). 28

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Pigtail Macaque

Rhesus Macaque

Uninfected pigtail macaques have increased damage to the :ght epithelial #arrier and high levels of 1JI in the lamina propria of the colon

Microbial translocation and immune activation after damage to the structural barrier

A recent study showed that compromised DastrointesFnal inteDrity in piDtail maca\ues (PTMs) was associated with microbial translocaFon (increased :P? in the submucosa), immune acF;aFon, and B:-‐17 producFon by Th17 cells.

(a)  Representative claudin-3 staining (brown) in colon of PTM (b)  Representative F#8=4)G'%H)"()%'@*)7,I8&%')A==,?8'@)-./.)J,'K012340LM6EL@ claudin-3 staining (brown) in colon of RM -‐ -‐ -‐

Beyond the Gluten-Free Diet for Optimal Healing

12-‐03-‐26

Aristo Vojdani, PhD

Uninfected pigtail macaques have increased damage to the :ght epithelial #arrier and high levels of 1JI in the lamina propria of the colon

The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism.

(d) Representative LPS staining (brown) in colon of PTM (e) Representative F#8=4)G'%H)"()%'@*)7,I8&%')A==,?8'@)-./.)J,'K012340LM6EL@ LPS staining (brown) in colon of RM

Physiol Rev, 2011; 91:154-176.

-‐ -‐ -‐

The intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur.

This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. Physiol Rev, 2011; 91:154-176

Physiol Rev, 2011; 91:154-176

Carrick 2012

100,000 Da

Two Key Transport Mechanisms

MOLECULAR SIZE

Paracellular – between the cells

Transcellular – through the cells

5,000 Da

LPS

GLUTEN PROTEIN

GLUTEN PEPTIDE

IMMUNE CHALLENGE ZONE NO IMMUNE CHALLENGE

2 500 Da

LACTULOSE MANNITOL

Beyond the Gluten-Free Diet for Optimal Healing

12-‐03-‐26

Aristo Vojdani, PhD

Next generation testing for Intestinal Antigenic Permeability Dysbiosis

Epithelial Cell Damage

Tight Junction Damage

Bacterial Endotoxin (LPS) IgG, IgM, IgA

Actomyosin Network IgA

Occludin / Zonulin IgG, IgM, IgA

Ja:ent literature helps the transi:on into a healthier life-‐style for the gluten sensi:7e popula:on

The therapy for the disease is a gluten-free diet; however, the response to therapy is poor in up to 30% of patients, and dietary non-adherence is the chief cause of persistent or recurrent symptoms. N Engl J Med, 2007; 357:1731-1743

---

Beyond the Gluten-Free Diet for Optimal Healing

12-‐03-‐26

Aristo Vojdani, PhD

Lanzini et al. Aliment Pharmacol Ther, 2009; 29(12):1299-1308

Even minute traces of gliadin or their cross-reactive foods are capable of triggering a state of heightened immunological activity in gluten sensitive people. J Neurol Neurosurg Psych, 1997; 63:770-775

Gluten-Associated Cross-Reactive Foods & Food Sensitivity Rye, Barley Polish Wheat Spelt

Cow’s Milk

α-Casein β-Casein

Casomorphin

Butyrophilin

Whey Protein

Chocolate (milk)

Oats

Yeast

Coffee

Sesame

Buckwheat

Sorghum

Millet

Hemp

Amaranth

Quinoa

Tapioca

Teff

Soy

Egg

Corn

Rice

Potato

Milk

*Gluten-‐Containing Grains Rye Barley Spelt Polish Wheat

(a.k.a. KamutfK Camel’s WheatK CDypFan Wheat)

Foods Known to Cross-‐React With Puriﬁed Gliadin •  Food hypersensitivity and allergy

•  Irritable Bowel Syndrome

•  Intestinal lesions

•  Flour protein hypersensitivity

•  Anti-nutritional factors

•  Baker’s asthma

•  Cutaneous contact reactions

•  Gluten sensitivity

•  Inflammatory injury in the absorptive surface of small intestine

•  Chronic Fatigue Syndrome

•  Celiac disease

Cow’s Milk

Chocolate (milk)

Casein

Gluten Grains*

Casomorphin

Yeast

Milk Butyrophilin

Oats

Whey Protein

Coﬀee

*Rye, Barley, Spelt, Polish wheat

•  Fibromyalgia

Beyond the Gluten-Free Diet for Optimal Healing

12-‐03-‐26

Aristo Vojdani, PhD

Newly-‐Introduced and Over-‐Consumed Foods on GFD •  Cross-reaction with A5-B3 glycinin of soy, which could be involved in allergic reactions observed in cow’s milk allergic patients

•  GI symptoms in 50% of patients with Gluten Sensitivity and Celiac Disease •  Most common causes of food allergy in the first years of life •  Autoimmunity, in particular, type 1 diabetes, Behҫet’s disease, lupus and uveitis •  Modulate intestinal mucus discharge and defense against noxious agents

Sesame

Quinoa

Buckwheat

Tapioca

•  Induction of BBB permeability and induction of Apnea in SIDS

Sorghum

Teﬀ

•  Stimulation of antigen specific immune responses in both GALT and peripheral immune organs

Millet

Corn

Hemp

Rice*

Amaranth

Potato

•  Exacerbation of CNS inflammation •  Cross-reaction with myelin oligodendrocyte glycoprotein and induction of experimental autoimmune encephalomyelitis and Multiple Sclerosis

*Rice cross-‐reacts with wheat, but not gluten proteins

INTERPRETATION OF CROSS-‐REACTIVE AND NEW FOOD ANTIGENS

DAIRY-‐ SENSITIVITY

•  Nutritional benefits

•  Healthy alternative grain for patients needing to consume a low-glycemic diet

•  Anaphylactic shock

•  Sensitivity

•  Reduction of blood pressure

Antibody Array 4 Plate – Control Sample IgG + IgA

GLUTEN-‐ CONTAINING GRAINS

IN VITRO CROSS-‐ REACTION TO GLIADIN

NEWLY INTRODUCED FOODS ON GFD

Cow’s Milk

OVER-‐ CONSUMED ON GFD

Cow’s Milk

Rye

Casein

Barley

Casein

Sesame Hemp

Corn Rice

Casomorphin

Spelt

Casomorphin

Buckwheat

Potato

Milk Butyrophilin

Polish Wheat

Milk Butyrophilin

Sorghum

Whey Protein

Whey

Millet

Chocolate (milk)

Amaranth

Yeast

Quinoa

Oats

Tapioca

Egg

Coﬀee

Teﬀ

Common Food Allergens

Soybean

Antibody Array 4 Plate – Patient Sample IgG + IgA

Cow s Milk 1.0

α-Casein β-Casein 1.0

CasoMorphin 1.1

Milk Butyrophilin 1.1

American Cheese 1.0

Chocolate 1.0

Cow s Milk 2.4

a-Casein b-Casein 2.2

CasoMorphin 3.1

Milk Butyrophilin 4.2

American Cheese 3.0

Chocolate 2.2

Sesame 1.5

Hemp 2.0

Rye 1.0

Barley 1.0

Polish Wheat 1.1

Buckwheat 1.0

Sesame 2.4

Hemp 3.8

Rye 2.0

Barley 2.4

Polish Wheat 3.3

Buckwheat 2.2

Sorghum 1.0

Millet 1.2

Spelt 1.0

Amaranth 1.6

Quinoa 1.3

Yeast 1.9

Sorghum 2.2

Millet 3.1

Spelt 3.3

Amaranth 3.0

Quinoa 3.0

Yeast 4.1

Tapioca 1.3

Oats 1.0

Coffee 1.5

Corn 1.5

Rice 1.5

Potato 1.2

Tapioca 3.2

Oats 3.8

Coffee 3.6

Corn 2.2

Rice 2.6

Potato 3.0

Carrick 2011 p1

Beyond the Gluten-Free Diet for Optimal Healing

12-‐03-‐26

Aristo Vojdani, PhD

Diagnosed Nith Gluten Immune ReacFvity

What is Autoimmunity?

Implement Gluten-‐Free Diet Improvement ConFnue GFD

Assess GFD AnFgens and Cross-‐ReacFve Foods NegaFve

PosiFve

Assess IntesFnal AnFgenic Permeability NegaFve

PosiFve

Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response Is termed an autoimmune disease.

Non-‐Responsive

Use Results to Tailor Diet Improvement

Non-‐Responsive Remove All Cross-‐ReacFve Foods Regardless of Results Improvement

Test for Autoimmunity or Possible Viral InfecFons

Implement Gut Healing Protocol

Stay the Course

Non-‐Responsive Assess IntesFnal AnFgenic Permeability or Assess Gut Enzyme Make-‐Up

---

CONCLUSION •  The applicaFon of these anFbody arrays to human autoimmune disease alloNs for the idenFRcaFon of panerns or anFbody signatures, thus establishing the premises for increased sensiFvity and speciRcity of predicFon, as Nell as posiFve predicFve valuesI •  Using this high-‐throughput microarray method, it is possible to screen rapidly for dozens of autoanFbodies at loN costI

---

Diagnosed Nith Gluten Immune ReacFvity Implement Gluten-‐Free Diet Improvement ConFnue GFD

Non-‐Responsive Assess GFD AnFgens and Cross-‐ReacFve Foods NegaFve

PosiFve

Assess IntesFnal AnFgenic Permeability NegaFve

PosiFve

Take steps beyond the GFD for beUer pa:ent outcomes.

Use Results to Tailor Diet Improvement

Non-‐Responsive Remove All Cross-‐ReacFve Foods Regardless of Results Improvement

Test for Autoimmunity or Possible Viral InfecFons

Implement Gut Healing Protocol

Stay the Course

Non-‐Responsive

Assess IntesFnal AnFgenic Permeability or Assess Gut Enzyme Make-‐Up

Extending Health Span: an Orthomolecular Approach

12-‐03-‐26

Aileen Burford-Mason, PhD

Some definitions Extending Healthspan: An orthomolecular approach

Lifespan •  Bookends life between “alive” and “dead” Healthspan •  The length of Nme an individual can maintain good health, with minimal system dysfuncNon •  The ability of an individual to maintain or return to homeostasis in response to health challenges

Aileen Burford-Mason PhD Orthomolecular Medicine Today

Vancouver BC. 27th -‐29th April 2012

Life expectancy vs. health expectancy

DegeneraNve disease of ageing

World Health Organization 2000

•

Cardiovascular disease and stroke

•  Disability-‐adjusted life expectancy (DALE) introduced by WHO in 2000

•

Type 2 diabetes

•  Ill-‐health rated according to degree of severity

•

Osteoporosis

•  This calculaNon is then subtracted from overall life expectancy to esNmate Heathy Life Expectancy

•

Eye disease

•

DemenNa and Al[heimer\s disease Hearing loss

–  ↑ BP; ↑ cholesterol, CRP, homocysteine

–  Separates life into disability-‐free years and years lived in poor health

–  Insulin resistance; metabolic syndrome

–  To be legally blind or immobile more serious than having diabetes

–  osteopenia

–  Cataract; glaucoma; drusen; AMD

•

Healthspan by Country

Healthspan may be set before birth

World Health Organization 2004

Separates life into disability-free years (DALY) and years lived in poor health

Hypothesis: Maternal under nutriNon in pregnancy results in an imbalance between fetal needs and nutrient supply •  Structure and funcNon of many key organs is altered in the fetus •

•  191 countries rated

–  Top country was Japan – 74.5 yrs –  Boaom country was Sierra Leone – 25.9 yrs –  Canada ranked 12th – 72 years –  USA ranked 24th!! – 70 years

•  •

Note: 2010 ﬁgures will be issued in 2012

Short term beneﬁt: ensures fetal survival Long term consequences: changes in structure and physiology of “vital organs” eventually lead to the development of chronic diseases in adult life

Extending Health Span: an Orthomolecular Approach

12-‐03-‐26

Aileen Burford-Mason, PhD Survival eﬀects of prenatal famine

Survival eﬀects of prenatal famine van Abeelen A, et al. Am J Clin Nutr 2012;95:179-‐83

van Abeelen A, et al. Am J Clin Nutr 2012;95:179-‐83

•  Research quesNon: Are there long term consequences of periconceptual under nutriNon in the oﬀspring? •  Methods: Examined overall and cause-‐speciﬁc adult mortality among term singleton births (n=1991) exposed to the Dutch famine (1944-‐1945)

•  Results: 206 (10%) died during follow-‐up

•  Women conceived during the famine had higher overall mortality, higher mortality from CVD, cancer, and breast cancer •  Adjustments for smoking, social class, or size at birth did not change results •  No impact on male mortality

•  Prenatal famine exposure in early, mid or late gestaNon compared to singleton term births not exposed to famine

•

Conclusions: Adult mortality in women was aﬀected by under nutriNon in early pregnancy

Cohort proﬁle: The Herkordshire Ageing Study Syddall HE et al. Int J Epidemiol. 2010;39(1):36-‐43

•  Background: Unique set of infant records collected in Herkordshire, Ul, from 1911 to194m recently discovered •  Follow-‐up: Surviving men and women born 1920-‐1930 (n=6m03) and sNll living in early 1990s underwent extensive invesNgaNons •  Results: low birth weight term infants had higher incidence of chronic diseases of ageing

Measuring Healthy Aging

–  Coronary heart disease, type 2 diabetes, metabolic syndrome, insulin resistance and osteoporosis

Chronological Age vs. Biological Age •

Telomeres and Telomerase •  Telomeres: DNA complexes that cap the end of chromosomes, promoNng geneNc stability •  When cells divide telomeres shorten.

Chronological Age: Nme on earth in years is ﬁxed – can’t stop the clock !! •  Hayﬂick number suggest 120-‐125 years is maximum human lifespan

•

•  Eventually diminish to the point that cells can no longer divide

Biological age: indicator of cellular health

•  Telomerase replenishes telomeres when cells divide

•  Reflects consistent ability to repair and maintain Nssues as the years go by •  Not fixed. Influenced by genes, environment, lifestyle (exercise, smoking) and diet

•  High levels of telomerase expressed in fetal and cancer cells

•  In cell culture oxidaNve stress and nutrients deﬁciencies shorten telomeres

•  Cellular marker of biological age: Telomere length/telomere shortening

•  Consider telomeres Lthe canaries in the mineshaqM (J Gerentol A Bio Sci Med Sci 2009;64(5):511-‐5)

Extending Health Span: an Orthomolecular Approach

12-‐03-‐26

Aileen Burford-Mason, PhD Dietary paaerns associated with telomere length

•

Diet and telomeres

•

Xrotein restricNon in pregnancy results in shorter telomeres in oﬀspring (The FASEB Journal.

2008;22:2037-‐2044) •  Aqer birth, over nutriNon of these same infants further shortens telomeres; increases risk of CVD

High saturated fat or low fat, high carbohydrate diets associated with shorter telomeres compared to a Mediterranean-‐style diet ( QarUn C et al. A+e (Dordr). 2011 Sep 6. [Epub ahead of print])

•

Rise in insulin resistance is associated with escalated telomere aariNon

High caloric intake associated with shorter telomeres (Am J Clin Nutr 2012; 95(2):479-‐487)

Dietary paaerns, food groups, and telomere length in the MulN-‐Ethnic Study of Atherosclerosis (MESA). Ne[leton JA et al. Am J Clin Nutr 2008; 88( 5):1405-‐1412

Nardner JZ et al. CirPulaUon 2005;111(17):2171-‐7.

•  Study: cross-‐secNonal study: AssociaNon of telomere

•  Study: nollowed young adults parNcipaNng in the Bogalusa Heart Study

length with dietary paaerns

–  840 white, black, and Hispanic adults –  Looked at intake of whole grains, fruit/vegetables, low-‐fat dairy, nuts/seeds, nonfried fish, coffee, refined grains, fried foods, red meat, processed meat, sugar-‐sweetened soda

–  Assessed changes in BMI, insulin resistance and leukocyte telomere length over 10-‐12 years

•  Results: over the study period, telomere shortening was associated with

•  Results: Intake of processed meat inversely associated with telomere length

–  increased insulin resistance (p<0.001) –  increases in BMI (p< 0.001)

–  =ther foods or dietary paaerns did not show the expected relaNonship

Micronutrients associated with longer telomeres

Obesity and weight gain in adulthood and telomere length.

Kims S et al. Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):816-20

•  Study: examined associaNon between current and past BMI and telomere length

–  647 women ages 35 to 74 years

•  Results: ↑ BMI and hip circumference were inversely associated with telomere length

•  •  •

Higher blood levels of 25-‐hydroxy D Daily mulNvitamin/mineral use (women) Higher blood levels of B-‐vitamins

•

Magnesium (Nssue culture)

•

–  Weight gain since 30s and weight cycling were risk factors for shorter telomeres –  sreatest reducNon in telomere length seen in those overweight at age 30 and again a decade later

•  •

Higher blood levels of omega 3 fats Higher blood levels of vitamins C and E •

•  Conclusion: Maintaining a desirable weight in adulthood may help slow down aging

homocysteine < 7.5 μmol/L

esp. tocotrienols

Extending Health Span: an Orthomolecular Approach

12-‐03-‐26

Aileen Burford-Mason, PhD

Tocotrienol-‐rich fracNon prevents cell cycle arrest and elongates telomere length in senescent human diploid ﬁbroblasts

CorrecNng magnesium deﬁciencies may prolong life Rowe WJ. Clin Interv Aging. 2012;7:51-‐4.

•

Makpol S et al. J Biomed Biotechnol 2011;2011:506171

Review arNcle: Aging is associated with ↓↓ telomere length. Telomerase can elongate telomeres and

•  In vitro study: human ﬁbroblasts cultured with tocotrienol-‐rich vitamin E (TRF) for 24 hours

maintain chromosome stability •

•

•  Results: conNnued culture caused

Cardiovascular system ages x10 faster in space Associated ↓↓ reducNons of serum Mg (P < 0.0001)

•  TRF-‐treatment of these senescent cells for 24 hrs

–  telomere shortening and ↓ telomerase acNvity –  fewer dividing cells, and ↑ cell cycle arrest

Space travel is a good model of rapid aging •  •

•

–  eﬀect of TRF on senescence examined

However, binding of telomerase to telomeres is Mg dependent

–  elongated telomeres and restored telomerase acNvity

Conclusion: Space laboratory could give rapid answers regarding eﬀect of Mg deﬁciency on aging and telomere length

•  Conclusion: TRF can reverse cell cycle arrest associated with senescence

Tocotrienol rich fracNon supplementaNon improved lipid proﬁle and oxidaNve status in healthy older adults: A randomized controlled study

Chin SF, et al. Nutr Metab (Lond). 2011;8(1):42.

•  Study: RCT. Eﬀect of tocotrienols on lipid proﬁle and oxidaNve stress in healthy subjects (n=62)

•  Results: At 6m the supplemented group had

–  increased HDL (p < 0.01) –  Decreased protein carbonyl content (P < 0.001) –  Advanced glycosylaNon end products (AGEs) went down in the 50+ group (p < 0.05)

–  2 age groups: 35-‐49yrs (n = 31) and >50yrs (n = 31)

•  Methods: Subjects given tocotrienol-‐rich vitamin E (TRF) 160mg/day or placebo for 6m –  TRF was 74% tocotrienols and 26% α-‐tocopherol –  Blood samples obtained at 0, 3 and 6 months

•  Conclusion: improved cholesterol, AGE and anNoxidant vitamin levels, and reduced protein damage indicates redox balance was restored aqer TRF supplementaNon

•  Results: Aqer 3m the TRF group had ↑plasma total vitamin E (p < 0.01), parNcularly α-‐tocopherols

Telomere length in early life predicts lifespan. Heidinger BJ et al. Proc Natl Acad Sci U S A. 2012;109(5):1743-‐8.

•  Background: AariaNon in telomere length (TL) in those of the same age may be related to variaNon in potenNal longevity

Are life span and healthspan connected?

–  Studies where TL is tracked from early to end of life are lacking –  Diﬃcult to carry out in long lived species

•  Study: measured TL in zebra ﬁnches (n = 99) from the nestling stage and at various points to end of natural lifespan –  Lifespan varied from <1 yr to ~9 yr

Extending Health Span: an Orthomolecular Approach

12-‐03-‐26

Aileen Burford-Mason, PhD

Telomere length in early life predicts lifespan. Heidinger BJ et al. Proc Natl Acad Sci U S A. 2012;109(5):1743-‐8.

•  Results: TL at 25 d was a strong predictor of realized lifespan (P < 0.001)

What makes me so certain that the natural human lifespan is far in excess of the actual one is this. Among all my autopsies (and I have performed over 1000), I have never seen a person who died of old age. In fact, I do not think that anyone has ever died of old age yet. We invariably die because one vital part has worn out too early in proporUon to the rest of the body. Dr. Hans Selye (1907–1982)

–  Cirds living the longest had relaNvely long TLs at all points measured –  ReproducNon increased adult TL aariNonO Jut efect was transient and did not inﬂuence survival

•  Conclusion: Study provides ﬁrst evidence for a relaNonship Jetween TL and lifespan Note: Authors comment that day 25 in the life of a zebra ﬁnch would be the equivalent of adolescence in human lifespan

How widespread are vitamin and mineral deficiencies? (Data from 2004 Canadian Community Health Survey )

Women

How widespread are nutritional deficiencies?

PeﬁniNon of EsNmate Average Reeuirement (EAR) – Health Canada

How widespread are vitamin and mineral deficiencies? (Data from 2004 Canadian Community Health Survey )

Men

“The EAR is the median daily intake value that is

esUmated to meet the requirement of half the healthy individuals in a life-‐stage and gender group. At this level of intake, the other half of the individuals in the speciﬁed group would not have their needs met.”

www.hc-‐gc.cagfn-‐angnutriUongreferencegtablegindex-‐eng.phphdef

Extending Health Span: an Orthomolecular Approach

12-‐03-‐26

Aileen Burford-Mason, PhD Bone health is aﬀected by mulNple nutrient deﬁciencies

Extending healthspan: Why we can’t focus on single nutrients •  All nutrients are required by all organs

•  Vitamin D and calcium (Binkley N. Arch Biochem Biophys. 2012 Feb 13.

–  Absence of any one compromises the acNvity of others, either directly or indirectly

•  •  •  •  •  •  •

•  All organs are eﬀected by deﬁciencies of any single nutrient –  A nutrient cannot support the health of one organ and undermine the health of another

•  jutriNonal deficiencies of essenNal nutrients are widespread –  By definiNon this affects the health of mulNple Nssues

•  Using the current “gold standard” RCT approach to studying this complexity is impossible…

[Epub ahead of print]

Magnesium (Rude RK, et al. J Am Coll Nutr. 2009;28(2):131-‐41) Zinc (Yamaguchi M. Mol Cell Biochem. 2010;338(1-‐2):241-‐54) Vitamin K (Falcone TD et al.; PM&R. 2011 Jun;3(6 Suppl 1):S82-‐7) B-‐vitamins (Baines M et al. Bone. 2007;40(3):730-‐6) Vitamin C (Falch JA et al. Scand J Clin Lab Invest.1998 May;58(3):225-‐8) Protein (Tucker KL. Curr Osteoporos Rep. 2009;7(4):111-‐7) Omega 3 fats (TarUbian B et al. Nutr Metab (Lond). 2011;8:71)

CombinaNon therapies and the theoreNcal limits of evidence-‐based medicine

Omega 3 fat deﬁciency aﬀects mulNple organs and systems

Saver JL, Kalafut JL. Neuroepidemiology 2001;20(2):57-‐64

•  Background: MulNple promising treatments are being developed for all major medical disorders

•  Brain health (Karr JE et al. Nutr Neurosci. 2011 Sep;14(5):216-‐25) •  Cardiovascular health (Mozaﬀarian D, Wu JH. J Am Coll Cardiol. 2011

–  Many of these may be complementary –  Can we design clinical trials to determine the opNmum combinaNon of therapiesg

Nov 8;58(20):2047-‐67)

•  Eye health (Krishnadev N et al. Curr Opin Ophthalmol. 2010 May;21(3): 184-‐9)

•  Bone health (TarUbian B et al. Nutr Metab (Lond). 2011 Oct 15;8:71) •  Oral health (Iwasaki M et al. Prostaglandins Leukot Essent Fa[y Acids.

•  Methods: exisNng strategies for tesNng combinaNon regimens are described

2011;85(2):107-‐12)

•  Cancer prevenNon (Cockbain AJ et al. Gut. 2012;61(1):135-‐49) •  Autoimmune disease (Iwami D, et al. Int Immunopharmacol. 2011;11 (3):384-‐9)

–  applied to two condiNons, Alzheimer’s disease and ischemic stroke

CombinaNon therapies and the theoreNcal limits of evidence-‐based medicine Saver JL, Kalafut JL. Neuroepidemiology 2001;20(2):57-‐64

•  Results: In 2001 there were 7 drugs approved for prevenNng or slowing progression in Alzheimer diseaseY 5 for ischemic stroke prevenNon •  TesNng eycacy of these in combinaNon would require

Nutrition and brain health

–  Alzheimer’s disease: 127 trials, enrolling 63,500 paNents, taking 2m6 years –  Ischemic stroke: 31 trials, enrolling 1m6,000 paNents and taking 155 years

Extending Health Span: an Orthomolecular Approach

12-‐03-‐26

Aileen Burford-Mason, PhD Red blood cell omega-‐3 faay acid levels and markers of accelerated brain aging Tan ZS, et al. Neurology 2012; 78: 658–664

Nutrition and the Brain •  The brain may be the ﬁrst organ to detect inadeeuate nutriNon

•  Cross-‐secNonal Study: –  Framingham Oﬀspring cohort (n=1575; 67+/-‐ 9 yrs), free of demenNa. Brain imaging, neuropsychological assessment carried out; red cell DHA and EPA checked

–  Averaging only 2% of total body weight, it uNli[es 20% of nutrients, circulaNng oxygen and glucose

•  Results: Compared to those in the 3 higher euarNles, those in the lowest euarNle of DHA had

•  There is therefore a high ﬁxed cost of brain funcNon

–  For opNmal brain funcNon an opNmal molecular environment is needed –  The harder you work the brain, the more nutrients and oxygen it needs

–  signiﬁcantly reduce brain volumes (P=0.009) –  poorer scores on tests of visual memory, execuNve funcNon, and abstract thinking (P=0.008, P=0.004, and P=0.004, respecU5ely)

Eﬀects of high-‐dose B vitamin complex with vitamin C and minerals on subQecNve mood and performance in healthy males

Kennedy DO et al. Psychopharmacology (Berl) 2010 Jul;211(1):55-‐68

•  Results: taking an MVM improved

•  RCT: placebo controlled double-‐blind

–  Mood –  Perceived stress –  CogniNve performance during intense mental processing –  Physical vigor

•  assessed eﬀect of 1 month treatment with a mulNvitamin and mineral complex (MVM) on physical and psychological funcNoning •  215 males (30-‐ 55 yr) in full-‐Nme employment B1 = 15mg (1.2mg) C = 500mg (90mg) B2 = 15mg (1.3mg) B5 = 23mg (5mg) B6 = 10mg (1.3mg) B12 = 10mcg (2.4mcg) Folic acid = 400mcg (400mcg)

•  Conclusion: Healthy members of the general populaNon may beneﬁt from augmented levels of vitamins/minerals via direct dietary supplementaNon

BioNn = 150mcg (30mcg) jicoNnamide = 50mg (16mg) Calcium = 100mg (1000mg) Magnesium = 100mg (400mg) Zinc = 10mg (11mg)

Vitamin B12 status and rate of brain volume loss in community-dwelling elderly

jutrient biomarker paaerns, cogniNve funcNon, and MRI measures of brain aging. Bowman GL et al Neurology 2012;78(4):241-‐9

Vogiatzoglou A et al. Neurology. 2008;71(11):826-32

•  Study: Cross-‐secNonal relaNonship between nutrient status, cogniNve funcNon and brain imaging in demenNa-‐free elders

•  Study: 5-‐yr prospecNve study of B12 and brain volume in community-‐dwelling older subQects without cogniNve impairment (n=107; 61-‐87 yrs) •  Results: vitamin B(12) in the boaom terNle (r308 pmol/ L) was associated with increased loss of brain volume (odds raNo 6.17, 95% CI 1.25-‐30.47).

–  Oregon Brain Aging Study cohort (n = 104; age range 87 ± 10 yrs; 62% female)

•  Findings: favorable cogniNve funcNon and MRI measures associated with

–  high plasma omega-‐3 fats, B vitamins (B1, B2, B6, folate, and B12), C, D, and E –  Low plasma trans fats

Note: many laboratory reference ranges report “normal” B12

as p1CC pmolgL. OpUmal may be 1000-‐2000 pmolgL (Prousby J. JOM 2010;25(2):77-‐88)

Extending Health Span: an Orthomolecular Approach

12-‐03-‐26

Aileen Burford-Mason, PhD

High Plasma Levels of Vitamin E Forms and Reduced Alzheimer’s Disease Risk in Advanced Age

The Eﬀects of >ulNvitamins on CogniNve Performance: A SystemaNc Review and >eta-‐Analysis

Kivipelto M et al. J Alzheimers Dis. 2010;20:1029–1037

Grima NA et al. J Alzheimers Dis. 2012 Feb 13. [Epub ahead of print]

•  Study: A demenNa-‐free sample of 232 subQects aged 80+ yrs followed for 6 yrs

•  Study: systemaNc review and meta-‐analysis of RCTs of mulNvitamins and cogniNve funcNon •  Results: 10 trials suitable for inclusion (n=3200). ConNnued use of mulNvitamin for v1m

–  Plasma levels of all 8 forms of vitamin E checked

•  Results: high plasma levels of vitamin E at baseline associated with a reduced risk of AD

–  improved immediate free recall memory (p < 0.01), but not delayed free recall memory (p = 0.56) or verbal ﬂuency (p = 0.26)

–  neuroprotecNve eﬀect of vitamin E was related to the combinaNon of diﬀerent forms of vitamin E

•  Conclusion: All forms of vitamin E protect against Alzheimer’s – not α-‐tocopherol alone

•  =ther cogniNve abiliNes such as execuNve and visuospaNal funcNons under-‐researched

Citicoline: Pharmacological and clinical review, 2006 update.

Double-‐blind placebo-‐controlled study with ciNcoline in AP=E genotyped Alzheimer~s disease paNents. Eﬀects on cogniNve performance, brain bioelectrical acNvity and cerebral perfusion

Secades JJ, Lorenzo JL. Methods Find Exp Clin Pharmacol. 2006 ;28 Suppl B:1-56

Alvarez XA et al. Methods Find Exp Clin Pharmacol. 1999;21(9):633-‐44

•  CiNcoline: required for the biosynthesis of structural phospholipids in cell membranes •  Experimentally increases

•  •

–  cell membrane phosphaNdylcholine, phosphaNdylethanolamine, and phosphaNdylserine;

•  Improves learning and memory

•

–  Increases CNS norepinephrine and dopamine –  Precursor for acetylcholine (the brain’s “memory manager”) –  Inhibits apoptosis in cerebral ischemia and potenNates neuroplasNcity

Citicoline in clinical practice

Study: 12-‐week RCT of 1000mg ciNcoline or placebo in mild to moderate Alzheimer’s (n =30; age 57-‐87 yrs) Results: ciNcoline was well tolerated –  No side eﬀects reported Compared to placebo, ciNcoline –  improved cerebral blood ﬂow and the brain bioelectrical acNvity –  improved cogniNve performance in paNents who were AP=E E_ posiNve. This was more pronounced in mild demenNa

Citicoline in clinical practice •  Treatment: ciNcoline 250mg capsules

•  Case report: female university professor (59 yrs)

–  Healthy diet, regular exercise, no current medicaNons

–  Started on 2 capsules twice daily for 1 month. Problem resolved

–  mulNvitamin –  addiNonal vitamin C, D, E (full spectrum), magnesium –  ﬁsh oil

•  Gradually decreased dose to ﬁnd personal opNmal dose

•  Current supplement regime

–  Week 1 → 500 mg am + 250 mg pm. Benefit maintained –  Week 2 → 250 mg am + 250 mg pm. Dose ineffective

•  Recent onset of diyculNes with word retrieval –  =ccurred during lectures and at meeNngs –  Stress related?

12-‐03-‐26

Extending Health Span: an Orthomolecular Approach Aileen Burford-Mason, PhD

Recent advances in berry supplementation and agerelated cognitive decline

Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neurocognitive performance. Spencer JP. Proc Nutr Soc. 2008 May;67(2):238-52

Willis LM et al. Curr Opin Clin Nutr Metab Care. 2009 Jan;12(1):91-4

•  Review arNcle: suggests dietary-‐derived phytochemicals acNvate a number of neuronal signalling pathways pivotal for memory and learning •  Many diverse phytochemicals have the potenNal to:

•  Review: explores studies on beneﬁts of berry consumpNon for brain funcNon during aging (animal studies)

–  berry ﬂavonoids and polyphenols accumulate in brain following long-‐term consumpNon –  this posiNvely impacts learning and memory

–  improve human memory and neuro-‐cogniNve performance –  protect vulnerable neurons –  enhance exisNng neuronal funcNon –  sNmulate neuronal regeneraNon (i.e. aqer injury)

•  AnNoxidant-‐rich foods act not just as free radical neutralizers but interact directly with aging neurons

–  this increases the capacity of neurons to maintain proper funcNoning during aging

BenfoNamine

Thiamine(vitamin B1)

– one to watch –

•  (ssenNal for glucose and lipid metabolism and needed for

•  Fat soluble form of thiamine developed in Japan in the early 60~s to treat alcoholic neuriNs

–  the funcNoning of the heart, other muscles, and the nervous system –  the producNon of gastric 0Dl –  synthesis and release of acetylcholine

–  superior absorpNon –  longer maintenance of blood and Nssue stores

•  Inhibits formation of AGEs •  May be more efecNve than thiamine for treaNng diabeNc neuropathies, reNnopathies and angiopathies (Thornalley PJ. Curr Diabetes Rev. 2005;1(3):

•  Depleted by exercise, high-‐ carb diets, excess alcohol intake, and many drugs

–  anNbioNcs; 0RT and oral contracepNves; some chemotherapies; digoxin; phenytoin; thiazide and loop diureNcs

287-‐98)

•  Water soluble. Not well stored (1-‐3 weeks)

Xowerful beneﬁcial efects of benfoNamine on cogniNve impairment and β-‐amyloid deposiNon in amyloid precursor protein/presenilin-‐1 transgenic mice Pan X et al. Brain. 2010;133(Pt 5):1342-‐51

“It has generally been supposed that beriberi is a deficiency disease due to lack of vitamin B1. Deficiency diseases, however, are never limited to lack of a single factor, and although there is a B1 deficiency in beriberi the disease is undoubtedly an avitaminosis due to lack of the whole B group.”

•  Background: disturbance of brain glucose metabolism seen in Alzheimer’s disease (AD)

–  Thiamine is a co-‐factor for several rate limiNng enzymes in glucose metabolism –  In animal studies, thiamine deﬁciency causes increased β-‐ amyloid generaNon, neuronal cell death and neuroﬁbrillary tangles, very similar to AD.

•  Study: In an animal model of AD, benfoNamine improved cogniNon and reduced amyloid

Bicknell F, Xrescoa F. In: The Vitamins in Medicine.

–  more efecNve than other forms of thiamine

William Heinemann Lond. 1942 p107

Extending Health Span: an Orthomolecular Approach

12-‐03-‐26

Aileen Burford-Mason, PhD

?hree case reports to illustrate clinical applicaNons in the use of erythrocyte transketolase Lonsdale D. Evid Based Complement Alternat Med. 2007 Jun;4(2):247-‐50

•  Background: erythrocyte transketolase is a reliable funcNonal marker of thiamine dedciency –  However, transketolase requires both thiamine and magnesium as co-‐factors

www.aburfordmason.ca

•  Report: 3 cases of thiamine dedciency idenNded by

abnormal erythrocyte transketolase acNvity –  >ain presenNng symptom was e)treme faNgue

•  Required both thiamine, magnesium and infusions of mulNple vitamins and minerals to recover and normalize transketolase

Hormones and Dysregulation Spectrum Syndrome Kent MacLeod, BPharm

12-03-26

! !

What is ! Dysregulation Syndrome?

! Hormones and the Dysregulation Syndromes (Fibromyalgia-like conditions) ! ! Orthomolecular Approaches! ! !

•  Pain originating from sensitization of the Central Nervous System •  Classic disease example is Fibromyalgia •  Pain continues long beyond initialization •  Characterized by allodynia •  It is a highly complex disease involving genetic and neuroendocrine / hormonal inﬂuences as well as a myriad of complex biological factors affecting CNS

Dysregulation or CSS! Cluster of Modern Diseases !

Central Sensitivity Syndrome or CSS ?

Muhammad Yunus MD, University of Illinois

•  Central sensitivity syndrome is probably a better descriptive than dysregulation syndrome or ﬁbromyalgia, since pain originates from the Central Nervous System

Bi-Directional Nature of ! CSS Disorders

Common Disorders ! Associated with CSS •  Restless leg syndrome •  Temporomandibular joint Disorder •  Chronic fatigue syndrome •  Chronic headachesmigraine & tension •  Dizziness •  Ear pain and tinnitus •  Vestibular disorder •  Interstitial cystitis

•  Fibromyalgia •  Irritable bowel syndrome •  Meniere s disease •  Movement disorders •  Multiple chemical sensitivity •  Rheumatoid arthritis •  Sleep disorders •  Vulvodynia •  Depression

•  •  •  •

Sleep Migraine Depression Back pain - 67% of patients with idiopathic chronic low back pain were found to have ﬁbromyalgia •  Myofascial Pain Syndrome •  Chronic pain causes shrinkage of grey matter and other physical changes in brain consistent with ﬁbromyalgia and CSS

Hormones and Dysregulation Spectrum Syndrome

12-03-26

Kent MacLeod, BPharm Prevalence of Fibromyalgia Syndrome (FMS) in other ! Central Sensitivity Syndromes (CSS)!

Prevalence of Fibromyalgia Syndrome (FMS) in Chronic Painful Diseases with Structural (Organic) Pathology (DWSP)!

Yunus, MB (2012) Pain Res Treat 2012: 584573.!

What are CSS disorders?! It s all in your head

Cost of Fibromyalgia

•  80 billion US$ in USA for chronic health ﬁbromyalgic conditions, in up to 50 million women alone •  Fibromyalgia patients cost 3 x more

•  Objective conditions based on objective pathology of neuro-imaging and neurobiology •  It is NOT all in your head •  Sometimes, to this day, the notion persists that these disorders are made up, or are psychosomatic

Oxycontin: ! Canada/Ontario and USA

Population Aging and The Determinants of Healthcare Expenditures: !

•  Is being prescribed for ﬁbromyalgia and related conditions—sales increase 50x 10yrs •  On ﬁbromyalgia patient websites it s touted as miraculous , closest thing to a cure •  Not recommended by European or North American guidelines •  Kills more Canadians than heroin and cocaine combined - more ER visits than heroin and cocaine •  Government-sponsored physician created junkies with complete communities addicted •

The Case of Hospital, Medical and Pharmaceutical Care in British Columbia 1996-2006

•  Ballooning of healthcare costs not related to aging •  Related to more and more specialists, and increase in neuropsychiatric medications •  These conditions are the modern health care dilemma Morgan, S. and Cunningham, C. (2011) Healthcare Policy 7(1): 68-79

Hormones and Dysregulation Spectrum Syndrome

12-03-26

Kent MacLeod, BPharm Sensitivity Spectrum Syndrome! Interventions Improving CSS!

Effectiveness of Approved ! Drugs in Fibromyalgia

Pregabalin •  # needed to treat = 11, with signiﬁcant side effects •  Treat 11 to achieve 50% response in 1 person •  Side effect withdrawal 11-28% Duloxetine •  Number needed to treat = 8 •  Side effects all patients - 1/6 require withdrawal

Moore RA, et al. (2009) Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. Jul 8; (3):CD007076. Lunn MPT, et al. (2009) Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database of Systematic Reviews Issue 4. Art. No.: CD007115.

Hormones In CSS:! CSS Pain Disorders are More Prevalent in Women

•

Pain Response & Role of Estrogens in CSS! Glutamatergic tonus - Estrogen increases

sensory neurotransmission •  Opiatergic - Estrogen decreases mu receptor neurotransmission •  Serotonergic - upregulate inhibitory •  Affective states - estrogen improves mood and sleep •  Anti-inﬂammatory (prostaglandin) •  Stress - cortisol and prolactin response restored with estradiol

•  Migraine Headache, Temporomandibular Joint Disorder (TMJD) and IBS in younger women age 18-50 years •  Fibromyalgia, rheumatoid arthritis and osteoarthritis are more common after menopause •  Overall CSS affects up to 9x more women than men National Institute of Dental and Craniofacial Health http://www.nidcr.nih.gov/datastatistics

Martin VT (2009) Ovarian Hormones and Pain Response - A Review of Clinical and Basic Science Studies. Gend Med Suppl 2 168-192

Estrogen and Progesterone Effects on CNS Pain during Menstrual Cycle!

Role of Progesterone ! in Pain Response

Martin VT (2009) Ovarian Hormones and Pain Response A Review of Clinical and Basic Science Studies. " Gend Med Suppl 2: 168-192.

•  Downregulates nerve sensitivity •  Downregulates glutamate excitotoxicity in neurons (Nilsen et al. (2002) Endocrinology 143: 205-212.) •  Downregulates cardiac ischemia in women (Rosano G, et al. (2000) J Am Coll Cardiol 36: 2154-2159.)

•  GABA-mimetic - Progesterone increases opening of GABA receptors and increases concentration of cortical GABA (Martin VT (2009)

Gend

Med Suppl 2 168-192)

Hormones and Dysregulation Spectrum Syndrome

12-03-26

Kent MacLeod, BPharm Role of Estrogen: ! Menstrual Migraine! •  Migraines occur when blood levels of

Estrogen in Fibromyalgia! •  Only one trial of estradiol or any estrogen in ﬁbromyalgia – no beneﬁt: low dose estradiol patch •  Premarin, Provera increase pain

estradiol fall below 45 pmol/l •  Giving estradiol 1.5mg transdermal gel prevented migraine •  Similar effects for menstrual TMJ and IBS

Stening, KD et al. (2011)Hormonal replacement therapy does not affect selfestimated pain or experimental pain responses in post-menopausal women suffering from ﬁbromyalgia: a double-blind, randomized, placebo-controlled trial. Rheumatology (Oxford) 50(3):544-51. Wise, EA et al. (2000) Clinical pain perception and hormone replacement therapy in postmenopausal women experiencing orofacial pain. Clin J Pain 16(2): 121-6.

Somerville BW (1971) The role of progesterone in menstrual migraine. Neurology 21: 853–859. Dennerstein L, et al. (1988) Menstrual migraine: A double-blind trial of percutaneous estradiol. Gynecol Endocrinol. 2: 113–120.

Hormonal Interventions in ! CSS Pain ! identical •  Use of bio- or human

Hormone Intervention in Menopausal Women ! ! Proven to Improve: •  Sleep •  •  •  •  •  •

hormones: pioneer Dr. J Wright •  Use of hormone data from the clinical laboratory - treating a woman or man as a whole •  Fibromyalgia or CSS conditions are a symptom as part of a cluster of symptoms

Mood Inﬂammation Hot ﬂashes Night sweats Pain Bone density and other menopausal symptoms

Position Statement North American Menopause Society 2012! •  Overall, it is suggested that treatment with

•

hormone therapy should be individualized - that it will depend on the severity of a woman's symptoms, impairment of quality of life, her personal risk-factor status, and her personal preferences •  WHI study ongoing: 1 death / 10,000 women with the estrogen only arm; less deaths from cancer than placebo

Position Statement NAMS! - still confusing! …all progestin and estrogens should be treated

the same… •  Even though they have potentially different properties and likely to be differences in relative potency, androgenicity, glucocorticoid effects, bioavailability •  Transdermal vs conjugated estrogens - less stroke risk •  Human progesterone has never been shown to increase cancer but synthetics have

Hormones and Dysregulation Spectrum Syndrome

12-03-26

Kent MacLeod, BPharm ! Synthetic versus Human Identical Hormones in CSS! hormones Synthetic versus Human

Central Sensitivity Syndrome! Interventions Improving CSS!

•  •  Have signiﬁcant differences on the pain receptor pathways •  Affect of hormones on pain pathways are complex and all current research is with human hormones •  Dosages should be adjusted according to laboratory data and individual symptoms

Nutritional and Dietary Effects on Estrogen •  High insulin increases aromatase increasing estrogen •  Vitamin D expresses progesterone and estrogen receptors •  Cruciferous vegetables increase estrogen metabolism •  Anti-oxidants prevent oxidation of estrogen metabolites to potent estrogen compounds •  Methylation 2 and 4 methoxyestrones B12, folate and B6 dependant (Mg)

Central Sensitivity Syndrome! Interventions Improving CSS!

Nutritional and Dietary Effects on Estrogen (cont d)

•  Ovaries sensitive to iron •  B-glucuronidase in bowel destroyed by antibiotics, preservatives and poor diet •  Phytoestrogens in vegetables modulate estrogen receptors •  Magnesium essential for COMT enzymes and glucuronyl transferase •  Low vitamin E anti-oxidants associated with disrupted estrogen levels

Hormones and Dysregulation Spectrum Syndrome

12-03-26

Kent MacLeod, BPharm

Obesity, High Insulin and Pain

Diet and Fibromyalgia

•  Bariatric surgery improved ﬁbromyalgia 90% •  Skipping breakfast or lacking protein makes blood sugar worse and contributes to weight gain •  Overweight women eating signiﬁcant protein at breakfast ate 300 calories less per day (30 pounds weight loss 1 year) •  University of Guelph: What people ate for breakfast caused spikes of insulin and was major contributor to diabetes . Coffee and carbohydrate was the worst

•  Elevated glucose and fluxes in blood glucose decrease threshold of pain and maximum pain tolerated •  Obesity correlates to fibromyalgic pain •  Incidence of fibromyalgia is higher in diabetes •  Insulin affects estrogen metabolism Okifuji, A. et al. (2010) Relationship Between Fibromyalgia and Obesity in Pain, Function, Mood, and Sleep. The Journal of Pain 11 (12): 1329 Morley, GK et al. (1984) Mechanism of pain in diabetic peripheral neuropathy: Effect of glucose on pain perception in humans. The American Journal of Medicine 77(1): 79-82

Hooper, MM et al. (2007) Musculoskeletal ﬁndings in obese subject before and after weight loss with bariatric surgery. Int Jour Obesity LOND 31(1): 114-20 Vander Wal, JS (2005) Short-Term effect of eggs on satiety in overweight and obese Subjects J Am Coll Nutr 24: 510-515 Moisey LL et al. (2008) Am J Clin Nutr Caffeinated coffee consumption impairs blood glucose homeostasis in response to high and low glycemic index meals in healthy men. 87(5): 1254-61.

Type 2 Diabetes and Mitochondrial Dysfunction Dysregulation

High Insulin Precedes Diabetes •  Postprandial challenge - insulin, blood sugar •  Fasting blood sugar above 5.0 •  BMI elevated •  Hip to waist ratio: men <0.95; women<0.8

•  Lowell: Journal Science 2005 •  First step in type 2 diabetes is mitochondrial dysfunction of skeletal muscle •  Then mitochondrial dysfunction of beta-cells in pancreas •  Warburg effect - increase lactate •  Abnormal mitochondrial function in trapezius muscle of FMS sufferers. Kalyan-Raman UP et al. (1984) Muscle pathology in primary ﬁbromyalgia syndrome: a light microscopic, histochemical and ultrastructural study. Journal of Rheumatology 11(6): 808–813.

Mitochondrial Nutrients in Fibromyalgia!

Statins Increase Diabetes Risk in Postmenopausal Women

•  Coenzyme Q 10 300mg day in small trial was significantly beneficial to FIQ fibromyalgia scores •  Acetyl-l-carnitine RCT trial: Significant benefits in fibromyalgic quality of life and depression after 10 weeks

•  153, 840 women at baseline without diabetes •  Aged 50 to 79 years •  Statin use was associated with a 48% increased risk for developing diabetes

–  Dosage 500mg twice daily –  No side effects Cordero MD et al. (2011) Coenzyme Q(10): a novel therapeutic approach for Fibromyalgia? Mitochondrion 11(4):623-5. Rossini M et al. (2007) Double-blind, multicenter trial comparing acetyl l-carnitine with placebo in the treatment of ﬁbromyalgia patients. Clin Exp Rheumatol 25(2):182-8.

Culver, AL et al. (2012) Statin use and risk of diabetes mellitus in postmenopausal women in the Women s Health Initiative. Arch Int Med 172(2): 144-52.

Hormones and Dysregulation Spectrum Syndrome

12-03-26

Kent MacLeod, BPharm

Are Statins Affecting Fibromyalgia?

Are Statins Effective for ! Low Risk Individuals?

•  Up to 25% of users have muscle related problems •  Signiﬁcant adverse impact of statin use on patients with ﬁbromyalgia

•  Cochrane meta-analysis of 14 trials involving 34, 272 patients •  Deaths were reduced on statins, but authors conclude effect is not large enough to justify costs and potential adverse effects •  Widespread use of statins in people at low risk of cardiovascular events, is not supported by the existing evidence.

Mascitelli L et al. (2008) Detrimental Effect of Statin Therapy in Women With Fibromyalgia. Arch Intern Med 168(11): 1228-1229.

Taylor, F et al. (2011) Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev Jan 19 (1): CD004816.

Central Sensitivity Syndrome! Interventions Improving CSS!

Antidepressant Medications and Risk of CSS/Fibromyalgia

•  any drug or substance that mobilizes neurotransmitters depletes, disrupts and disturbs them •  Not studied •  Higher rates of muscle aches, pains (as high as 25%) with antidepressant •  Higher rates of sleep disturbances •  Weight gain

Anti-depressant Medications and Risk of Relapse

Meta-Analysis of all Studies of Antidepressant Medications

•  Biggest risk factor for relapse of depression is previous use of antidepressants •  Meta-analysis demonstrates patients using anti-depressant medications almost twice as likely to relapse

•  In mild to moderate depression, antidepressant medication does not help better than placebo •  Any medication that mobilizes neurotransmitters deplete, disrupt and disturb

•  Paul Andrews (2012) Frontiers in Psychology

JAMA (2010) 303(1): 47-53

Hormones and Dysregulation Spectrum Syndrome

12-03-26

Kent MacLeod, BPharm

Anatomy of a Sugar Craving

Orthomolecular Inﬂuences on Neurotransmitter Balance!

•  #1 High insulin •  #2 Low serotonin and dopamine •  any drug or substance that mobilizes neurotransmitters depletes them •  This explains how anti-depressant medications increase weight as well as drug tolerance

•  Virtually every single hormone including sex hormones •  Thyroid and insulin have proven to impact neurotransmitter balance •  Every single micro- and macronutrient appear to affect neurotransmitter balance

Nutritional & Biochemical Inﬂuences ! on Neurotransmitter Balance & Function! •  •  •  •  •  •  •  •  •

Magnesium COMT dependent, a2 delta Copper metabolism of excess norepinephrine Zinc - SOD dismutase, ion gate regulation B12, folate, B6 - methylation Vitamin D - expression of serotonin and dopamine receptors Amino acid/Protein - direct precursors Mitochondrial Function Vitamin C and E, anti-oxidants catecholamine metabolism Iron

S-Adenosyl Methionine Affects Serotonin and Dopamine

Tryptophan and Amino Acids •  Tryptophan proven to desensitize CNS in humans •  Altered amino acid profile (tyrosine) in fibromyalgia versus controls •  Tryptophan metabolism altered in fibromyalgia •  5-HTP - Double blind placebo controlled trial, significant improvement in fibromyalgia

•  S-adenosyl methionine: effective in depression; equivalent to anti-depressants in several trials at 400mg 3 times daily •  Fibromyalgia - two controlled trials at 400mg 3 times daily as well

•

Parcell ND (2002) Sulphur in Human nutrition and applications in medicine. Alter Med Review 7(1): 22-44.

•  •

Bazzichi L et al. (2009) Altered amino acid homeostasis in subjects affected by fibromyalgia. Clin Biochem 42(10-11): 1064-70. Schwarz MJ et al. (2003) Experimental evaluation of an altered tryptophan metabolism in fibromyalgia. Adv Exp Med Biol 527: 265-75. Caruso I et al. (1990) Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. J Int Med Res 18(3): 201-9.

Hormones and Dysregulation Spectrum Syndrome

12-03-26

Kent MacLeod, BPharm Orthomolecular or Correct Intervention for CSS

Melatonin in Fibromyalgia

•  Melatonin comes from serotonin in complete darkness •  Controlled studies prove melatonin effective in Fibromyalgia at doses of 3-5mg •  Melatonin proven to increase progesterone secretion of ovaries •  Durlach from France demonstrated that dysregulation of pineal gland alters Magnesium metabolism •  Sleep disruption is common in ﬁbromyalgia

•  Macronutrition, weight regulation -insulin/glucose status; hip/waist ratio; pay attention to carbs /caffeine that spike insulin •  Micronutrient status - assess and correct •  Hormone levels, including thyroid •  Estrogen and progesterone levels affect pain at multiple sites - adjust/individualize using human-identical hormones •  Neurotransmitter status and balance - the amino acid 5-Hydryoxytryptophan is effective •  Assess environment: sleep, drugs, toxins, xenoestrogens

Wilhelmsen et al. (2011) Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies. J Pineal Res 51(3): 270-7. Webley, GE and Luck, MR (1986) Melatonin directly stimulates the secretion of progesterone by human and bovine granulosa cells in vitro. J Reprod Fertil 78(2):711-7. Durlach, J et al. (2005) Magnesium depletion with hypo- or hyper- function of the biological clock may be involved in chronopathological forms of asthma. Magnesium Research 18 (1): 19-34.

Orthomolecular Approaches to CSS-BCB testing

Orthomolecular Interventions! with Proven Effectiveness

•  Provides data-based approaches for nutritional, dietary and hormonal intervention •  Over 60 panels tested thru blood and urine •  Assessment of Hormones (adrenals, thyroid, sex hormones) - through blood •  Assessment of Nutritional Biochemistry (vitamins, minerals, amino acids, fats, proteins, toxicology) •  Assessment of mitochondria •  Assessment of Neurotransmitters (mood, sleep, appetite)

•  Mg – most commonly deﬁcient nutrient; is effective in balancing neurotransmitters and estrogen; for muscle relaxation as calcium channel regulator: Mg glycinate 400mg elemental daily •  Magnesium proven effective in ﬁbromyalgia •

Bagis S et al. (2012) Is magnesium citrate treatment effective on pain, clinical parameters and functional status in patients with ﬁbromyalgia? Rheumatol Int. Jan 22. [Epub ahead of print]

•  •  •  •  •

Acetylcarnitine Co-enzyme Q10 S-Adenosyl-Methionine Melatonin 5 Hydroxytryptophan

•  Available NutriChem clinic www.nutrichem.com

Central Sensitivity Syndrome! Cluster of Modern Diseases !

What is Happening NOW in Canada and USA

Muhammad Yunus MD University of Illinois

•  Explosion of iatrogenic problems and costs caused by medications, anti-depressants and statins, that may be contributing to CSS syndromes •  Many patients with CSS rely on oxycontin which is destroying lives in Canada and US. •  They are brought to this point by using approved ﬁbromyalgic medications which have poor results with signiﬁcant side effects •  Explosion of costs with real damage

12-03-26

Is there a Holy Grail for Hormone Testing? George Gillson, MD, PhD

Great Expecta3ons for Hormone Tests

Is there a Holy Grail for Hormone Tes3ng5

•  Endogenous hormone = Supplemented hormone •  Transdermal = oral = subcutaneous pellet = patch = troche = injec3on •  All hormone levels should “line up”, e.g. low testosterone symptoms = low serum total testosterone = low serum bioavailable testosterone = low salivary testosterone = low urine testosterone •  We assume assume that someone, somewhere has all this stuﬀ ﬁgured out… •  Reality Check: –  There is no “ Theory of Everything” for lab tes3ng –  There is no model that links all types of tes3ng together, under all circumstances

George Gillson MD PhD Rocky Mountain Analy3cal Calgary, Alberta gillson@rmalab.com

GLAND

Hormone

??????????

receptor

Hormone “gospel”: only free unconjugated hormone is important Why would the least populous hormone form be the most important?

Endogenous Hormone Produc3on •  !"#$#%&'(#$))&"*+,$-"., when people are making their own hormones, any of the popular tes3ng modali3es Sserum, blood spot, saliva, urineT are able to iden3fy significant hormone deficiency or hormone excess •  There is no one best way to measure this stuff •  Each tes3ng modality has its advantages and piUalls

All these forms are not interchangeable Hormone bound to SHBG or other carrier protein

SHBG and Tissue Uptake of Steroids

Capillary

•  Proteins called ﬁbulins can bind SHBG and direct seZuestra3on of blood-‐borne SHBG in extravascular spaces •  Ng KM et al. J Biol Chem 2006;281:15853-‐15861. Evidence that ﬁbulin family members contribute to the steroid-‐ dependent extra-‐vascular seZuestra3on of sex hormone-‐ binding globulin. •  Brain cells take up SHBG •  Uptake may be regulated by estradiol receptors •  Caldwell JD et al. Neuroendocrinol 2007;86:84-‐93

Free unconjugated steroid

Vnly the free steroid is supposed to be able to get out of blood into 3ssue, as it is the only form small enough to ﬁt through the cracks between the cells which line the capillary walls

Is there a Holy Grail for Hormone Testing?

12-03-26

George Gillson, MD, PhD

Conjugated Hormones

Serum vs Urine Tes3ng

•  Conjugates are hormones that have extra bits stuck on them to render the molecules water-‐ soluble

•  Serum tes3ng measures unconjugated hormones (unless speciﬁcally stated e.g. DHEAS) •  Urine tes3ng measures conjugated hormones (unless speciﬁcally stated e.g. urinary free cor3sol)

–  Extra bits (incomplete list): •  •  •  •

Sulphate Sugar e.g. glucuronide Glutathione Sulfonyl methane

•  Conjugates are made in the liver and in many other 3ssues (e.g. skin? kidneys? breasts? gut mucosa)

•  Serum and urine tests are looking at two diﬀerent pools of hormone!

–  Belanger A et al. J Steroid Biochem Mol Biol 1998;65:301-‐310

•  Conjugates may be considered as storage forms •  !f overall hormone produc3on is low or high? the level of conjugates should also be low or high

Urine Hormone Tes3ng Measures Conjugates

Conjugated hormone

Hydrolysis destroys informa3on

Also, if you are sulphate deﬁcient, that type of conjugate won’t appear in urine as much

This form is heavily inﬂuenced by factors aOec3ng the liver

Unconjugated hormone

Saliva

Urine

This form may reﬂect what’s going on in a speciﬁc -ssue

Serum A urinary hormone level is not the same as a salivary hormone level e.g. urine “estradiol” is not the same as salivary estradiol

A urinary hormone level is not the same as a serum hormone level e.g. urine “estradiol” is not the same as total serum estradiol

Is there a Holy Grail for Hormone Testing?

12-03-26

George Gillson, MD, PhD

Urinary Estrogens Estradiol

% of Total 5.3

Estrone Estriol

15.0 11.1

16OH estrone 4OH estradiol

7.3 1.2

4OH estrone 2OH estradiol

3.1 3.6

2OH estrone 4methoxyestradiol

37.6 0.2

4methoxyestrone 2methoxyestradiol

0.5 0.7

2methoxyestrone

8.0

Urine Estrogens

EOect of Estrogen Hupplementa3on on Urinary Estrogens in Postmenopausal Women

Major form of estrogen in urine

Estrogel Topical

E2 Dose (avg)

N/A

850 mcg

500 mcg

1500 mcg

2-OHE1 ng/mg Cr

1.7

2.9

8.4

8.6

16-OHE1 ng/mg Cr

0.9

1.7

4.5

2.3

Response to Oral Administration of 100 mg Progesterone

Topical

Endogenous

Serun progesterone (ng/ml)

Progesterone

Urine

BiEst Vaginal

Urine estrogen metabolites reflect supplementation with various topical forms of estradiol

Xu X et al. J Clin Endocrinol Metab 1999;84:3914-3918.

Pregnanediol glucuronide

No Estrogen BiEst Supplementation Topical

Urinary PDG does not increase after application of progesterone cream to skin O’Leary P et al. Clin Endocrinol 2000;53:615-620.

\o P7- is found in the urine aker topical progesterone supplementa3on

Topical Pg doesn’t have the same propensity to form the glucuronide conjugate!

RIA

LC-MS MS

LCMSMS measures only progesterone

Erroneous conclusion is that topically-‐applied progesterone isn’t absorbed

Progesterone + progesterone metabolites: immunoassay can’t tell them apart

Time after administration (hours)

Comparison of the pharmacokinetics of Crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women. Levine H, Watson N.Fertil Steril 2000;73:516-521.

Serum Testosterone

The free hormone assay signiPcantly underes3mates the amount of hormone thought to be able to get into 3ssue? compared to bioavailable hormone measurements Can be low by as much as a factor of ten Is especially inaccurate in women Consensus of clinical chemists is that free testosterone should not be used

Is there a Holy Grail for Hormone Testing?

12-03-26

George Gillson, MD, PhD

Serum Hormone Levels Aker Use of Hormone Cream

Serum Hormone Levels Aker Use of Sublingual/Topical Solu3on

•  It’s clear that you can drive serum (and urine, depending on the hormone) levels up to the physiologic range with topical hormones •  Serum levels are the last to move •  It oken takes supraphysiologic doses of hormone to do it •  Examples:

•  Sublingual hormones can yield sensible serum levels •  Want most of the dose to go straight in through the mucosa; swallowed SL hormone à equiv. to oral •  Hormone solu3on for topical applica3on •  Absolute ethanol: Propylene glycol (60:40) will yield physiologic serum levels at near-‐physiologic doses

–  200 mg/d of testosterone in cream base to elevate serum total testosterone to high normal range –  Pg and E2 doses of hundreds of mg/day (Pg cream) and 5-‐15 mg/day (E2 as BiEst) to reproduce physiologic serum hormone levels (e.g. Wiley Protocol)

Dried Capillary Bloodspot

Compounded Human Iden3cal Hormone Case Series

•  Is not whole blood •  Is more or less a 3ssue sample •  Limited data available, but indica3on is that bloodspot hormone levels are much higher than serum levels taken in parallel (following applica3on of hormone cream, at least for Pg and Testosterone) •  Supports use of lower doses •  Must be very careful not to sample ﬁnger3p (s) exposed to hormone cream

•  MAHMUD 2009 •

Gynecol Endocrinol. 2009 Aug 19:1-‐5. Natural hormone therapy for menopause. Mahmud K.

•  •

189 women average age 54 yrs Average followup: 30 months (2 years 6 months), some followed up to 4 years, none less than 12 months Topical BiEst (80:20), 2.5 mg bid -‐ dose 3trated to symptom relief with absence of breast tenderness

•

–  Aimed for 50 pg/ml in serum

•

Sublingual progesterone triturate 50-‐100 mg/day

•

+/-‐ Oral DHEA 25 mg qd – bid given to women with low or low normal serum DHEAS at baseline

•

+/-‐ “Peri-‐vaginal” testosterone vanishing cream used in women with low/low normal serum testosterone at baseline

–  Aimed for 4 ng/ml in serum

–  Aimed for 120 mcg/dL DHEAS in serum

–  Aimed for 25 ng/dL in serum

Normalized

Increase in bloodspot very closely tracks increase in serum

0.97 0.13

This ﬁnger was habitually used to apply cream

Example Calculation

These are the 3ssue levels established in noncontaminated 3ssues (≈12x midrange normal serum level) Serum clearly does not numerically reject 3ssue hormone content

Baseline

+2 Hours

Saliva

0.52

13.2

Serum

3.9

13.5

Saliva/Serum

0.13

0.97

At baseline the non-‐ contaminated DBS sites are achieving ≈ 20-‐fold concentra3on of hormone from serum (Blue bar) This same factor of ≈ 20 also applies 2 hours aker applica3on of cream to a remote site (Red bar) Saliva, rather than overes3ma3ng 3ssue deposi3on of hormone following topical applica3on, is actually underes3ma3ng itm The “applicator” ﬁnger seems to have become par3cularly adept at concentra3ng hormone from serum

Is there a Holy Grail for Hormone Testing?

12-03-26

George Gillson, MD, PhD Salivary Hormone Levels

Saliva duct endplate

How does the hormone get from the capillary to the duct endplate??

In the capillary and in the duct endplate, you have rela3vely non-‐ water soluble molecules trying to dissolve in a watery medium (plasma or saliva), so the concentra3ons in both ﬂuids are about the same

Hormones get into saliva by par33oning from the cell membranes of the cells that line the duct endplate

[Hormone] in saliva is approximately the same as [Hormone] in the capillary

In order to see high levels of hormone in saliva, you have to establish high levels of hormone in the 3ssue that makes up the duct endplate

Saliva reflects unconjugated free hormone in blood, but is not identical to it

But the two measurements are not identical

Non HC brain damage

Saliva and Serum Cor3sol

Normal controls

•  In serum, 10t of the cor3sol is free, the rest is bound to albumin and cor3sol binding globulin •  Wree cor3sol in serum =A.M. serum cor3sol 100 ng/ml x 0.1 = 10 ng/ml •  A.M. salivary cor3sol 2-‐15 ng/ml •  Salivary cor3sol numerically reﬂects the free cor3sol component of serum Total serum cor3sol and salivary cor3sol are generally well-‐correlated

HC damage Caregivers

The CAR is regulated by the hippocampus Abolishment of the hippocampus (e.g. due to stroke) ﬂauens the CAR

-‐Buchanan TN et al. Circadian regula3on of cor3sol aker hippocampal damage in humans. Biol Psychiatry 2004;56:651-‐656.

Yonsei Med J 2007;48:3793-88. Salivary Cortisol and DHEA Levels in the Korean Population: AgeRelated Differences, Diurnal Rhythm, and Correlations with Serum Levels. Ahn RS, Lee YJ, Choi Jy et al.

Hippocampal volume on MRI is associated with the magnitude and shape of the CAR: smaller HC volume = smaller and ﬂauer CAR

HC damage had no eﬀect on the rest of the day curve The caregivers are as bad oﬀ as the pa3entsm

Is there a Holy Grail for Hormone Testing?

12-03-26

George Gillson, MD, PhD

Waking up is hard to do… Normal

Flat

Condi3ons which eDhibit this kind of CARR -‐Hippocampal damage -‐Increased age -‐Cardiovascular disease -‐Autoimmune condi3ons -‐Clinical depression -‐Cogni3ve impairmentoAlsheimerls -‐Auachment anDiety -‐Overtraining?

Maximum Enhancement Factor

Enhancement Factor vs Waking Cortisol 4 3.5 3 2.5 2 1.5 1 0.5 0 0

*Hot flashes, night sweats, brain fog, memory problems, depression

In postmenopause, severity of low E2 complaints starts to kick up when E2 < 1.5 -1.8 pg/ml

CAR sampled __ 3mes over the course of a year or so, in one Olympic Athlete

Waking Cortisol (ng/ml)

y = 91.501x + 1.0154 R2 = 0.7958

BreastTenderness

Breast Tenderness

Symptom severity is not proportional to “On-cream” salivary E2 level ( a score of 3 indicates severe breast tenderness)

2.5

14000 12000 10000 8000 6000 4000 2000 0

Avg Sx Score

Avg Pg (pg/ml)

Avg Pg Result vs Evening Pg Cream Dose bid dosing only

2 1.5 1

Endogenous Range

0.5 0 1

100

1000

E2 Halivary E_ aker cream Salivary supplementa3on (pgoml)

100

120

ExcessFacialBodyHair

Evening Pg Dose (mg)

Facial Hair Growth

Avg Sx Score

Saliva reflects applied dose of hormone (when cream is used) Saliva reflects stored body burden of cream-supplemented hormone

Symptom severity is not proportional to “On-cream” salivary Testosterone level ( a score of 3 indicates severe facial hair growth)

Endogenous Range

2.5 2 1.5 1 0.5

Salivary hormone levels achieved via cream supplementation do not represent the clinical picture

0 0

100

150

200

250

300

(pg/mL) Halivary T aker Salivary cream sTestosterone upplementa3on (pgoml)

Why?? •  A por3on of the hormone measured in saliva aker topical hormone applica3on may be gevng to the salivary glands by travelling over or across the body surface (via shallow subdermal lympha3cs or through subcutaneous fat) •  This por3on never sees the systemic circula3on

Is there a Holy Grail for Hormone Testing?

12-03-26

George Gillson, MD, PhD SALIVA Testo aker Applica3on of Androgel

Salivary T after application of Androgel to various body parts

Supraclavicular )uge eleva3on over baseline

Tesosterone (pg/ml)

10000 1000

4 hours

10 3000

2500

2000

Time after application (minutes) 25 mg Androgel to L foot

25 mg Androgel to supraclavicular area

25 mg Androgel to L forearm

25 mg Androgel to R Buttock

25 mg Androgel to Abdomen

1400

1200

1000

800

600

400

200

100

1500

1000

Same oscilla3ons as those published by Lewis and also seen in serum by Mazer

Level eventually stabilizes

10000

500

100

The closer the applica3on site is to the head, the higher the “wave”

100000

Tesosterone (pg/ml)

100000

Time after application (minutes)

-‐Lewis J et al. Maturitas 2002;41:1-‐6. -‐Mazer N et al. J Sex Med 2005;2:213-‐226.

“Observed Range” vs “Normal Range”

Peak Salivary Testo vs Ristan>e 8rom ;ppli>a-on Site 100000

Supraclavicular

•  On-‐Cream ranges are “Observed Ranges” not “Normal Ranges” •  An Observed Range is what is commonly OBSERVED •  An Observed Range may not reﬂect a clinically op3mum range •  Depends on: )ormone, Base, Applica3on site, Sampling Interval, Dosing Schedule, Dura3on of Yse

Peak Salivary Testosterone (pg/ml)

10000

Forearm 1000

Foot

Abdomen and Buttock

100

;ppro*imate 2istan>e 8rom appli>a-on site to saliva glan2 (in>9es)

This implies that some component of what is seen in saliva gets there by travelling over the body surface

Effect of Base on Time Profile in Saliva, after Application of Hormone in Cream

DO NOT OVERINTERPRET !! •  Don’t slavishly 3nker with hormone doses to get the salivary hormone levels into the Observed Ranges •  They are not clinically validated ranges! •  We don’t know the level of salivary Pg at which you can say “OK, the endometrium is protected” •  It will be diﬀerent for each woman, each base, each site of applica3on, each sampling interval

Is there a Holy Grail for Hormone Testing?

12-03-26

George Gillson, MD, PhD So…am I saying we shouldn’t measure hormone levels in saliva aker we use topical hormones?

DO NOT OVERINTERPRET !! •  Don’t ﬁddle around with dosing, trying to achieve some magic ra3o of Hormone = to Hormone B in saliva •  This has never been scien3ﬁcally validated

•  No. Do it! •  Ynderstand the limita3ons and strengths of your tests •  Salivary hormone levels aker topical hormone use can be very helpful for troubleshoo3ng

“Salivary progesterone measurements conﬁrm transdermal absorp3on, but to our knowledge, there is no empirical associa3on between progesterone dosage and salivary concentra3ons that can be used to treat menopausal symptoms.” O’Leary P et al. Clin Endocrinol 2000;53:615-‐620

Avg Pg (pg/ml)

Avg Pg Result vs Evening Pg Cream Dose bid dosing only

So…am I saying we shouldn’t measure hormone levels in saliva aker we use topical hormones?

y = 91.501x + 1.0154 R2 = 0.7958

14000 12000 10000 8000 6000 4000 2000 0 0

100

•  No. Do it! •  Some prac33oners advocate doing a saliva test in the “oﬀ” period, several days or a week aker discon3nua3on of the topical hormone, to gauge “accumula3on” of hormone in the body •  I think this has merit; the saliva level does track body burden of hormone

120

Evening Pg Dose (mg)

The finding of a low/high level of a hormone despite an average dose might point to: Poor absorption/excessive absorption Non-compliance/over-compliance Problem with composition of topical (actual dose lower/higher than labelled)

Next menses started here

This is most feasible if you’re doing saliva testing or spot urine testing 43 years old, BMI 23, regular menses, acne, oily skin, Testo high end of range

Is there a Holy Grail for Hormone Testing?

12-03-26

George Gillson, MD, PhD

There is no Holy Grail of Testing

Know thy lab test as explicitly as you can

Symptoms rarely correlate well to just one thing

Last Pg use

CONCLUSIONS

Pa3ent uses progesterone cream fg.e mg bid, d2 daysomonth Supplemented Pg is stored and released at appropriate 3me

2/19/2011

9oc;y 6ountain Analy3cal Don’t let the lab test do all your thinking!

•  •  •  •

Located in Calgary, Alberta www.rmalab.com Founded in 2002 Accredited by the College of Physicians and Surgeons of Alberta •  We are held to the same standards as hospital laboratories and laboratories servicing the government medical system

Remember to treat the Patient first!

Just be thankful you’re not my dentist

CONCLUSIONS 2/19/2011

Treating Childhood Asthma

12-‐03-‐26

Jonathan Wright, MD

One %olu)on for the Wheezing… and Other Aspects of Childhood Asthma

Bray GW. The Hypochlorhydria of Asthma in Childhood. Quarterly Journal of Medicine, January 1931; XXIV:181-197

Jonathan V. Wright, MD Orthomolecular Medicine Today Conference April 27-‐29, 2012 – Vancouver, BC 1

Jonathan V. Wright, MD

Results of Fractional Gastric Analysis

§  Achlorhydric………………....18.…9% §  “Pronounced” hypochlorhydria…………….96…48%

§  200 Asthmatic Children §  Ages 6 Months to 12 Years

Jonathan V. Wright, MD

§  “Mild” hypochlorhydria…..46...23% §  Normal…………………….……40…20%

Jonathan V. Wright, MD

Age

Gillespie, M. Hypochlorhydria in asthma with special reference to the age incidence. Quarterly Journal of Medicine 1935; New Series No. 16; 397-405

Jonathan V. Wright, MD

# of cases

Low free acidity

1-‐10

88%

11-‐15

60%

16-‐20

14%

21-‐30

41%

31+

53%

Jonathan V. Wright, MD

Treating Childhood Asthma

12-‐03-‐26

Jonathan Wright, MD

The Initial Clue Wetzel NC. Growth failure in school children as associated with Vitamin B12 deficiency. Science 1949; 110:651

Jonathan V. Wright, MD

One child with “intractable” asthma was given ten (10) micrograms “crystalline” vitamin B12 orally every day. [is asthma)c whee/ing disappeared in one week.

Simon SW. Vitamin B12 therapy in asthma and chronic dermatoses. J Allergy 1951; 22:183

Jonathan V. Wright, MD

20 Adults, “Intractable” Asthma Kaufman RE. Eﬀect of vitamin B12 in asthma. Annals of Allergy 1951;9:517.

§  1000 micrograms vitamin B12 weekly IM, four weeks. §  Eighteen (90%) reported some improvement in whee/ing, breathing with eaer)on, sleep, or “general condi)on”. §  None stopped prior therapy.

Jonathan V. Wright, MD

Treating Childhood Asthma

12-‐03-‐26

Jonathan Wright, MD

8 Asthma)c Adults Caruselli M. Sulla terapia dell’asma con vitamina B12. Riforma Medica (Naples)66: 841-‐864. Abstracted JAMA 1952;150(17): 1731

§  8 asthma)c adults Vitamin B12 p.o. or IM. §  5 to 900 micrograms daily. §  Only the individual given 900 micrograms daily reported improvement. §  Conclusion: Vitamin B12 was not useful.

Jonathan V. Wright, MD

2 of 10 Had Return of Wheezing: §  12 adult asthma)cs given IV vitamin B12: 30,000 micrograms QD, 15-‐20 days.

§  1 afer 3 months. §  1 afer 8 months.

§  Wheezing eliminated in 10 (83%).

Jonathan V. Wright, MD

§  Repeat IV B12 eliminated wheezing again.

Jonathan V. Wright, MD

Degree of Improvement

Crocket JA. Cyanocobalamin in asthma. Acta Allergologica 1957;XI:261

Jonathan V. Wright, MD

Age

Slight

Moder ate

Marked

% Mod/ Marked

0-‐10

83%

11-‐20

74%

21-‐30

67%

31-‐40

52%

41-‐50

38%

51-‐60

14%

Jonathan V. Wright, MD

Treating Childhood Asthma Jonathan Wright, MD

Treating Childhood Asthma

12-‐03-‐26

Jonathan Wright, MD

Other Important Nutrient Factors in Asthma Treatment ISot Kust asthmaAc BheeTingL

Rowe AH, Young EJ Bronchial asthma due to food allergy alone in ninety-‐Nve paAents. JAMA 1959;169:1158-‐1162

§  Allergy elimina)on, desensi)/a)on §  Betaine Hydrochloride – Pepsin as needed §  Fish Oil §  Magnesium – IV, p.o., topical §  Pyridoxal phosphate §  Vitamin C Jonathan V. Wright, MD

Jonathan V. Wright, MD

Ogle KA, Bullock JD. =hildren Bith allergic rhiniAs andUor bronchial asthma treated Bith eliminaAon diet. Ann Allergy 1977;39:8-‐11

Hoj L et al. A double-‐blind controlled trial of elemental diet in severe perennial asthma. Allergy 1981;36:257

Jonathan V. Wright, MD

Basomba A. The role of food allergy in children’s bronchial asthma. J. Asthma Res. 1967;5:129

Jonathan V. Wright, MD

THE END

Jonathan V. Wright, MD

Potent, Natural Anti-Cancer Agents

12-‐04-‐01

Jonathan Wright, MD

Orthomolecular Medicine Today Conference April 27-29, 2012 – Vancouver, BC

2-METHOXYESTRADIOL, 5α-ANDROSTANE-3β, 17β-ADIOL (“3β-Adiol”)

Free Archive Access for Attendees Available, April 27 – May 10, 2012

POTENT “NOVEL”, NATURAL ANTI-CANCER AGENTS

www.bioidenticalhormonesociety.org

orthoconf april2012

Jonathan V. Wright, MD 2

Testosterone -R 5α

5α-ANDROSTANE-3β, 17β-ADIOL (“3β-Adiol”), ESTROGEN RECEPTOR BETA

e as

5β- DHT

5α- DHT H β-

5β-Androstanediol

AND

PROSTATE CANCER

5α-Androstane-3β, 17β-diol (“3β-Adiol”) 5α-Androstane-3α, 17β-diol (“3α-Adiol”)

Jonathan V. Wright, MD

5α-DHT

Jonathan V. Wright, MD

5-Alpha Reductase Over-Inhibition

3β-HSD

5α-Androstane-3β, 17β-diol (3β-Adiol)

§  “…finasteride, by blocking the conversion of testosterone to dihydrotestosterone, inhibits the production of 3β-androstanediol, thus suppressing ER-β and preventing the differentiation of epithelium.”

Estrogen receptor beta (ERβ)

§  See: Imamov O, Lopatkin NA, Gustafsson JA. Estrogen receptor beta in prostate cancer. NEJM. 2004 Dec 23;351(26): 2773-4.

5α-Androstane-3α, 17β-diol (3α-Adiol) Jonathan V. Wright, MD

Jonathan V. Wright, MD

Potent, Natural Anti-Cancer Agents

12-‐04-‐01

Jonathan Wright, MD

Testosterone Metabolites Serum Test 5-α Reductase Over-inhibition

Prostate Cancer Prevention Trial

Patient taking Propecia, 1 mg, & Rogaine

§  18,000 + men, PSA < 3, 7 years

Serum Test

Result

Ref. Range (ng/mL)

Testosterone (Te)

8.8

2.6-8.9

DHT (5α-Dihydrotestosterone)

0.42

0.24-0.84

5α-Androstane-3β, 17β-diol

2.0 LOW

4.0-20.2

5α-Androstane-3α, 17β-diol

2.5

2.3-10.5

3β-Adiol/(DHT+3α-Adiol) Ratio

0.7 LOW

0.8-6.5

Jonathan V. Wright, MD

§  Finasteride v. Placebo §  Finasteride Group: §  Cancer 18.4% §  37% of these more aggressive types

§  Placebo Group: §  Cancer 24.4% §  Of these 22.2% more aggressive types 7

Jonathan V. Wright, MD

5-alpha Reductase Inhibitors (5-ARI) & Prostate Cancer

5-alpha Reductase Inhibitors (5-ARI) and Prostate Cancer

§  “5ARI reduce prostate cancer risk but may increase the risk of high-grade disease in men who are undergoing regular screening for prostate cancer using prostate specific antigen and digital rectal examination. Effects are consistent across race, family history and age and possibly 5ARI but were limited to men with baseline PSA values <4.0 ng/mL.”

Wilt TJ, et al. Five-alpha-reductase Inhibitors for prostate cancer prevention. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD007091.

§  Information is inadequate to assess the impact of 5ARI on mortality. Jonathan V. Wright, MD

5α-‐DHT

Jonathan V. Wright, MD

3β-‐HSD

5α-‐Androstane-‐3β, 17β-‐diol (3β-‐Adiol)

Hypothetically Desirable Ratio: (3β-Adiol) > 5α DHT + (3α-Adiol)

Estrogen receptor beta (ERβ)

Anti-carcinogen > Pro-carcinogen + Pro-carcinogen

5α-‐Androstane-‐3α, 17β-‐diol (3α-‐Adiol) Jonathan V. Wright, MD

Jonathan V. Wright, MD

Potent, Natural Anti-Cancer Agents

12-‐04-‐01

Jonathan Wright, MD

Testosterone Metabolites Serum Test 5-α Reductase Over-inhibition

Testosterone Metabolites: Example of Normal Test Values Serum Test

Result

Ref. Range (ng/mL)

Testosterone (Te)

6.5

2.6-8.9

DHT (5α-Dihydrotestosterone)

0.76

0.24-0.84

5α-Androstane-3β, 17β-diol

12.0

4.0-20.2

5α-Androstane-3α, 17β-diol

7.5

2.3-10.5

3β-Adiol/(DHT+3α-Adiol) Ratio

1.5

0.8-6.5

Jonathan V. Wright, MD

?.@/(-&-.A4(9&?*+;/:4.1&2&B91&C&=+9.4(/&

Ref. Range (ng/mL)

Testosterone (Te)

8.8

2.6-8.9

DHT (5α-Dihydrotestosterone)

0.42

0.24-0.84

5α-Androstane-3β, 17β-diol

2.0 LOW

4.0-20.2

5α-Androstane-3α, 17β-diol

2.5

2.3-10.5

3β-Adiol/(DHT+3α-Adiol) Ratio

0.7 LOW

0.8-6.5 14

Oliveira A, Coelho P, Guedes F, Mahecha G, Hess R, Oliveira C. 5α-Androstane-3β, 17β-diol (3β-diol), an estrogenic metabolite of 5α-dihydrotestosterone, is a potent modulator of estrogen receptor ERβ expression in the ventral prostate of adult rats. Steroids. 2007;72:914-922

Jonathan V. Wright, MD

§  AR (Androgen Receptor) causes proliferation and functional activation (secretion) of the prostatic epithelium, and

Guerini V, Sau D, et al. The androgen derivative 5αandrostane-3β, 17β-diol inhibits prostate cancer cell migration through activation of the estrogen receptor β subtype. Cancer Research 2005;65:5445-5453

§  ERβ (Estrogen Receptor Beta) suppresses proliferation and promotes differentiation of the prostatic epithelium. §  Imamov O, Shim G-J, et al. Estrogen Receptor beta in Health and Disease. Biology of Reproduction 2005;73:866-871. Jonathan V. Wright, MD

Result

Jonathan V. Wright, MD

"In your presenter's experience, the majority of men taking patent medicine 5a-‐reductase inhiKitors have metaKoMite raNos demonstraNng signiﬁcant 5a-‐reductase over-‐inhiKiNon. A minority of men using saQ paMmeRo aMso have 5-‐reductase over-‐ inhiKiNon, as do an even smaMMer minority using zinc and even GLA." Jonathan V. Wright, MD

Serum Test

Jonathan V. Wright, MD

Potent, Natural Anti-Cancer Agents

12-‐04-‐01

Jonathan Wright, MD

“3β-Adiol not only inhibits PC3-Luc cell migratory properties, but also induces a broader anti-tumor phenotype by decreasing the proliferation rate, increasing cell adhesion, and reducing invasive capabilities in vitro.”

Dondi D, Piccolella M et al. Estrogen receptor β and the progression of prostate cancer: role of 5α-androstane-3β, 17β-diol. Endocrine-Related Cancer (2010);17:731-742

--Dondi et al.

Jonathan V. Wright, MD

“In vivo, continuous administration of 3β-Adiol reduces growth of established tumors and counteracts metastasis formation when PC3-Luc cells are engrafted s.c. in nude mice or are orthotopically injected into the prostate.”

“All these 3β-Adiol activities are mediated by ERβ and cannot be reproduced by the physiological estrogen, 17β-estradiol…” --Dondi et al.

--Dondi et al.

Jonathan V. Wright, MD

3β-Adiol: Mechanisms of Action Against Prostate Cancer “Since 3β-Adiol has no androgenic activity, and cannot be converted to androgenic compounds, the effects here described entail a novel potential application of this agent against human PC.”

3β-Adiol activates ERβ which sustains normal epithelial phenotype, impedes epithelial à mesenchymal transition, specifically by: §  Repression of VEGF-A (Vascular Endothelial Growth Factor A) Expression §  Destablization of HIF-1a (Hypoxia-Inducible Factor 1a) §  Reduction of “Snail1” (acronym derivation unknown) Relocation Cytoplasm -> Nucleus

--Dondi et al.

Jonathan V. Wright, MD

Potent, Natural Anti-Cancer Agents

12-‐04-‐01

Jonathan Wright, MD

3β-Adiol: Mechanisms of Action Against Prostate Cancer

Endogenous Stimulation, 3β-Adiol

“….high Gleason grade cancers… exhibit significantly more HIF-1a and VEGF-A and Snail1 nuclear localization compared to low Gleason grade cancers.”

§  §  §  §  §  §

§  Mak P, Leav I et al. Erβ Impedes Prostate Cancer EMT by Destabilizing HIF-1a and Inhibiting VEGF-Mediated Snail Nuclear Localization: Implications for Gleason Grading. Cancer Cell 2010 April 13;17(4): 319-332. Jonathan V. Wright, MD

Tri-Iodothyronine (T3) NADH Lithium Coconut Oil Olive Oil All Trans-Retinoic Acid (ATRA)

Jonathan V. Wright, MD

SNmulaNon of 3β-‐Adiol by Coconut and Olive Oils?

3 Beta Adiol generaNng-‐enSyme acNvity with olive and coconut oils added Dietary lipids and steroido9enic func@on:

3β-‐HSD (“3β-‐Adiol”)

5a-‐DHT-‐-‐-‐-‐-‐à5a Androstane 3β,17β-‐diol

17β-‐HSD

§  Although 3β-‐Adiol not directly measured, since 3β-‐HSD, 17β-‐HSD both signiﬁcantly greater, it’s very likely that 3β-‐Adiol increases with olive and coconut oil su@@lementaNon.

Enzyme Ac@vi@es

Soy

Olive

Coconut

Grapeseed

3B-‐HSD

1.88 ± 0.05”

3.23 ± 0.10

2.50 ± 0.06

0.96 ± 0.02

17B-‐HSD

0.15 ± 0.02”

0.41 ± 0.05

0.29 ± 0.03

0.08 ±0.01

§  Hurtado de Catalfo, GE et al, Dietary lipids modify redox homeostasis and steriodogenic stat5s ion rat tes6s7 Nutri@on 24, 2008:717-‐726

§  “…Animals fed with the olive oil and coconut oil diets showed the highest tes6cular levels of an6oxidants in addi6on to signi9cantly high levels of testosterone and 3β-‐ or 17 β-‐hydroxy-‐ steroid dehydrogenase enzymes…” §  Hurtado de Catalfo, GE et al, Dietary lipids modify redox homeostasis and steriodogenic status ion rat tes6sD dutriNon 24, 2008:717-‐726

2-‐METHOXYESTRADIOL VERSUS CANCER

Jonathan V. Wright, MD

Potent, Natural Anti-Cancer Agents

12-‐04-‐01

Jonathan Wright, MD

Some Cancers Inhibited by 2-Methoxyestradiol

2-Methoxyestradiol v. Cancer

Prostate Breast Ovarian Pancreatic Gastric Osteosarcoma Chondrosarcoma Leukemia

The antiproliferative and apoptotic effects of 2-methoxyestradiol have been confirmed in studies of prostate cancer cell lines.

Jonathan V. Wright, MD

Drissa A et al. Tocopherols and saponins derived from Argania spinosa exert an antiproliferative effect on human prostate cancer. Cancer Invest, 2006; 24(6):588-592. 31

Jonathan V. Wright, MD

2-Methoxyestradiol v. Cancer

§  Thirty-three patients with refractory prostate cancer and a mean PSA of 122.40 ng/mL were given either 400 or 1200 mg/day of oral 2-methoxyestradiol over 16 weeks in a phase II, randomized, double blind, multicenter study.

Miller KD et al. A phase I safety, pharmacokinetic and pharmacodynamic study of 2-methoxyestradiol (2MeOE2) in patients with refractory metastatic breast cancer. Proceedings of The American Society of Clinical Oncology 2001;170:20-43a.

Jonathan V. Wright, MD

§  PSA numbers either stabilized or declined 21-40% in many patients receiving 1200 mg/day of 2-methoxyestradiol.

Jonathan V. Wright, MD

Uterine Fibroids and Estrogen:

§  Estrogen increases the size of fibroids..or does it?

§  Estrogen increases the size of fibroids… or does it?

§  2-MeOHE2 is a potent antiproliferative/ apoptotic and collagen synthesis inhibiting agent in human and rat leiomyoma cells.

§  Estriol has been described to be a weak and short-acting estrogen without an increased risk of endometrial proliferation and hyperplasia.

§  Anti-angiogenic and apoptotic effects of 2-MeOHE2 on leiomyoma cells occur at a concentration of as low as 1 micromole.

§  Gynecol Endocrinol. 1999 Dec; 13 (6):382-9

§  J Soc Gynecol Investig. 2006 Dec;13(8): 542-50. Epub 2006 Nov 7. Jonathan V. Wright, MD

Jonathan V. Wright, MD

Potent, Natural Anti-Cancer Agents

12-‐04-‐01

Jonathan Wright, MD

Mayo Clinic animal research found that 2-methoxyestradiol can: §  Effectively target breast cancer cells; §  Prevent the spread of breast cancer cells to bone; §  Protect bone from osteolysis; §  Is much more effective in smaller quantities when not swallowed, but injected. Jonathan V. Wright, MD

Cicek M, et al. 2-Methoxy-estradiol Suppresses Osteolytic Breast Cancer Tumor Progression In vivo. Cancer Res. 2007 Nov 1;67(21):10106-10111.

Jonathan V. Wright, MD

Improving Methylation §  §  §  §  §

Stress & Estrogen Methylation §  Stress, especially prolonged stress, reduces methylation of estrogens.

S-adenosylmethionine (SAMe) Methylsulfonylmethane (MSM) Betaine (Betaine Hydrocholoride) 5-methyltetrahydrofolate Methylcobalamin

Jonathan V. Wright, MD

§  The required “methyl groups” get used in catecholamine methylation instead.

Jonathan V. Wright, MD

THE END

Jonathan V. Wright, MD

The Reversal of Coronary Atherosclerosis: Theory and Practice12-‐03-‐26 Thomas Levy, PhD

Reference Checking Go to: http://www.ncbi.nlm.nih.gov/pubmed/

The Reversal of Coronary Atherosclerosis Theory and Prac6ce

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The Origin of All Disease: <ncreased Oxida6ve >tress

<ncreased Oxida6ve >tress A state exis/ng when the produc/on of free radicals (highly reac/ve pro-‐oxidants) in the human body exceeds the bodyBs an/oxidant capacity to neutraliCe them, or to prevent their produc/on in the Erst place. Oxida/ve stress always results when there is a rela/ve deﬁciency of an6oxidants and/or there is a rela/ve excess of free radicals. [Halliwell 141 312]

What disease you have depends directly on: 1. The DURATION of the increased oxida/ve stress a. Acute b. Chronic 2. The LOCATION of the increased oxida/ve stress a. Extracellular b. Intracellular (subcellular organelles) c. The /ssues and/or organs aSectedT as well, which areas of the body are spared 3. The DEGREE of the increased oxida/ve stress 4. The COMBINATIONS of the above three factors (for example, low-‐ degree, extracellular: inUamma/onT high degree, intracellular: malignancy)

Redox Biology: Basic Principles

Redox Biology: Basic Principles Pro-‐oxidants are ALL toxic. Toxins are ALL pro-‐oxidants. ALL pathogens induce increased oxida/ve stress Pro-‐oxidants = Toxins / Toxins = Pro-‐oxidants Even though there is a tremendous variety of molecular structure among all of the known toxins, they ALL SHARE the property of taking electrons from other molecules, inducing increased oxida6ve stress. If a molecule does not cause the loss of one or more electrons from another molecule, it IS NOT TOXIC. Toxicity cannot exist unless electrons end up being taken from other molecules

Pro-‐oxidant Takes electrons away from other molecules (oxida6on) An6oxidant Gives (or restores) electrons back to molecules (redBc6on)

The Reversal of Coronary Atherosclerosis: Theory and Practice12-‐03-‐26 Thomas Levy, PhD Coronary Atherosclerosis Clinico-‐Pathophysiology, Early Findings

Coronary Atherosclerosis

Wolbach and Howe found that the state of scurvy (even before the discovery of vitamin C) is a disease of the ground substance. [Wolbach, S. and P. Howe (1926) Intercellular substances in experimental scorbutus. Archives of Pathology and Laboratory Medicine 1:1-‐24] Willis found that acute scurvy could produce early atherosclero/c lesions in guinea pigs on a scorbu/c diet for only 15 days (12 days needed to produce profound VC deple/on in the body). This was in the presence of normal cholesterol levels. [Willis G 69 17 (1953)]

All coronary atherosclerosis begins due to increased oxida/ve stress in the endothelial layer of the coronary arteries. This results in a progressive deficiency of vitamin C in this part of the arterial wall. As the vitamin C deficiency involves a greater por/on of the arterial wall, the pathology becomes more extensive. Autopsy studies have documented severe vitamin C deficiency in areas of atherosclerosis, and no ascorbic acid was found at sites of thrombosis. [Willis 72 500 (1955)]

Coronary Atherosclerosis Clinico-‐Pathophysiology, Early Findings

Conversely, Willis found that the administra/on of vitamin C to scorbu/c guinea pigs would block the induc/on of atherosclerosis, even when they were fed extra cholesterol, independently documented to induce and accelerate atherosclerosis development.

Willis also noted that it had been documented that:

“Widespread atherosclerosis and arterial thrombosis

in young people was reported amongst fatal cases of malnutri/on in prison camps.” [Lamy, M, M. Lamofe, and B. Lamofe (1946) Bull et mem Soc med d hop de Paris, 435]

Coronary Atherosclerosis Clinico-‐Pathophysiology, Early Findings

9xida6&e >tress F the Fenton %eac6on Mainly taVing place inside cells, the Fenton reac/on occurs when an electron is chemically donated to hydrogen peroxide, which causes the forma/on of the hydroxyl radical. The dona/on of this electron most commonly occurs due to “reac/ve” or “unbound” iron present in the cytoplasm, when ferrous ion (Fe2+) gives up an electron to hydrogen peroxide, becoming ferric ion (Fe3+) while eSec/vely producing hydroxyl radical and water from the peroxide.

Willis concluded: 1. VC deficiency produces atherosclerosis in guinea pigs regardless of whether scurvy is acute or chronic. 2. Scurvy would induce atherosclerosis even when cholesterol levels are normal 3. The VC-‐deficient ground substance in the arterial wall greatly promotes calcifica/on, hemorrhage, and thrombosis 4. Acute infec/on alone could induce atherosclerosis in guinea pigs

The Reversal of Coronary Atherosclerosis: Theory and Practice12-‐03-‐26 Thomas Levy, PhD

Oxida6&e >tress F the Eenton %eac6on

IG?ortant -onsidera6ons 1. The hydroxyl radical formed by the henton reac/on is the most reacFve free radical known to chemistry. [Chen SX 260 726] 2. Because the hydroxyl radical is so reac/ve, it can also be considered the most toxic toxin known to chemistry. 3. The hydroxyl radical will rapidly and irreversibly oxidize virtually any molecule in the body. Because of this, it does not migrate, as it always reacts with whatever is present the moment it is formed.

IG?ortant -onsidera6ons 4. The hydroxyl radical rapidly oxidizes carbohydrates, RNA, DNA, lipids, and amino acids. 5. There exists NO speciﬁc enzyme or enzyma/c reac/on that can neutralize the hydroxyl radical, meaning that the oxida/ve damage sustained by nearby, vital biomolecules is the only way to quench its reac/vity and to “remove” it from the cytoplasm. 6. Bactericidal an/bio/cs kill bacteria by s/mula/ng the produc/on of hydroxyl radicals. [Kohanski 130 7a7]. An/bio/c-‐resistant bacteria do not overproduce hydroxyl radicals upon exposure to the an/bio/c. [Kim m 413 105]

Oxida6&e >tress and Iron

Excess Oxida6&e >tress, Iron, and Atherosclerosis

Iron is essen/al for cell life and health, and just as essenFal for normal cell death. It is vital as a nutrient, and it is vital as a normal intracellular toxin. When excess iron is present inside the cell, there is always increased intracellular oxida/ve stress (IGS). Iron excess is arguably the most overlooked major factor in the clinical management of all chronic degenera/ve diseases, especially coronary artery disease and cancer.

Xroper management of the pa/entns iron status will help to both reverse coronary atherosclerosis, as well as stabilize evolving coronary atherosclerosis when substan/al other pro-‐oxida/ve factors are also in play. As a single factor, excess iron in the endothelium is a very strong atherosclerosis accelerator.

Iron Excess

herri/n levels reliably reflect the iron stores of the body. While inflammatory condi/ons might slightly elevate a ferri/n level, it is never falsely low. Depending upon the laboratory, the “normal” range of ferri/n ranges from about 20 to 400 ng/ml. This “normal” range is intended to allow the majority of the developed worldns popula/on to have a normal levelT however, due to iron for/fica/on of foods, loss of tradi/onal forms of excre/on, and iron supplementa/on, the vast majority of adults have excess stores of iron and can be considered iron-‐toxic.

The real “normal” level of iron should range between 12 and 25 ng/cc. As a prac/cal point, the bodyns iron status can be considered normal no mafer how low the measured ferri/n is, as long as there is no evidence of a microcy/c, hypochromic (iron-‐ deﬁcient) anemia.

The Reversal of Coronary Atherosclerosis: Theory and Practice12-‐03-‐26 Thomas Levy, PhD

Iron Excess & Vascular Disease Eerri6n Studies

The probability of caro/d atherosclerosis for a man with a ferri/n of 156 ng/cc is twice what it is for a man with a ferri/n of 21 ng/cc. [Kiechl 14 1625] Men with ferri/n levels greater than 200 ng/cc had more than a 200% higher incidence of myocardial infarc/on than men with levels less than 200 ng/ cc. [Salonen 86 803]

In children and pre-‐menopausal women, serum ferri/n levels average about 25 ng/cc. As post-‐menopausal ferri/n levels increase, myocardial infarc/on risk increases. \ates of myocardial infarc/on increase earlier in men, in whom ferri/n levels increase from the childhood levels as early as the late teens. [Sullivan J 1293] Basically, onens life/me of iron accumula/on accurately tracks their likelihood of developing coronary artery disease.

Iron Excess & Vascular Disease Eerri6n Studies

Elevated levels of iron (and copper) are found in human atherosclero/c plakues. Jigher cholesterol levels also correlated with iron accumula/on. [Stadler 24 949] For the same reasons that are being noted with iron accumula/on (Fenton chemistry upregula/on), copper, as well as iron, should never be supplemented by most individuals, and when legi/mate deﬁciencies of either are documented, then supplementa/on should be very low-‐dose, closely monitored, and should never be con/nued indeﬁnitely.

Iron reduc/on by phlebotomy resulted in lowered ferri/n levels, accompanied by a signiﬁcant age-‐ related improvement in CVD outcomes, less new cancer diagnoses, and less cancer-‐related death. Gver a six-‐year period, par/cipants who died had ferri/n levels of approximately 135 ng/cc and the survivors had ferri/n levels of approximately 84 ng/ cc. [Depalma 51 1498]

Iron Excess & Vascular Disease Eerri6n Studies

Excess 9xida6&e Stress %educ6on \educing oxida/ve stress inside cells and in the extracellular space is always the main goal in trea/ng ANY medical condi/on, as ALL symptoms and pathology are produced by pro-‐oxidant mechanisms. For coronary artery disease, the main target for allevia/on of ongoing excess oxida/ve stress is the endothelium of the coronaries, later to be followed by a more complete penetra/on and suﬀusion of the arterial wall with vitamin C and surrounding extracellular areas.

Even decreasing the level of ferri/n below 50 ng/cc has clearly documented beneficial effects: Blood donors with a mean ferri/n level of 17 ng/cc demonstrated signiQcantl/ impro&ed arterial elas6cit/ compared to blood donors with mean ferri/n levels of 52 ng/ cc. [Zheng 25 1577] This implies very minimal upregula/on of Fenton chemistry in the endothelial has clear nega/ve effects on vascular contrac/lity and reac/vity. As well this documents posi/ve effects for the comple/ng a full de-‐ironing protocol.

The Reversal of Coronary Atherosclerosis: Theory and Practice12-‐03-‐26 Thomas Levy, PhD

G. C. Willis et al. T"e <ni6al 5'oo,

Willis, G., A. Light, and W. Gow (1954) Serial arteriography in atherosclerosis. Canadian 6'di#a/ !((*#ia>*n ?*8"na/ 71:562-‐568 In this study, only 500 mg of ascorbic acid three /mes daily were given to 10 men, average age of 64, for periods ranging from 2 to 6 months. 6 controls received no vitamin C.

Femoral angiogram results: 1. There was no regression in any plaque in the control group (3 with bigger plaques; 3 with visibly unchanged plaques) 2. In the 10 treated pa/ents: a. 3 of 10 showed some plaque growth and some unchanged plaques b. 1 of 10 showed no discernible plaque changes c. 6 of 10 showed both shrinking plaques and unchanged plaques

G. C. Willis et al. T"e <ni6al 5'oo,

Notes and conclusions: 1. Progression and regression of arterial plaques in humans can occur over a rela/vely short period of /me 2. In a given pa/ent with changes, only progression or only regression was noted. No pa/ent showed plaques evolving in opposite direc/ons 3. gy orthomolecular standards, a very /ny dose of vitamin C caused angiographically-‐documented plaque regression in a maoority of pa/ents studied. No “spontaneous regressiond occurred in any pa/ent not receiving vitamin C

Why weren’t the results more clear-‐cut? 1. Qach pa/ent has unique toxin loadsHexposures. When that toxin amount is not neutralized with suﬃcient vitamin C, progression, at whatever rate, of atherosclerosis is what would be expected. 2. The amount of vitamin C was small, but s/ll suﬃcient to oboec/vely and posi/vely impact 6 of 10 pa/ents 3. The current goal in the treatment of atherosclerosis in mainstream medicine is to slow, or at best stabilize, the progression of atherosclerosis

G. C. Willis et al. T"e <ni6al 5'oo,

DentalToxinsN<n,e26ons As the work of Willis et al. demonstrated, posi/ve beneﬁts from simple, rela/vely low-‐dose vitamin C can be enough to begin the oboec/ve reversal of atherosclerosis. Jowever, elimina/ng the reason for the ini/al deple/on of vitamin C in the arterial walls is the best way to assure a posi/ve and profound reversal of exis/ng atherosclerosis. As well, Willis et al. studied peripheral arteries. The coronary arteries receive much higher amounts of dental toxins and pathogens than the arteries anywhere else in the body, and they will be much more resistant to resolu/on by good supplementa/on only.

The irrefutable conclusion, then, is that the evolu/on of atherosclerosis can be stopped, and even reversed, when vitamin C can be adequately restored to depleted areas in the aﬀected arteries. This then begs the ques/on: If a focal arterial deﬁciency of vitamin C is the iniFator of all coronary disease, then: Lhat iniFates the iniFator?

The Reversal of Coronary Atherosclerosis: Theory and Practice12-‐03-‐26 Thomas Levy, PhD

At"eros2lerosis Evolu6on: One Treatment Model

DentalToxinsNIn,e26ons hor op/mal treatment, pro-‐oxidant (toxin/infec/on) sources need to be addressed in:a!!iFon:to an/oxidant administra/on/supplementa/on. Dental In,e26ons and Toxins XCri62alY 1. Root canal treated and any other infected and/or abscessed teeth (infec/ous, toxic) 2. Periodontal disease (infec/ous, toxic) 3. Implants (toxic, ouen infec/ous) 4. Toxic dental metals and chemicals 5. Cavita/ons (toxic, low-‐grade infec/ous)

Rath, M. and A. Niedzwiecki (1996) Nutri/onal supplement program halts progression of early coronary atherosclerosis documented by ultrafast computed tomography. Journal of !;;l%'3 @u.r%>on 48:68-‐78 hollowing coronary artery calciEca/on as an index of evolving coronary atherosclerosis, the authors found: 1. Annual progression rate without interven/on: 44% 2. 15% decrease of progression over one year with supps 3. No progression with pa/ents with early stages of coronary atherosclerosis

At"eros2lerosis Evolu6on One Treatment Model

Vitamin C: T"e Mul6@C 5roto2ol

1. However, the model of Rath and Niedzwiecki included a daily dose of 150 mg calcium and1.5 mg copper 2. The daily dose of vitamin C was 2,700 mg of vitamin D3 was 600 IU of L-‐lysine was 450 of L-‐proline was 450 3. No part of the protocol involved removing daily toxin exposures 4. wet, a clearly posi/ve response rela/ve to no treatment was obtained.

Vitamin C: Intravenous

1. Gral liposome-‐encapsulated vitamin C (for op/mal intracellular access by ascorbate) 2. Mul/gram doses of sodium ascorbate powder, taken several /mes daily, up to or reaching bowel tolerance (in order to minimize gut toxicity & support extracellular access by ascorbate) [Cathcart 7 1359; Cathcart 18 61] 3. Gral administra/on of ascorbyl palmitate (for op/mal fat-‐ soluble access by ascorbate) [Pokorski 53 311; Pokorski 10 193; Mendirafa 26 81] 4. Intermifent IV administra/on of ascorbate (to op/mize extracellular access by ascorbate, as well as to further support intracellular pools of ascorbate)

Vitamin C: Intravenous

In general, for any given administra/on of IVC, give from 1 to 1.5 grams per kilogram of body weight; 50 grams might be perfect for a 110-‐pound woman, but not remotely enough for a 250-‐ pound man. Most children will do well on 25 to 50 grams infused at a /me. Qarly doses should be high (loading dose before maintenance concept) Also, the extent of infec/on and/or the degree of toxin accumula/on and ongoing toxin exposure/produc/on will greatly aﬀect what your proper dose of vitamin C should be.

Mhen the condi/on demands op/mal biodelivery of the vitamin C, use: HEAT (Hormone-‐Enhanced Ascorbate Therapy) U/lize regular, Humulin insulin with the IV infusion; between 5 and 20 units of insulin is added to the bofle/bag of vitamin C Use lower amounts when infusion is rapid (an hour); use higher amounts when infusion is slow (3 to 4 hours)

The Reversal of Coronary Atherosclerosis: Theory and Practice12-‐03-‐26 Thomas Levy, PhD Vitamin C: Intravenous

Zinimal 9ther >upplementa6on

HEAT therapy is important for clinical success, par/cularly in pa/ents with advanced coronary artery atherosclerosis. The endothelial cells have /ght junc/ons that could impair large inUuxes of vitamin C auer early smaller amounts allow this aspect of the endothelium to “heal” Insulin augmenta/on of vitamin C delivery will further enhance the delivery of reduced vitamin C into the cells, and the addi/on of a liposome delivery system can further promote the deep penetra/on of vitamin C into the arterial wall, even auer more superﬁcial healing has occurred or is well underway.

1. Mg glycinate, 200 mg orally twice daily 2. L-‐lysine, 2,000 mg orally twice daily 3. L-‐proline, 500 mg orally twice daily 4. Vitamin D3, 10,000 units orally daily 5. Vitamin K2, 1 mg (1,000 mcg) orally twice daily 6. Omega-‐3 krill oil, 300 mg orally twice daily 7. AVOID added calcium in any form 8. AVOID iron supplementa/on 9. AVOID copper supplementa/on

Iron Excess: Treatment

Recap 1. Dental infec/ons, especially root canals, and related toxins are the primary causes for the deple/on of vitamin C in the coronary arteries, and therefore are singularly the most important factors for atherosclerosis developing in probably a majority of aﬀected pa/ents, especially non-‐smokers. Heavy smoking, via the direct toxicity of inhaled toxins along with the extreme toxicity of the universally-‐induced chronic periodontal disease, causes a great deal of CAD. However, smoking cessa/on with quality supplementa/on can reverse many such individuals if no other signiﬁcant dental toxicity is present.

Goal: Ferri/n level less than 25 ng/cc (without evidence of anemia)

1. Regular phlebotomy [Dwyer 72 504] 2. Inositol hexaphosphate (IP6), a nutrient iron and calcium chelator, one to three grams daily on an empty stomach [Graf 8 61; Graf 262 11647] 3. Far infrared sauna therapy [Hohnadel 19 1288; Beever R 55 691; Kihara 53 214] 4. Aerobic physical exercise [Nyyssonen 140 148] 5. Prescrip/on iron chela/on (desferrioxamine, deferasirox) [Zhang W 235 633; Agarwal 77 185] 6. Op/ons depend on clinical urgency, especially y5

Recap

Recap 5. Many cases of atherosclerosis resolu/on can be resolved with less than the en/re suggested protocol, but a treatment failure can not be considered to occur with anything less than the full protocol. 6. The protocol should completely resolve, to normal or near-‐normal coronary arteries, over 90p of pa/ents with moderate CAD. 7. The protocol should drama/cally lessen CAD in over 75p of all pa/ents with moderate to severe CAD. 8. On extremely advanced CAD, the protocol will have a variable response, depending largely on whether the vitamin C has access to the aﬀected arterial plaques.

2. Atherosclerosis has been proven to be a completely reversible condi/on, especially when not in the most advanced of stages. 3. The way to reverse atherosclerosis, and to keep such a reversal from deteriora/ng, is to eﬀec/vely restore and then maintain normal levels of vitamin C in the coronary arteries, especially the endothelial lining cells. 4. Qﬀec/ve therapy can be documented with angiography, stress tes/ng, and ultrafast computed tomography to document calcium mobiliCa/on, which must occur if the atherosclerosis is resolving.

12-03-26 Stress, the Autonomic Nervous System and Cardiovascular Disease

Thomas Alexander, MD

Hans Selye (1907-‐1982) •  Was the one who coined the term stress •  Stress – eustress and distress •  3h4sical and emo6onal stress induced a 3a7ern that8 i9 le: untreated8 alwa4s leads to in9ec6on8 illness8 disease8 and e;entuall4 death.

Stress, the Autonomic Nervous System and Cardiovascular Disease Thomas Alexander, M.D, thomasalexandermd.com Vancouver, BC April 28th, 2012

Alarm Stage

General AdaptaJon Curve

Alarm ReacJon

Resistance

•  •  •  •  •  •  •  •  •

LxhausJon

Resistance Stage

SympatheJc nervous system arousal Adrenal medullary sJmulaJon ACTH released CorJsol released Growth hormone released NrolacJn released Oncreased thyroidal acJvity Gonadotropin acJvity increased Anxiety

@Ahaus6on Stage

•  ReducJon in adrenal corJcal acJvity •  ReducJon in sympatheJc nervous system acJvity •  HomeostaJc mechanisms enPaPed

•  LnlarPement oQ lymphaJc structures •  TarPet orPan diseaseRdysQuncJon •  Oncreased vulneraSility to opportunisJc disease •  NsycholoPical exhausJonT depression •  NhysioloPical exhausJonT disease.

12-03-26 Stress, the Autonomic Nervous System and Cardiovascular Disease

Thomas Alexander, MD

Pathways of Stress Induced AcJvaJon

Neural Axes: Fight, ﬂight or freeze

•  Neural Axes •  Neuroendocrine Axis •  Endocrine Axes

•  SympatheJc Nervous System •  ParasympatheJc Nervous System •  Neuromuscular Nervous System

Event •  •  •  •

Threatening 04/3athe6+ =+6;a6on Posterior hypothalamus Cranial and sacral spinal cord •  Norepinephrine •  Arousal

Neuro-‐endocrine •  ?A – YA seconds aZer the fact •  Adrenal medulla releases norepinephrine and epinephrine – delivered to muscle ﬁbres via nerve cells

•  Non-‐threatening •  Eara-‐#4/3athe6+ =+6;a6on •  Anterior hypothalamus •  Cranial and sacral spinal cord •  Acetylcholine •  KelaxaJon

Neuro-‐Endocrine Axis

Increased arterial blood supply Increased blood supply to brain Increased cardiac output and heart rate Increased sJmulaJon of skeletal muscle Increased plasma free fa]y acids, triglycerides, total cholesterol •  Increased release of endogenous opioids

•  Decreased blood ﬂow to kidneys, GI tract, skin •  Increased risk of thrombus formaJon •  ^eading to hypertension, thrombus formaJon, arrhythmia and increased risk of sudden cardiac death

•  •  •  •  •

12-03-26 Stress, the Autonomic Nervous System and Cardiovascular Disease

Thomas Alexander, MD

Adverse E_ects of Prolonged SympatheJc SJmulaJon

Endocrine Axes •  :ost prolonged and hardest to sJmulate •  Hypothalamic-‐pituitary-‐adrenal corJcal system •  CRF to ACTH to corJsol and corJsone

•  •  •  •

Increased glucose producJon Iastric IrritaJon Increased release of free fa]y acids Increased suscepJbility to non-‐thromboJc myocardial necrosis (Takotsubo Cardiomyopathy or Broken-‐Heart Syndrome) •  Immune System Supression

Adverse E_ects of Prolonged SympatheJc SJmulaJon

Fight, ﬂight or freeze

•  helplessness, hopelessness, depression, passivity, the percepJon of no control, immunosuppression and gastrointesJnal symptomatology

•  When confronted with a life threatening situaJon, our raJonal brains may become confused and over-‐ ride our insJnctual impulses. Confusion can lead us to being frozen in fear leading to the creaJon of traumaJc symptoms. Symptoms that originate from the amassing of unleashed energy stored in our nervous systems. When we are not able to unleash and liberate these powerful forces, we become vicJms of trauma.

The RelaxaJon ResponseT The Counterbalance

The Freeze Response •  Adrenal glands pump either adrenaline or noradrenalin into the body. Adrenaline causes the state of hyper-‐alertness in which blood pressure, heart rate, muscle tension all increase. Pupils dilate and blood ﬂow to the extremiJes decrease, while the ﬂow to the head and trunk increase so that the individual can think and move be]er and more auickly. AlternaJvely when noradrenaline is pumped into the system, a freezing reacJon can take place. :oving and acJng becomes dibcult as if moving in slow moJon.

•  Three minutes aZer this is acJvated, your stress response burns out. The parasympatheJc nervous system is acJvated and your metabolism, heart rate, breathing rate, muscle tension and blood pressure, all return to normal levels and homeostasis is achieved.

12-03-26 Stress, the Autonomic Nervous System and Cardiovascular Disease

Thomas Alexander, MD

The work of Meyer Friedman and colleaguesT Stress the forgo]en Factor

Stress and Cholesterol

Meyer Friedman Originator of the term Type A Behavior and Dr. Gerald Friedland Study of 40 accountants. January 1957 – normal cholesterol levels, normal clogng Jmes. ^evels tested bi-‐weekly. In April as tax deadlines approached – average blood cholesterol rose abruptly, clogng Jmes accelerated. May and June cholesterol dropped back down to normal.

•  Implanted electrodes in the hypothalamus of rats and studied behavior and their cholesterol levels •  Savage, free-‐VoaJng hosJlity •  Cholesterol and triglyceride levels increased if just a li]le fat was added to their diet •  If diet completely fat free there was no increase in their cholesterol levels

San Francisco Kecurrent Coronary PrevenJon Project

1013 Post MI (90% men, 95% Type A)

270 Standard Cardiac Counseling

21.2 % recurrence

151 Neither

20.2 % recurrence

592 Cardiac Counseling plus Type A behavioral modi[caJon

12.9 recurrence rate (p < 0.005)

Meyer Friedman •  First heart a]ack at age 55 – lived to be 90 and died of non-‐cardiac causes. •  Type A behavior versus personality •  from Cannonball Mike to Time is my friend

The review panel accepts the available body of scienJ[c evidence as demonstraJng that type A behavior is associated with an increased risk of clinically apparent CHD. This risk is greater than that imposed by age, elevated values of systolic blood pressure and serum cholesterol, and smoking and appears to be of the same order of magnitude as the relaJve risk associated with the la]er three of these other factors.

12-03-26 Stress, the Autonomic Nervous System and Cardiovascular Disease

Thomas Alexander, MD

TradiJonal Risk Uactors for Heart Disease •  •  •  •

Hyperlipidemia Smoking Diabetes Overweight

Cause versus eﬀect

The Roseto Story: As told by Dr. John Bruhn and Dr. Stewart Wolf During a mean 94 months of follow-‐up, the intervenJon group had a 4B% lower rate of fatal and nonfatal ﬁrst recurrent CVD events, 45% fewer recurrent acute myocardial infarcJons and a ?@% lower all-‐cause mortality

Treatment of the Stress Response

So what is stress?

12-03-26 Stress, the Autonomic Nervous System and Cardiovascular Disease

Thomas Alexander, MD

How do you go from this..

to this?

Video Clip •  Biofeedback training •  Neurofeedback •  Choices and percepJonT Counseling etc.

Thank you!

!MT %n'amma*on ,ancouver 2012 Inflammation and Neuropsychiatric

12-‐03-‐26 Illness: Treatment and Testing Protocols

James Greenblatt, MD

The Problem %n'amma*on and neuropsychiatric illness@ Treatment and tes*ng protocols

•  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 life*me –  And approximately 15% of these will eventually commit suicide

Bames CreenblaEF MD

Depression

The Solu*on Depression is NOT a Prozac deﬁciency

Response to Psychopharmacologic Treatment 50% improvement of the primary symptoms of depression is the standard measure of treatment response •  20-‐V0% do not show substan*al clinical improvement •  2W3 of pa*ents treated for depression con*nue to have residual symptoms

88 1

OMT %n'amma*on Vancouver 2012

12-‐03-‐26 Inflammation and Neuropsychiatric Illness: Treatment and Testing Protocols

James Greenblatt, MD

Placebo -‐ depression

Decep*on and Proﬁt

35-‐45R of pa*ents improve in their treatment of depression – even if they are given only a sugar pill

•  Based on studies from 1987 to 2004: – Medical literatures suggests that 94R of an*depressant trials have posi*ve beneﬁcial results •  Actual number of posi*ve studies is closer to 51% •  Appr+,i./0el3 145 +6 0he ne9/:ve 0ri/ls sub.i?ed 0+ 0he FDA were never published •  Conclusion: About half of an*depressant trials failed to show a beneﬁt that exceeded that of a placebo

Turner, et al. (2008). The New England Journal of Medicine, 358: 252-‐260

How Much aonger Can be Con*nue to Complain?

Mental %llness and Gene*cs

¡  Marcia Angell, MD, a former editor of the New England Journal of Medicine reviewed three books that highlight the explosion of an*depressant use in our society and eues*ons the efec*veness of an*depressants.

Epigene*cs

¡  g%f psychoac*ve drugs are useless…why are they so widely prescribed by psychiatrists and regarded by the public and the profession as something akin to wonder drugs? ”

Most of the risk for depression is likely environmental factors

Depression and %n'amma*on

THE ZEEBRA •  •  •  •  •  •  •  •  •

Gene*cs have clearly been shown to be associated with increasing or decreasing risks for Mood Disorders

T – Take Care of Yourself H -‐ Hormones E – Exclude

The Brain on Fire

Z – Zinc and Other Minerals E – Essen*al FaEy Acids E – Exercise and Energy B – B Vitamins and Other Vitamins r – referenced-‐EEG A – Amino Acids and Protein

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OMT Inﬂamma*on ,ancouver 2012

12-‐03-‐26 Inflammation and Neuropsychiatric Illness: Treatment and Testing Protocols

James Greenblatt, MD

Inﬂamma*on is associated with All Major chronic Illnesses

Chronic inﬂammatory disorders •  Rheumatoid arthri*s

•  •

¡ M ul*ple sclerosis

•  •

¡ A sthma

•  •

Examples of Inﬂamma*on

Cancer Heart disease Asthma Diabetes Alzheimer’s DEPRESSION

sickness behavior

Inﬂamma*on can occur in silence without symptoms for years

Sickness behavior

Cytokines and sickness behavior

•  An immunological model of depression •  The nonspeciTc reac*on to infec*on and inﬂamma*on •  Symptoms include –  Lethargy –  Malaise –  Decreased concentra*on –  Decreased appe*te –  Decreased interest in pleasurable things –  Weakness •  “Depression-‐like symptoms”

•  Sickness behavior is mediated by pro-‐inﬂammatory cytokines –  IL-‐1, IL-‐6, TNF-‐alpha, IFN-‐gamma •  Cytokines travel from peripheral immune system to the brain via aﬀerent neurons •  Research has demonstrated the levels of circulatory cytokines correlate with levels of anxiety, depression, and cogni*ve impairment

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Cytokines and Depression

Depression and Inﬂamma*on Link between an overac*ve immune system and depression

•  Pa*ents with major depressive disorder had signiTcantly higher TNF-‐alpha levels than controls1

•  Prolonged infec*on or injury produces chemicals called pro-‐ inﬂammatory cytokines •  These pro-‐inﬂammatory cytokines can contribute to depression by causing changes in the neurotransmiEers associated to mood •  Cytokines can also lead to deTciencies in neurotransmiEers by con*nually s*mula*ng their release

•  Proinﬂammatory cytokines were signiTcantly higher in pa*ents with depression •  An*-‐inﬂammatory cytokines were signiTcantly lower in pa*ents with major depression •  Sertraline therapy led to a decrease in some pro-‐ inGammatory cytokines and an increase in an:-‐inGammatory cytokines2 1. Huang TL, and Lee CT., (2007). Psychiatry Clin Neurosci. 61(4):415-‐20 2. Sutcigil L, et al., (2007). Clin Dev Immunol. 2007:76396

An*-‐inﬂammatories and An*depressant augmenta*on

Inﬂamma*on and Depression

•  4 week open-‐label study: 24 pa*ents with major depression who are considered non-‐responders •  Pa*ents given 160 mgWday acetylsalicylic acid (ASA) and their current an*depressant treatment

•  These cytokines ac*vate the tryptophan-‐ and serotonin-‐ degrading enzyme indoleamine 2,3-‐dioxygenase (IDO)

L-Tryptophan

5-HTP

X ST

•  Combina*on SSRI-‐ASA was associated with a response rate of 52.4%

•  Ac*ve ID! degrades serotonin and its precursor tryptophan which may explain the reduced availability of serotonergic neurotransmission in major depression

•  Remission achieved in 43% of the total sample and 82% of the responder sample

Müller N, and Schwarz MJ. Mol Psychiatry. 2007;12(11):988-‐1000.

Mendlewicz J, et al. Int Clin Psychopharmacol. 2006;21(4):227-‐31

Reported side eﬀects of interferon treatment of hepa**s c

Interferon Therapies and Depression •  Psychiatric side eﬀects occurred in 30W93 pa*ents with chronic hepa**s C (32%)1 –  3 cases (10%) mania –  15 cases (50%) irritable hypomania –  12 cases (40%) depressive mixed states

•  Suicide •  Apathy •  Sexual •  Insomnia •  Irritability •  Cogni*ve defects

•  Symptoms appeared within 4 weeks of treatment with interferon1

•  2N-‐3N& of pa:ents who ha;e hepa::s O and who are treated with interferon are at risk for depression2 1. Constant A, et al. J Clin Psychiatry. 2005 Aug;66(8):1050-‐7. 2. Hauser P Gastroenterol Clin North Am. 2004;33(1 Suppl):S35-‐50.

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Inﬂamma*on and maKor depression

Inﬂamma*on and depression

Raison CL, Lowry CA, Rook GA. Arch Gen Psychiatry. 2010;67(12):1211-‐24

•  Inﬂammatory cytokines can cause symptoms of depression

Two Theories…

•  Higher levels of inﬂammatory cytokines are associated with depression

1.  Microorganisms previously ubiquitous in soil, food, and the gut, but that are largely missing from industrialiSed socie*es, may contribute to increasing rates of MDD in the modern world1

•  Treatment of depression with an*depressants and ECT decrease pro-‐inﬂammatory cytokines •  Cytokine therapy for cancer and autoimmune disorders cause cogni*ve changes, including depression and suicidal idea*on

2.  Adap*ve mechanism that evolved where symptoms of depression conserved energy for stronger inﬂammatory responses to Tght infec*ons?

Mul*ple !pportuni*es for oew Treatment !p*ons

Sharing tryptophan?

Inﬂamma*on

•  Tryptophan is essen*al for the survival of infec*ous microbessconsump*on of tryptophan is part of the infec*ous process

A physiological process ac*vated in a similar manner by a diverse range of environmental factors

•  Withdrawal of tryptophan is part of the complicated immune system defense against microbes

A diverse range of depressogenic, environmental factors

Sources of inﬂamma*on •  SAD: Standard American Diet (high in sugar, processed foods, and trans fats) •  Environmental toxins •  Low grade infec*ons (Lyme disease) •  Food and Environmental Allergies

•  Stress •  Dysbiosis and diges*ve problems •  Sedentary lifestyle •  outri*onal deTciencies •  Inadequate sleep and sleep disorders

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Sleep Gepri/a*on and %nﬂamma*on

Sleep Gepri/a*on and %nﬂamma*on •  Modest sleep restric*on: 6 hWnight for 1 wk

Vgontzas AN, et al., Ele/a*on of plasma cytokines in disorders of ePcessi/e day*me sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab. 1997;82(5):1313-‐6.

•  25 young, healthy, normal sleepers (12 men and 13 women) were studied for 12 consecu*/e nights

Vgontzas AN, et al., Circadian interleukin-‐6 secre*on and euan*ty and depth of sleep. J Clin Endocrinol Metab. 1999;84(8):2603-‐7.

•  Ater 1 wk of sleep restric*on:

–  Subjects were signiﬁcantly sleepier and performed worse in 4 areas of psychomotor skills –  24-‐h secre*on of %a-‐6 was increased –  TNF-‐alpha was increased only in men

Vgontzas AN, et al., Chronic insomnia is associated with a shit of interleukin-‐6 and tumor necrosis factor secre*on from nighume to day*me. Metabolism. 2002;51(7):887-‐92.

•  Modest sleep loss is associated with signiﬁcant sleepiness, impairment of psychomotor performance, and increased secre*on of pro-‐inﬂammatory cytokines

Vgontzas AN, et al., Ad/erse efects of modest sleep restric*on on sleepiness, performance, and inﬂammatory cytokines. J Clin Endocrinol Metab. 2004;89(5):2119-‐26.

Vgontzas AN, et al., J Clin Endocrinol Metab. 2004;89(5):2119-‐26.

Stress and inﬂamma*on Stress-‐induced ele/a*on of glucocor*coids enhances immune func*on in CNS /ia microglia ac*/a*on and prolifera*on and loss of astrocyte numbers and /olume

Miller, et al., Biol Psychiatry 2009;65:732-‐734

Allergies and Depression

Miller, et al., Biol Psychiatry 2009;65:732-‐734

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James Greenblatt, MD

Lyme disease

Allergies Linked to Depression •  Doubling of risk for depression in a person suﬀering from allergies •  Proinﬂammatory cytokines, proteins released by immune cells, rush to protect an allergic person from pollen or other allergens that have entered the body •  Immune system weakened by allergies and immune system linked to neurotransmiEers •  Women more likely to become depressed and men more likely to have anxiety-‐type disorders from allergies

Image Courtesy of Jeroen van Oostrom

2002-‐2010: Canada Online Healthlink, Inc

Depression associated with Candida albicans infec*ons

Gum Disease and inﬂamma*on Dr. Susan Karabin, Past President of the American Academy of Periodontology: “…researchers now suspect that the more severe symptoms [of gum disease], namely swollen, bleeding gums; recession around the gum line, and loss of the bone that holds the teeth in place, may be caused by the chronic inﬂammatory response to the bacteria2 infec:on, rather than the bacteria itself.”

•  “…depression is commonly related to prolonged or repeated courses of broad-‐spectrum an*bio*cs or to birth control pills, which promote the overgrowth of Candida albicans on mucous membranes.” •  “Depression and other disorders related to C. albicans can be suspected from clinical history, followed by a therapeu*c response to oral nysta*n and a yeast-‐free, low-‐carbohydrate diet.” Crook WG. JAMA. 1984;251(22):2928-‐9.

Clostridia metabolites

How do we measure inﬂamma*onc

•  HPHPA = 3-‐(3-‐hydroxyphenyl)-‐3-‐ hydroxypropionic acid •  This compound is made by anaerobic bacteria of the Clostridium genus •  HPHPA is a metabolite of the amino acid m-‐ tyrosine (3-‐hydroxyphenylalanine •  In experimental animals HPHPA depletes brain catecholamines and causes symptoms of au*sm (stereotypical behavior, hyperac*vity, and hyper-‐reac*vity)

Direct •  •  •  •

Quinolinic Acid

HPHPA Clostridia Food Allergies Yeast

Indirect

•  CRP •  Ferri*n

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HPHPA

Reynold

gThere is an increased urinary excre*on of a 3-‐(3-‐hydroxyphenyl)-‐3-‐hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointes*nal tract, in urine samples from pa*ents with au*sm and schizophrenia.y

…and OCD and Depression Shaw, William. %/:03<.(+*$%#/0.643#(4#9$=>9$?@A=ABC$=>DEF>9$

C-‐reac*ve protein (CRP)

Jake 16 y/o

•  CF*1/E:;1')*+01-8 (CRP) is a protein found in the blood •  CRP is synthesized by the liver in response to factors released by fat cells (adipocytes) •  Measuring CRP level is a screen for infec*ous and in'ammatory diseases •  Rapid, marked increases in CRP occur with in'amma*on, infec*on, trauma and *ssue necrosis, malignancies, and autoimmune disorders

Associa*on between depression and elevated C-‐reac*ve protein

The associa*on between C-‐reac*ve protein levels and depression

•  Data from the Third oa*onal Health and outri*on jxamina*on Survey, a representa*ve sample of the LS popula*on from 1988 to 1994

•  Cene*cally homogeneous oorthern minland 1966 Birth Cohort was followed un*l age 31 (n = 5269)

•  6149 individuals aged 17 to 39 years who were free of cardiovascular diseases and chronic in'ammatory condi*ons

•  In male subjects, elevated hs-‐CRP levels (> or =1.0 mg/L) increased the probability for severe current and recurrent depressive episodes 1.7-‐fold and 3.1-‐fold, respec*vely

•  Among men:

–  History of a major depressive episode was associated with elevated CRP, par*cularly for recent episodes (up to 6 months before assessment) –  Men with a history of major depressive episode had 2.77 *mes higher odds of elevated CRP compared with never-‐depressed men

•  hs-‐CRP level of >3.0 mg/L increased the probability for recurrent depression up to 4.1-‐fold

Danner, et al., Psychosom Med. 2003;65(3):347-‐56

Liukkonen T, et al. Biol Psychiatry. 2006;60(8):825-‐30.

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James Greenblatt, MD

(<<+E-/:+8'>10C118'B1)*1<<-+8'/8@' OFR1/E:;1'S*+01-8

CRP and Brain Func*on

•  508 healthy adults (mean age 48.5 years; 49% women, 88% white) residing in central MassachuseEs

•  Markers of systemic inﬂamma*on are related to cogni*ve deTcits (declines in processing speed and execu*ve func*oning)1 •  Individuals with detectable CRP demonstrated lower performance on memory tasks involving recall and recogni*on2 •  Poorer self-‐rated health is associated with elevated serum inﬂammatory markers among generally healthy older adults3

•  Data were collected at baseline and at quarterly intervals over a 1 year period per individual •  Individuals with higher depression scores have higher levels of hs-‐CRP •  Depression score was correlated to hs-‐CRP levels in women.

1. Trollor JN, et al., Age (Dordr). 2011 Aug 19. [Epub ahead of print] 2. BeEcher BM, et al. Brain Behav Immun. 2011 Aug 6. [Epub ahead of print] 3. Chris*an LM, et al. Psychoneuroendocrinology. 2011;36(10):1495-‐504.

Ma, et al. Cardiol Res Pract. 2010;2011:286509

New use for sta*n •  Dec. 2009 FDA has agreed to broader labeling for rosuvasta*n (Crestor) •  Rosuvasta*n may be used in pa*ents with normal LDL-‐cholesterol levels but who have elevated levels of C-‐reac*ve protein and other cardiac risk factors

S*1;18:+8'-<'S+<<->21'

Quinolinic acid: an endogenous metabolite that produces axon-‐sparing lesions in rat brain

Quinolinic acid •  Kynurenine pathway involves the breakdown of tryptophan into quinolinic acid and other metabolites

“Intracerebral inKec*on of the neuroexcitatory tryptophan metabolite, quinolinic acid, has behavioral, neurochemical, and neuropathological consequences … Its quali*es as a neurotoxic agent suggest that quinolinic acid should be considered as a possible pathogenic factor in neurodegenera*ve disorders.i

•  Quinolinic acid has a potent neurotoxic eﬀect

–  It is involved in neurodegenera*ve processes such as AIDS demen*a complex, Alzheimer's disease, `un*ngton's disease, amyotrophic lateral sclerosis, mul*ple sclerosis and Parkinson's disease Depression

Schwarcz R, Whetsell WO Jr, Mangano RM

Science. 1983;219(4582):316-‐8.

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Inﬂamma*on and depression Cytokine-‐induced IDO deﬁciency of tryptophan, serotonin, and melatonin

Pro-‐inﬂammatory Cytokines

IDO

Tryptophan

Serotonin

Melatonin

Q Acid

Glutamate neurotransmiEers

gRe/isedi Inﬂamma*on and depression

INFLAMMATION AND DEPRESSION

¡  Allergies ¡  Chronic inﬂamma*on

Raison CL, Lowry CA, Rook GA. Arch Gen Psychiatry. 2010;67(12):1211-‐24.

•  •  •  •  •

Mg EFAs Lithium OPC Curcumin

Raison CL, Lowry CA, Rook GA. Arch Gen Psychiatry. 2010;67(12):1211-‐24.

EXTRA, EXTRA – Exercise Is Good!

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Omega-‐3 supplementa*on lowers inﬂamma*on and anxiety in medical students

Omega-‐3 maEy acids and inflamma*on Research studies suggest that levels of omega-‐3 faEy acids may directly influence the magnitude of the inflammatory response to stress and depression

•  68 medical students •  Blood samples taken during lower-‐stress periods and on days before an exam •  Students received either n-‐3 (2.5g/d, 2085mg EPA and 348mg DHA) or placebo containing propor*ons of faEy acids found in the typical American diet •  Students who received n-‐3 showed –  14% JdK, ecrease in lipopolysaccharide interleukin Kiecolt-‐Glaser et al., Brain Behav Immun. 2011 (JLPS) ul 19. s*mulated [Epub ahead of print] 6 (IL-‐6) produc*on –  20% reduc*on in anxiety symptoms –  No signiﬁcant change in depressive symptoms

Omega-‐3s and Suicide in Military

EmA Restora*on

•  Study of 800 U.S. servicemen and women who commiEed suicide between 2002 and 2008 (compared to 800 who didn’t)

It takes at least 10 weeks for cerebral membranes’ highly unsaturated faEy acid levels to recover following chronic deﬁciency.

•  Personnel with medical records showing low blood levels of DHA were 62% more likely to have been suicide vic*ms than those with the highest levels •  Study found that U.S. service personnel generally have low levels of DHA in their blood

Bourre, et al., Prostaglandins Leukot Essent maEy Acids, 1993

Lewis, et al., J Clin Psychiatry, 2011 [E-pub ahead of print]

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Omega-‐3s May Have Ability to Delay or Prevent Psychosis

Amy

•  Study par*cipants: 81 adolescents or young adults with sub-‐threshold psychosis

20 y/o College Student

•  Supplementa*on: 1.2 g omega-‐3 faEy acids (700 mg EPA and 480 mg DHA) or placebo daily for 12 weeks •  Ater 40 weeks:

–  5% (2 out of 41) in omega-‐3 group developed psychosis –  28% (11 of 40) in placebo group developed psychosis

Amminger, et al., Archives of General Psychiatry, 2010, 67(2): 146-‐154

EPA?

Fish?

Liquid?

Ua*o?

DHA?

Dose?

Mercury?

Magnesium

Krill?

Flax?

Lithium

One of the ﬁrst minerals to disappear from food when processed and one of the ﬁrst minerals to leave the body when there is stress

•  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

¡ Decrease cor*sol levels, a known cause of sleep disrup*on.

Magnesium has direct an*-‐in'ammatory proper*es in the CoS

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Lithium and Suicide

Lithiated Lemon-‐Lime Soda

•  Study examined life-‐threatening or fatal suicidal acts in over 300 bipolar type I and type II pa*ents before, during, and following long-‐term lithium treatment •  Pa*ents had been ill for over eight years •  On lithium: rate of suicides and aEempts decreased nearly 7-‐ fold Lithiated products were common in the early part of the 20th century and were believed to be healthful and help with hangovers

•  Lithium discon*nua*on: suicidal acts increased 14-‐fold above rates found during treatment 7 Up contained lithium citrate from 1929 un*l 1950

¡ First year off lithium: suicide rate rose 20-fold Tondo L, Jamison KR, Baldessarini RJ. Ann NY Acad Sci 1997

How Does Lithium Work?

Lithium and Suicide

•  Examined 27 Texas coun*es from 197Z-‐19Z7 •  Examined lithium levels in tap water in the 18 municipalities in Japan in relation to the suicide standardised mortality ratio •  Austrian study with nationwide sample of 6460 lithium measurements

New research supports the theory that lithium may reduce brain in'amma*on by adKus*ng the metabolism of the omega-‐3-‐ faEy acid DHA

¡ Overall suicide rate and the suicide mortality ra*o were inversely associated with lithium levels Schrauzer GN, Shrestha KP. Biol Trace Elem Res. 1990;25(2):105-13 Ohgami H, Br J Psychiatry. 2009;194(5):464-5 Kapusta, N.D., et al., The British Journal of Psychiatry (2011) 198: 346-350.

Basselin et al. The Journal of Lipid Research, 2010; 51 (5): 1049

Chicken or egg?

THE METAL MARVEL THAT HAS MENDED BRAINS FOR 50 YEARS

In'amma*on in the brain causes in'amma*on in the gut

LITHIUM—A SIMPLE METAL AND THE OLDEST DRUG IN PSYCHIATRY— MIGHT PROTECT THE BRAIN AGAINST MENTAL ILLNESS, ALZHEIMER’S, AND OTHER DISEASES. ONE PROBLEM: THERE’S NO PROFIT IN IT. BY PAUL RAEBURN; ADDITIONAL REPORTING BY MONICA HEGER

In'amma*on in the gut causes in'amma*on in the brain

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Catabasis pharmaceu*cals inc.

A new model

•  Raised $39.6 million in 2010 •  New drug “CAT-‐1004” •  A new drug in de/elopment to control inﬂamma*on for the treatment of diabetes

•  Hoor response rate to o/er 40 years of an*depressant prescrip*ons •  All current an*depressants afect serotonergic andWor noradrenergic neurotransmission •  be ha/e yet to iden*fy speciﬁc mechanisms of monoamine disturbances or imbalances •  Deﬁciencies of monoamines (serotonin, dopamine, norepinephrine) cannot fully explain the underlying pathology in depression

¡ The secret ingredients… ¡ !mega-‐3 faEy acids and salicylate

Depression as disorder of chronic inﬂamma*on

Comprehensive Psychiatric Resources 203 Crescent St., Suite 110 Waltham, MA 02453 T: 781-647-0066 www.comprehensivepsychiatricresources.com

•  ùge gap between neuroscience research and clinical prac*ce •  bhen brain func*on is aggra/ated by any sourcesinfec*ons, trauma, stroke, poisons, stress, nutri*onal deficienciess ac*/a*on of microgliasimmune cells in the brainscauses inflamma*on

www.JamesGreenblattMD.com @JGreenblattMD The Breakthrough Depression Solution Blog on PsychologyToday.com

•  As microglia become more ac*/e, there is an increase in the release of inﬂammatory chemicals –  Cytokines, chemokines, and excitotoxins (glutamate, aspartate, quinolinic acid)

Find the books on Facebook: The Breakthrough Depression Solution Answers to Anorexia

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Common Denominators of Childhood Mental Illness

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Ron Hunninghake, MD

(earning /b1ec3ves 1.  Dis3nguish between !"#$%&'()*+,!-+)(and ./#&%0*.&'(1&/#"2*.&'(3$1)#)(-0(.22&#))4( 2.  Name two fundamental pathways for re-‐ establishing cellular health. 3.  Become familiar with the components of the acronym: I.D.E.N.T.I.F.Y. T.H.E. C.A.U.S.E.S. 4.  DeQne a “causal loop” and how it func3ons to perpetuate chronic illness. 5.  (earn to iden3fy four elements in any chronic illness, with special aVen3on given to “Wingpin” elements and “missing piece” elements.

Common Denominators of Childhood Mental Illness Ron Hunninghake, MD Chief Medical Oﬃcer Riordan Clinic

Diagnosis and Treatment in Childhood Psychiatry and Care of the Chronically Ill

A Right-‐Brain Methodology “A broader approach is needed that beVer addresses and corrects the underlying causes of chronic illness.”

•  Diagnosis is commonly based solely on the sub1ec3ve 1udgment of the clinician. •  Pharmacologic treatment has become the norm and is typically geared to treat illness symptoms. •  Reliability of this diagnos3c system is poor and long term results of care are tenuous at best. •  Treatment tends to promote polypharmacy. •  A broader approach is needed that beVer addresses and corrects the underlying causes of chronic illness.

My Goals •  For 17 years I served as a protégé of the late Dr. Hugh Riordan, learning his approach to chronic illness, both mental and physical. •  Dr. Hugh, a psychiatrist, was a past president of the American Holis3c Medical Associa3on •  Hugh and Dr. Abram Hoﬀer were close friends and medical_nutri3onal collaborators •  Hugh was instrumental in crea3ng www.orthomolecular.com

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The Riordan Approach Seven Precepts of Care

•  A`er Hughas passing on banuary 7, 2005, I aVempted to codify his approach to pa3ents •  The Riordan Approach is composed of

1. 2. 3. 4. 5. 6. 7.

THE SEVEN PRECEPTS OF CARE

•  These precepts are not unique to Dr. Riordan •  A SYNTHESIS of the best of allopathic, ortho-‐ molecular, naturopathic, holis3c, integra3ve, and common sense ideals in the care of human beings who are hur3ng and seeking help_hope.

The Riordan Approach

Doctor-‐Colearner Rela3onship Iden3fy the Causes Characterize Biochemical Individuality Care for the Whole Person Food as Medicine Cul3vate Healthy Reserves Healing Power of Nature

Riordan Clinic www.riordanclinic.org

Care for the Whole Person

Healing Power of Nature

Cultivate Healthy Reserves

Food As Medicine

Safety & Service

Characterize Biochemical Individuality Staff - Colearner Relationships

Identify The Causes

IDENTIFY THE CAUSES

Common Denominators of Illness •  Special Thanks: •  Ralph Golan, M.D.

Infec3ons Diges3on Thyroid Emo3onal Hypo-‐ Nutri3on glycemia Toxins Endocrine Inhamma3on Food issues You – Self care

–  5p%mal 6ellness

•  Ken Bock, M.D. –  Healing the New Childhood Epidemics

•  Sid Baker, M.D. –  “Diseases as Concepts”

•  Mark Squibb –  Whole Health Network –  “Control Loops”

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Candida Adrenal Under ac3vity Stress-‐Spiritual Environs Structural

Common Denominators of Childhood Mental Illness

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Reduce

Improve

IDENTIFY THE CAUSES Causes Needing To Be Reduced InfecIon

Reduce & Improve

EmoIons

Thyroid

US CA

Inﬂamed

Adrenal

UnderacIve

ved pro

EN T

@utriIon

Environs

CulIvaIng Healthy RelaIon-‐ ships

m e I

Stress

What YOU can do…

o B g T

Endocrine

Foods

Hypo-‐

glycemia

/igesIon

in ed Ne

s use Ca

Candida

Toxins

You

The Role of Healthy AarenIng

to promote PeQer self-‐care

Structural

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Toxins

Inﬂamed

ArotecIng

!educIon R Improvement

Inﬂamed

Adrenal

Hypo-‐

Stress

glycemia

Environs

UnderacIve

Structural

What is a Disease?

CorrecIng Causal Loops

1.  Western medicine typically reduces complicated paVerns called “symptoms” into mental constructs called “diseases.” 2.  Doctors work under the over-‐simpliﬁed assump3on that one disease has one cause and thus one cure…i.e. “parsimony.” 3.  Fn chronic diseaseU there are always mul3ple interlocking causes underlying the perpetua3on of any symptom/disease process…“illness.”

Cause 1

Cause 4

Toxins

Candida

Endocrine

CORRECT THE CAUSES

EmoIons

(Safety)

Thyroid

Understanding

Foods

You

NutriIon

ID EN TI FY T

EmoIons

EducaIng

In1ecIon

C HE

You Thyroid

DigesIon

(Predictability)

NutriIon

In1ecIon

Structure

CA US E

Nurturance

AarenIng

RR CO

The Causal Triangle

The Seven Core Causes

Cause 2

Cause 3

CORECT THE CAUSES

What is a Causal Loop?

CorrecIng Causal Loops

4.  A causal loop is a chain of causes that interact in

such a manner that supports the persistence of their ongoing existence. 5.  Every chronic illness is a locked loop causal chain linking 2 or more (o`en 4) biological dysfunc3ons into a self-‐reinforcing paVern. 6.  Discovering and correc3ng the core elements of a pa3entas “causal loop” is key to breaking the driving paVern of the illness and thus relieving the underlying structure of the pa3entas symptoms.

DigesIon

Throid

NutriIon In1ecIon

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Anatomy of a Causal Loop

CorrecIng a Causal Loop

7.  In a complicated chronic illness, there can be

11.  Typically the “kingpin” element will stand

as many as FOUR elements that are sustaining the causal loop. 8.  M key element is o`en ac3ng as the “kingpin” that is fundamentally driving the illness 9.  Mn “undeQned” or dipcult to iden3fy element can thwart resolu3on of the illness process i the so-‐called “missing piece.” 10.  It is wise to aVack at least THREE elements in a suspected causal loop.

out as a prime target to begin correc3on.

12.  THREE resolu3on “hits” will generally break the loop and resolve the illness.

13.  TWO “hits” with one resolving the “kingpin” will typically control the illness.

14.  ONE “hit” will only moderate the causal loop with the illness o`en stubbornly persis3ng.

CAUSAL LOOP: …a chain of causes that interact in /igesIon a manner that InfecIon supports the persistence Thyroid NutriIon of their EmoIons Toxins ongoing existence Inﬂamed Adrenal

The InfecIon Causal Loop

Seven Causal Loops 1.  2.  3.  4.  5.  6.  7.

InfecIon EmoIons Toxins Candida Hypoglycemia Stress Inﬂamed

1.  Infec3on 2.  3.  4.  5.  6.  7.

Note: Each Causal Loop is named for its Foods inverted yellow triangle Hypo-‐ Candida Stress glycemia except #7 Structural Endocrine UnderacIve Environs

Emo3ons Toxins Candida Hypoglycemia Stress Inﬂamed

Kingpin: 7iges3on

/igesIon InfecIon Thyroid

NutriIon

The EmoIons Causal Loop

The Toxins Causal Loop

1.  Infec3on

2.  Emo3ons 3.  Toxins

Kingpin: Nutri3on

NutriIon

Foods

Kingpin: Thyroid

Thyroid

3.  Toxins

EmoIons

4.  Candida 5.  Hypoglycemia

2.  Emo3ons

Toxins

4.  Candida 5.  Hypoglycemia

Inﬂamed

6.  Stress

7.  Inﬂamed

106

Inﬂamed

Adrenal

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Common Denominators of Childhood Mental Illness Ron Hunninghake, MD

The Candida Causal Loop 1.  In@ec3on

1.  In@ec3on

Kingpin: Foods

2.  Gmo3ons

The Hypoglycemia Causal Loop 2.  Gmo3ons

Foods

3.  Toxins 5.  Hypoglycemia

Endocrine

7.  Inﬂamed

The Stress Causal Loop

The Inﬂamed Causal Loop

GnderacIve

4.  Candida

6.  Stress

7.  Inﬂamed

In1ecIon Loop

The PRIME Causal Loop

Note: the

yellow triangle

/igesIon

deﬁnes the Causal Loop

In1ecIon NutriIon

Hypo-‐

glycemia

5.  Hypoglycemia

Structural

Toxins

Inﬂamed

3.  Toxins

Stress

4.  Candida

EmoIons

2.  Gmo3ons

Adrenal

3.  Toxins

GnderacIve

Environs

1.  In@ec3on

Kingpin: Adrenal

5.  Hypoglycemia

glycemia

5.  Hypoglycemia

Environs

6.  Stress

2.  Gmo3ons

Hypo-‐

4.  Candida

6.  Stress

1.  In@ec3on

Inﬂamed

3.  Toxins

Candida

4.  Candida

Kingpin: Inﬂamed

/igesIon Thyroid

Common in chronic childhood illness

In1ecIon NutriIon

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Thyroid

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Ron Hunninghake, MD Oaen the leading cause agent of the illness

The Kingpin of the Causal Loop /igesIon

The FOUR Elements of a Causal Loop Can Be Folded into a Tetrahedron •  One face of the tetrahedron is o`en hidden from view. •  O`en represents the “missing piece.”

InfecIon @utriIon

Each causal loop can have a “missing piece” that escapes your considera3on.

D N I

D N T

Thyroid

N I T

Using The Riordan Approach

I D T

• Sub1ec3ve à Listening • Ob1ec3ve à Measuring • Assessment à Iden3fying • Plan à Correc3ng Causal Loops

Ob1ec3ve: (CSI + ICYou) 3. Characterize Biochemical Individuality

Sub1ec3ve: (Detec3ve Work) 1. Doctor_Co-‐learner Rela3onship 2. IDENTIFY THE CAUSES

Connect ;ith the Pa3ent as Co-‐learner Comprehensive Assessment History Adecuate 3me for Intake Intensive Listening (Golden Rule) Use of a Causal Methodology

D N T

4. Care for the Whole Person

Various Measurement Instruments: 3 day diet diary i symptom 3ming Food Sensi3vity Tes3ng_Implementa3on Thyroid Panel and a Reverse T3 Example: Selenium (nutrient levels) Example: Hb a1c (conven3onal tests) Comprehensive Diges3ve Stool Analysis Glucometer readings Vitacheck C urine test strips Many more…

D N T

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D N T 7

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Mood Disorders: Anxiety Depression Bipolar Schizophrenia Opposi3onal Adjustment Rx ADD and ADHD

EmoIons Loop • Processed foods • Niacin dependent • Food sensi3vi3es • Leaky gut issues • Drug-‐Nutrient interac3ons • Allergies • Trauma Foods

@&triIon

Calorie-‐rich Nutrient-‐poor Comfort-‐ea3ng “Fun Foods”

EmoIons Loop High Glycemic Dismembered “Food”

EmoIons Inﬂamed

@&triIon

Ken Bock:

Inﬂamed

Disease •  •  •  •  •  •  •  •  •  •  •

A1%sm, ADHD, Asthma, Allergies

Toxins Adrenal

CFIDS Crohn’s

BOSI

IC DM2

MalaPsorpIon

Restless Leg

IBS

Alcoholism Schizophrenia Parkinson’s Pain med addic3on Hepa3c Steatosis Diabetes Obesity Food Sensi3vi3es PCOS Celiac Au3sm

Toxicant •  •  •  •  •  •  •  •  •  •  •

Alcohol Adrenochrome Pes3cide residues Narco3cs (street or prescribed) Fructose (corn syrup solids) Processed sugars Non-‐whole foods Nndigested pep3des Testosterone Gluten Mercury?… Gluten? … B.O.S.I.?

Common EDCs:

B.O.S.I. Hypo-‐ thyroidism

Inﬂamed

Sick? Or Intoxicated?

Healing the New Childhood Epidemics: Thyroid

% Wholeness Glycemic Load ORAC Score Omega 6/3

EmoIons

Foods

Toxins Loop

InﬂammaIon Index:

PCB’s and PBDE’s Bisphenol A Phthalates DDT Dioxin Heavy metals

•  Bacterial Overgrowth of the Small IntesIne •  Chronic Fa3gue Syn. •  Fibromyalgia •  IBS / Malabsorp3on •  Osteoporosis •  Autoimmune Disease •  Thyroid disorders •  Candidiasis •  Inters33al Cys33s •  Restless Leg Syndrome •  Crohn’s Disease •  Diabetes Mellitus 2

–  Mercury –  Lead –  Arsenic

Endocrine Disruptors:

Thyroid

Preserva3ves Pes3cides Plas3cs Pharmaceu3cals (feed an3bio3cs) Heavy metals Pollutants Hormones Gene3c ModiQers

Toxins Inﬂamed

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Adrenal

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Thyroid as Kingpin

Candida Loop

Pituitary

Thyroid

TSH Toxins Inﬂamed

Thyroid

Adrenal

@egaIve Feedback Loop

5’

eio Stress din StarvaIon ase en Adrenal 1aIgue zym Chronic illness e Metal toxicity Key deﬁciencies ors t i -‐selenium ib Inh -‐vitamin D -‐others

T4 – less acIve Reverse T3

Foods

.&$3%B#

Candida

Inhibits 1uncIon

T3 – acIve

Endocrine

Candida Loop The 5pportunisIc Germ High CorIsol Stress

Environs

Hypoglycemia Loop Foods Poor Gut Flora

Candida

Endocrine

Inﬂamed Hypo-‐

Environs

glycemia

Environs

Hypoglycemia Loop

UnderacIve

Stress Loop Inﬂamed Hypo-‐ glycemia

Environs

Adrenal Stress

Under-‐ acIve

UnderacIve

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Structural

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Stress Loop Underac3ve

• Sedentary • Under-‐ challenged • Sleep disorder • Obesity • Fa3gue Under-‐ acIHe

Adrenal as Kingpin

• Broken Family • Parents working • Financial stress • Poverty • School issues • Peer pressure

Adrenal

Adrenal Stress

UnderacIHe

Structural

Stress Structural

Name one chronic disease that does not involve inhamma3on.

Inﬂamed Loop

=moIons

Inﬂamed

Inﬂamed Loop

Adrenal

Hypo-‐

glycemia

Ancestral Diet

Agricultural Industrial Diet Diet

% Wholeness

100%

90%

50%

30-40%

Glycemic Load

Very low

Medium

High

Very High

ORAC Score

Very high

Medium

Low

Very Low

Omega 6:3

1:1

5:1

10:1

> 20:1

Hypo-‐ glycemia

InﬂammaIon Index: % Wholeness Glycemic Load ORAC Score Omega 6/3

Dr. Andrew Weil’s An3-‐inhammatory Food Pyramid

The Inﬂammatory Index over Time Inflammatory Regulators

Toxins

=moIons

Toxins

Inﬂamed

•  Lack of vitality •  Chronic stress •  “Growing pains” •  Hypoglycemia •  Stomach aches •  Headaches •  Sleep disturbances •  Poor memory •  Food sensi3vi3es •  Learning disorders •  Low body temp •  Chronic worry •  Panic AVacks

Modern Diet

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Diﬃcult Pa3ents

DigesIon

Core Loop InfecIon

InfecIon

You

@utriIon

Thyroid

@utriIon

Thyroid

EmoIons

Toxins

EmoIons

Toxins

Inﬂamed

Inﬂamed Hypo-‐

glycemia

The Seven Core Causes

Severe Chronic Illness

Requires an Upward Spiral of CorrecIon

DigesIon InfecIon @utriIon

Thyroid

EmoIons

Toxins

Foods

Inﬂamed

Adrenal

Candida

Hypo-‐

Stress

Endocrine

glycemia

Environs

Using The Riordan Approach

• Su01ec3ve à Listening • O01ec3ve à Measuring • Assessment à Fden3fying • Plan à Correc3ng Causal Loops

Structural

UnderacIve

Plan: (Correc3ng is a process…) 5. Food as Medicine

Health Care Reform is…

6. Cul3vate Healthy Reserves 7. Healing Power of Nature

Doctor (& staﬀ) as Teachers: • No one gets 0eVer without ea3ng 0eVer • Focus on colorful, whole foods • Do not stack sensi3ve foods at one meal • Use supplements to supplement diet • Healthy Reserves include sleep, ﬁtness, friends, health care team, fun ac3vi3es, spiritual resources, and HOPE! • “We don’t treat_________ , we treat kids who happen to have ________.”

D N T

Self

InfecIon

Foods

You

@utriIon

Thyroid

EmoIons

Toxins

Inﬂamed

Adrenal

Hypo-‐

Stress

Candida Endocrine

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(Parent)

DigesIon

glycemia

Environs

UnderacIve

Care Reform

Structural

Common Denominators of Childhood Mental Illness

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Ron Hunninghake, MD

The Riordan Approach Seven Precepts of Care 1. 2. 3. 4. 5. 6. 7.

7octor-‐Colearner Yela3onship Iden3fy the Causes Characterize Biochemical Individuality Care for the Whole Person Food as Medicine Cul3vate Healthy Yeserves Healing Power of Nature

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Why Integrative Psychiatry is Vital Now

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Mary Braud, MD

Objec2ves •  Review data on trends in medica2on use •  Review conven2onal diagnos2c protocol in psychiatry and discuss limita2ons •  Examine other factors that contribute to emo2onal and behavioral challenges •  Provide sugges2ons for addressing these challenges •  Discuss how nutri2onal support can be integrated with therapy for the child or family while minimiNing the use of psychotropic medica2on.

Why Integra2ve Psychiatry is Vital Now Looking Beyond Diagnosis to Treat the Whole Child

The Startling News

Rising Use of An2psycho2cs

•  The Na2onal Ambulatory Medical Care Survey published in 2006 found that use of psychotropic medica2ons for teens increased 250 percent between 1994 and 2001. •  In 2001, one in every 10 oﬃce visits for a boy resulted in a prescrip2on for a psychotropic drug.

•  The number of oﬃce visits where an2psycho2c medica2ons were used increased from about 201,000 in 1993 to 1,224, 000 in 2002. Olfsen M, Blanco C, Liu L, Moreno C, Laje G. Na2onal Trends in the Outpa2ent Treatment of Children and Adolescents With An2psycho2c Drugs, 2006. Arch Gen Psychiatry 2006;63:679-‐685

Thomas CP, Conrad P, Casier R, GoodmanE. Trends in the Use of Psychotropic Medica2ons among Adolescents, 1994-‐2001. Psychiatry Services 2006;57(1):63-‐9

Polypharmacy Rising

Diagnosis in Psychiatry

•  Data from the 1996-‐2007 Na2onal Ambulatory Medical Care Survey reveals an increase in the percentage of child visits involving medica2ons from two or more classes, from 14.3% of psychotropic visits (1996-‐1999) to 20.2% (2004-‐2007). •  The combina2on of ADaD medica2ons with an2psycho2c medica2ons and an2depressants with an2psycho2c medica2ons also increased over the twelve year period.

•  Objec2ve data is not used to diagnose mental illness. •  Diagnosis is based on the personal judgment of the clinician and is subjec2ve. •  Gathering collateral informa2on can be 2me consuming but is very important to do. •  Reliability of this diagnos2c system is very poor.

Comer J, Olfson M, Mojtabai R. Na2onal Trends in Child and Adolescent Psychotropic Polypharmacy in Oﬃce-‐Based Prac2ce, 1996-‐2007. J Am Acad Child Adolesc Psychiatry 2010 October;49(10: 1001-‐1010.

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The Downsides of Diagnosis

•  Educate families about the limita2ons of diagnosis •  Encourage hope •  Zse the process of evalua2on to encourage careful observa2on and increased understanding of the child and the family (gathering data can foster communica2on] •  Zse trusted referral sources to gather addi2onal informa2on and assessments such as occupa2onal therapy evalua2on, educa2onal assessments and neuropsychological tes2ng

•  Diagnos2c labels tend to s2ck. •  Once a diagnosis is given, treatment approaches can become more narrow. •  Children label themselves as sick or broken when given a diagnosis.

Moving Beyond the DSM

The Role of Rela2onships •  Infants and young children need responsive, aduned caretakers. •  Many factors can interfere with a parent’s ability to provide this type of nurturing. It is es2mated that 1/3 adults have avoidant, ambivalent or resistant adachment paderns. •  Parental depression or stress can interfere with the development of secure adachment. •  Parents who have adachment challenges are likely to transmit the same to their children. •  Outside of the home, other adults need to be aduned also.

Some of the factors involved in the crea2on of emo2onal or behavioral challenges are: •  Rela2onships •  Stress •  Trauma •  Sensory processing diﬀerences

Ghosts in the Nursery

Paren2ng (isdom

gThere is a direct connec2on between how past experiences have shaped implicit memory and how they are reac2vated in the context of being with a child. If parents do not recognize this link, then they are at risk of enac2ng, without conscious awareness, learned behaviors and emo2onal responses that will dominate their behaviors and create their children’s adachment experiences.”

•  gParen2ng is the self-‐improvement experience that your kids trick you into taking.” Rev. Barry Ebert

D. J. Siegel, M. Hartzell. !"#$%&%'()#*+(,-$(.%/01$(23,4(New York: Jeremy P. Tarcher/Penguin, 2003

Mary M. Braud, MD 303-‐721-‐2901

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Suppor2ng 4arents

Stress in the Home

•  Helping parents understand themselves and their reac2ons to their child is incredibly valuable. •  We can educate parents about adachment and temperament in order to improve adunement. •  A healthier and happier parent can provide far more support than any therapist.

•  Children of all ages can be nega2vely ecected by stress no mader the cause. •  Marital discord, ﬁnancial challenges, illness and having a child with emo2onal challenges are poten2al sources of stress at home. •  =owering the stress response requires 2me, ecort and rela2onship. •  Stress and fear are the primary sources of nega2ve behaviors.

Stressed Children

School Can Be Stressful!!!!

•  Children are exquisitely sensi2ve to parental stress. •  Children olen don’t have the capacity to regulate the stress they experience. •  Gegula2on is rela2onship-‐dependent. •  Dysregula2on is the cause of all nega2ve behavior. •  If you want calmer kids, learn how to calm yourself.

•  Schools are required to place greater emphasis on academics. •  Most schools neglect the emo2onal needs of children. •  It is more important to create safety, trust and the ability to calm down than it is to learn how to read a book. •  When under stress, you can’t learn. You forget what you know and don’t remember what you are doing. •  Some school senngs Fust aren’t right for some children. •  Children don’t always act out at school but can exhibit behavior problems at home instead.

Dialing Down the Stress

Understanding Trauma •  Trauma is any event that is-‐ 1.  Unexpected 2.  Overwhelming 3.  Violent 4.  Threatening to a sense of safety 5.  Creates a feeling of terror

•  Breathing prac2ces, such as 4-‐7-‐8 breathing can be done with children. Inhale while coun2ng to 4, hold the breath for a count of 7, then exhale slowly for a count of 8. •  Yawning is a silly, but powerful, technique. •  There are a number of audio programs that have relaxa2on prac2ces for children of all ages. •  Gituals, such as ea2ng together or reading stories, are also soothing for stressed children.

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Trauma in Children

Trea2ng Trauma

•  Trauma during childhood can lead to changes in brain structure and func2on. •  The hippocampus and amygdala are par2cularly vulnerable. •  Abnormal ﬁring of the amygdala has a nega2ve impact on the development and func2on of the frontal cortex. •  The symptoms of trauma can easily be mistaken for those of other disorders. •  The sources of trauma include bullying, death, and abuse.

•  The elements needed to recover from trauma include: 1.  2.  3.  4.  5.

Safety Nurturance Stability Predictability Understanding

•  The Child Trauma Academy is a powerful resource for educa2ng families and professionals about the eﬀects of trauma and how to treat it.

Sensory Processing Diﬀerences

Addressing Sensory Diﬀerences

•  Dver-‐ or under-‐sensi2vity to touch, taste, smell, sound or sight can manifest as avoidance, deﬁance, or sensory seeking. •  Dver-‐ or under-‐sensi2vity to movement sensa2ons can result in either excessive or restricted movement. •  Unusually high or very low ac2vity levels can be seen. •  Problems with motor coordina2on are possible.

•  Start with screening •  pormal tes2ng to clarify •  Dccupa2onal therapy for treatment

C. S. Kranowitz. The Out-‐of-‐Sync Child. New York: Perigree, 1998

Punng it Together

Laboratory Assessment

•  A detailed assessment is the star2ng point. •  The process begins with interviews of the parents and child. Separate interviews for young children are suggested. •  +nclude teens in the conversa2on with their parents. •  Phone calls to therapists, schools and other professionals are strongly suggested to gather addi2onal informa2on.

•  The basics-‐CBC, chemistry proﬁle, thyroid assessment (for depression), Vitamin D, ferri2n, GCB magnesium, zinc •  Next level-‐Drganic acids, fady acid proﬁle, diges2ve tes2ng , food sensi2vi2es, serum amino acid levels •  Ter2ary tes2ng-‐aeavy metals, mineral levels.

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Star2ng Treatment

The Basic Plan

•  Dietary changes are olen indicated with many families needing to increase intake of fruits and vegetables, increase protein intake, and lower refined sugars. •  Elimina2on diet discussed at least brieqy at first visit. Tes2ng can also be reviewed and offered. •  Ac2vity is suggested when needed. •  Relaxa2on techniques taught during session and other resources provided. •  Referrals for other assessments given in this or subsequent visits.

•  Fady acid supplementa2on with 500 mg EPA and DHA •  Vitamin D minimum of 1,000 IU or higher if lab indicated •  B vitamin supplementa2on with speciﬁc methyla2on support ( methyl B12 and methyl folate) if indicated per organic acids •  An2oxidant support with vit A 5,000 IU, and Vitamin C (buﬀered) as tolerated.

The Basics Cont’d

ADHD

•  Mineral supplementa2on including:

•  Pycnogenol 1 mg/kg

–  zinc 15 to 30 mg –  iron if ferri2n below 30 mg/ml in doses of 1 mg/ kg to 3 mg/kg –  selenium 100 mcg –  magnesium citrate or glycinate star2ng at 100 mg

Treba2cká J, Kopasová S, Hradecná Z, Cinovský K, Skodácek I, Suba J, Muchová J, Zitnanová I, Waczulíková I, Rohdewald P, Duracková Z. Treatment of ADHD with French mari2me pine bark extract, Pycogenol. Eur Child Adolesc Psychiatry. 2006 Sep;15(6): 329-‐35. Epub 2006 May 13. [PubMed 16699814]

Lahat E, Heyman E, Livne A, Goldman M, Berkovitch M, Zachor D. Iron deﬁciency in children with aden2on deﬁcit hyperac2vity disorder. Isr Med Assoc. J. 2011 Sep;13 (9):520-‐3. [PubMed 21991711]

Dvoráková M, Sivonová M, Treba2cká J, Skodácek I, Waczuliková I, Muchová J, Duracková Z. The effect of polyphenolic extract from pine bark, Pycnogenol on the level of glutathione in children suffering from aden2on deficit hyperac2vity disorder (ADHD). Redox Rep. 2006;11(4):163-‐72 [PubMed 16984739]

Huss M, Völp A, Stauss-‐Grabo M. Supplementa2on of polyunsaturated fady acids, magnesium and zinc in children seeking medical advice for aden2on-‐deﬁcit/ hyperac2vity problems v an observa2onal cohort study. Lipids Health Dis. 2010 Sep 24;9:105 [PubMed 20868469]

Follow Up

Addressing Anxiety and Depression

•  Pa2ents usually return in 4 to 6 weeks, sooner if symptoms have been more concerning. •  Follow-‐up sessions may include family or focus on the child/teen. •  Children or teens can be seen for psychotherapy. •  Further contact with school or therapists is olen needed to co-‐ordinate care.

Amino acids for anxiety and depression

•  5-‐HTP 25 to 50 mg at bed2me •  5-‐HTP 25 to 50 mg in the morning and mid-‐day when symptoms are more pronounced •  Gaba support for anxiety including Gaba, taurine, theanine, inositol, glycine •  L-‐tyrosine to support catecholamines and thyroid •  Amino acid support can be guided by lab results when available.

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Results

Resources-‐Books

•  Happy families! •  Children and teens with mild to moderate anxiety and depression usually respond quickly and well to this approach. •  Where there is a history of trauma, adop2on, signiﬁcant mood lability or other co-‐ morbidi2es, results may take more 2me and a greater level of support.

Paren2ng D. J. Siegel, M. Hartzell. Pa#en&ng f#o+ the .nside Out. New York: Jeremy P. Tarcher/Penguin, 2003 S. Shannon; E. Heckman. Please Don’t Label My Child. New York: Rodale, 2007 L. Lan2eri. Building B+o&onal .ntelligence. Boulder: Sounds True, Inc., 2008

Resources -‐ Books

Resources -‐ Ar2cles

Trauma

B. Perry. The Boy Who Was Raised as a Dog. New York: Basic Books, 2006

Sensory Processing C. S. Kranowitz. The Out-‐of-‐Sync Child. New York: Perigree, 1998

Resources v Ar2cles

Resources -‐ Ar2cles

Lahat E, Heyman E, Livne A, Goldman M, Berkovitch M, Zachor D. Iron deﬁciency in children with aden2on deﬁcit hyperac2vity disorder. Isr Med Assoc. J. 2011 Sep;13(9):520-‐3. [PubMed 21991711]

Oner O, Oner P, Bozkurt OH, Odabas E, Keser N, Karadag H, Kizilgün M. Eﬀects of zinc and ferri2n levels on parent and teacher reported symptom scores in aden2on deﬁcit hyperac2vity disorder. Child Psychiatry Hum Dev. 2010 Aug;41(4):441-‐7. [PubMed 20238159]

Shannon S. Integra2ve Approaches to Pediatric Mood Disorders. Altern Ther Health Med. 2009;15(5):##.)

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Resources -‐ Ar2cles

Viktorinova A, Breba2cká J, Paduchova Z, Ursinyova M, Uhnakova I, Masanova V, Duracková Z. Natural polyphenols modify trace element status and improve clinical symptoms of aden2on-‐ dejcit hyperac2vity disorder. ?iomed Pharmacother. 2009 Oct 20. Epub ahead of print. [PubMed 19875267]

Huss M, Völp A, Stauss-‐Grabo M. Supplementa2on of polyunsaturated fady acids, magnesium and zinc in children seeking medical advice for aden2on-‐ dejcitfhyperac2vity problems v an observa2onal cohort study. Lipids Health Dis. 2010 Sep 24;9:105 [PubMed 20868469]

Resources -‐ Ar2cles Breba2cká J, Kopasová S, Hradecná Z, Cinovský K, Skodácek I, Suba J, Muchová J, Zitnanová I, Waczulíková I, Rohdewald P, Duracková Z. Breatment of ADHD with prench mari2me pine bark extract, Pycogenol. Eur Child Adolesc Psychiatry. 2006 Sep;15(6):329-‐35. Epub 2006 May 13. [PubMed 16699814]

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Treating the Hyperactive Child without Drugs

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Jonathan Prousky, ND, MSc

Part 1. The medicaliza%on of ADHD and the use of psychos%mulant medica%ons

Trea%ng The Hyperac%ve Child Without Drugs Jonathan E. Prousky, ND, MSc Editor, Journal of Orthomolecular Medicine Chief Naturopathic Medical Oﬃcer Professor, Canadian College of Naturopathic Medicine

The rise and rise of ADHD (Timimi 2005)

Some sta%s%csT

The construct of ADHD has become common place in the community ¢  Anyone can make a provisional diagnosis of ADHD ¢  It has become a self-‐fulﬁlling process ¢  The medical explanatory model has enormous cultural power ¢  ADHD has become a convenient diagnos%c dumping ground

¢

Psychos%mulant medica%ons have been used to treat problems associated with ADHD for more than 50 years ¢  Current es%mates suggest that 4-‐12% of WS youth have ADHD (see Christakis 2004 for sources) ¢  Some 3 million youth are on psychos%mulant medica%ons in the WS

Are psychos%mulant medica%ons e]ec%ve^ In Canada, the es%mated prevalence of prescribed psychos%mulant medica%ons and ADHD diagnosis is less than 3%, but the percentage of school-‐age children prescribed psychos%mulant medica%ons for ADHD went from 43% in 2000 to 59% in 2007 (Brault 2012) ¢  The es%mated worldwide pooled prevalence of ADHD among those 18 years of age or younger is 5.29% (Polanczyk 2007)

¢

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Are psychos%mulant medica%ons safe (Breggin 1999)? ¢

This review (Charach 2011) noted the following about interven%ons: l  Parent behavior training had the best Strength of Evidence (SOE) for improving child behaviour l  A single good quality study on methylphenidate yielded low SOE for improving child behavior and for reducing symptoms l  Evidence from a single good quality study of atomoxe%ne demonstrated low SOE for symptom reduc%on l  Evidence from a single good quality study of combined psychos%mulant medica%on with behavioral/psychosocial interven%ons provided low SOE

They produce a con%nuum of central nervous system toxicity that begins with increased energy, hyper-‐alertness, and over-‐focusing on rote ac%vi%es These toxic reac%ons progress toward obsessive bcompulsive or persevera%ve ac%vi%es, insomnia, agita%on, hypomania, mania, and some%mes seiEures ¢

¢

¢  Their use commonly results in apathy, social withdrawal, emo%onal depression and docility ¢  They also cause physical withdrawal including rebound (about 5-‐10 hours acer the last s%mulant dose) and dependence

¢  They inhibit growth, and produce various

cerebral dysfunc%ons, some of which can become irreversible ¢  Their therapeu%c eﬀects are a direct expression of their toxicity

(Swanson 2003) ¢

@ot unusual for psychos%mulant adverse drug reac%ons to be poten%ally misiden%ﬁed as therapeu%c or beneﬁcial among children diagnosed with ADHD (data derived from 20 controlled clinical trials): l

¢  When used to treat children with ADHD,

methylphenidate acts primarily by blocking the dopamine transporter and increasing extracellular dopamine in the striatum, a mechanism that is strikingly similar to the mechanism of ac%on of cocaine

l  deduced social interac%ons, talking, or sociability Decreased responsiveness to parents and other children l  Increased solitary play l  Diminished play l  Compliance, especially in structured environments l  Depressed, sad, easy/frequent crying

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(Breggin 2000) ¢  …by suppressing emo%onal and

¢  …more eﬀort should be made to

behavioural signals of distress and conﬂict, s%mulants allow adults to ignore the needs of children in favour of crea%ng a controlled environment.

iden%fy and to address the genuine individual needs of the children in our families and schools whether or not they are signalling their distress or conﬂict with ADHD-‐like behaviours.

Bart 2. Trea%ng the hyperac%ve child without drugs

Vitamins

(Hoﬀer 1971) This single-‐blind trial assessed the therapeu%c eﬀects of administering niacin or niacinamide to children under 13 years of age ¢  The diagnoses of these children varied; most had hyperac%vity ¢  Thirty-‐eight children entered the study in 1967, but 6 could not complete the required three-‐year study period

All children were given 1500-‐6000 mg of niacinamide, or rarely, niacin, if there was no response to the niacinamide. ¢  Each child also took 3000 mg of ascorbic acid daily, and rarely, very small doses of tranquilizers or an%depressants ¢  Acer the child recovered, vitamin B3 was discon%nued and the child con%nued with an equivalent dose of placebo, along with ascorbic acid and very small doses of tranquilizers or an%depressants (if previously prescribed) ¢  Each child was kept on placebo un%l heashe relapsed, at which point the parents resumed the vitamin B3 treatment.

¢

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(Hoﬀer 2004)

¢

At the conclusion of the trial in 1974, he had a cohort of 37 children to report on. ¢  Out of 37 children in total, 19 were normal, 6 were much improved, 3 were not improved, and the results for 9 were not known ¢  Thus, 25 out of 37 children (68%) were normal or much improved by the addi%on of niacinamide or niacin

¢  Of the 32 children in the study, 24 went through the treatment-‐placebo-‐treatment cycle. Only Hoﬀer and the children’s’ parents were privy to the exact treatment, but the children were blinded In all 24 cases, the children recovered while taking vitamin B3, then relapsed within one month of taking placebo, and recovered again when resuming vitamin B3. ¢  The remaining 8 pa%ents in this study were almost recovered, and had yet to be placed on placebo

¢

(Hoﬀer 2004) ¢  Study of i110j pa%ents

¢  If you take only those children where their behaviour was rated before and at ﬁnal evalua%on, than 53 out of 84 (63%) were much improved or well at ﬁnal evalua%on ¢  If children that simply improved were also added to the above cohort, than 70 out of 84 (83%) responded to treatment

(Brenner 1982) ¢ Brenner conducted 2 complex

¢  In 1982, Dr. Arnold Brenner reported on his experiences with 100 youth (ages 4-‐15) given brief therapeu%c trials with single doses of specific B-‐ complex vitamins ¢  The majority of youth had a diagnosis of MBD with hyperkinesis, alen%on span deficit, distrac%bility, impulsivity, emo%onal instability and learning deficits. ¢  The majority of youth were on s%mulant medica%on (i.e., d-‐amphetamine or methylphenidate), which was discon%nued prior to clinical trials with specific B-‐complex vitamins

single-‐blinded controlled trials. ¢ In all cases, the parents and youth were blinded, but not Brenner

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(Shaw 2010) 9/:"%&;<5$='8;5&$#7-8'">'$5<"#? B vitamins are structurally similar to methylphenidate, i.e., a dopamine analogue. B vitamins might also func%on as dopamine analogues and bind to the dopamine transporter, leading to a concomitant increase in synap%c dopamine concentra%on, which in turn might ac%vate the postsynap%c dopamine receptor and thus ameliorate the symptoms of ADHD

¢  From the responder group, 20 out of 60

¢

youth (33%) had sustained clinical responses from the long-‐term use of B-‐ vitamins ¢  Nf one uses the en%re group, than 20 out of 100 youth (20%) had sustained clinical responses from the long-‐term use of individual B vitamins

3,=<:=;'67%$87#'@'37#;+$='A7);)0' 375+"#,%+7;#%B'4,::=;8;#%$<"#'

(Kaplan 2004) ¢

Children with mood and behavioral problems (N = 11; 7 boys, 4 girls; 8-‐15 years old) par%cipated; 9 completed this open-‐label trial. For the 9 completers, improvement was sta%s%cally signiﬁcant on seven of the eight Child Behavior Checklist scales, as were the other ra%ng scales, i.e., the pouth =utcome ques%onnaire , and the poung ?ania Ra%ng Scale (p values for all ra%ng scales from 0.05-‐0.001). The eﬀect sizes for all the outcome measures were large.

(Rucklidge 2010)

¢

¢  The effect sizes of this broad interven%on, encompassing a vast amount of micronutrients, was likely larger that effect sizes from individual nutrients ?ood lability and its behavioural manifesta%ons might be manifesta%ons of metabolic deficiencies in essen%al neurobiological pathways

¢

125

A database analysis of 41 children with ADHD taking a broad-‐spectrum nutri%onal supplement, found a signiﬁcant improvement in symptoms over a 6-‐month period ¢  76% of pa%ents eQperienced a r 30% reduc%on in symptoms from their baseline scores ¢  63% of pa%ents eQperienced a r 50% reduc%on in symptoms from their baseline scores

Treating the Hyperactive Child without Drugs

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Jonathan Prousky, ND, MSc

Diet

(Niederhofer 2011) Celiac disease is markedly overrepresented among pa%ents presen%ng with ADHD ¢  =f the 6Z pa%ents with ADHD, 10 were posi%ve for celiac disease. Acer ini%a%on of the gluten-‐free diet, pa%ents or their parents reported a signiﬁcant improvement in their behaviour and func%oning compared to the period before celiac diagnosis and treatment

¢  …diet modiﬁca%on plays a makor role in

¢

the management of ADHD and should be considered as part of the treatment protocol (Schnoll 2003)

(Pelsser 2011) The restricted eli8ina<"n diet* had a significant beneficial effect on ADHD symptoms in 32 (64%) of 50 children, and reintroducing foods led to a significant behavioural relapse in clinical responders

¢  Blood tests assessing IgG levels against

¢

foods did not predict which foods might have a deleterious behavioural effect. The effect of the diet was consistent and had a similar effect in reducing both ADHD and opposi%onal defiant disorder symptoms

*Denotes: dice, turkey, lamb, a range of vegetables (leluce, carrots, cauliﬂower, cabbage, beet), pears and water, plus potatoes, fruits, and wheat

(Johnson 2011)

(Nigg 2012)

¢  Reduce sugar intake: …the chronic eﬀects of excessive sugar intake may lead to altera%ons in mesolimbic dopamine signaling, which could contribute to the symptoms associated with ADHD

¢  GH"idance "> ar<Icial >""d c"l"rs? An es%mated \% of children with ADHD may have symptoms related to synthe%c food colours. This meta-‐analysis concluded that the eﬀects of food colors were notable were but suscep%ble to publica%on bias or were derived from small, non-‐generalizable samples

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Exercise

(Taylor 2009) Children with ADHD concentrated beler acer the walk in the park than acer the downtown walk (p = .0229) or the neighbourhood walk (p = .0072). Eﬀect siEes were substan%al and comparable to those reported for recent formula%ons of methylphenidate ¢  Twenty minutes in a park seung was suAcient to elevate alen%on performance. vDoses of naturev might serve as a safe, inexpensive, widely accessible new tool in therapeu%c management of ADHD symptoms

¢

(Gapin 2010)

(Hill 2011)

¢  Eighteen boys (M age = 10.61, SD = 1.50)

¢  Exercise interven%ons have a posi%ve

with ADHD were recruited to complete four execu%ve func%on (EF) tasks. Moderate-‐to-‐vigorous intensity physical ac%vity was posi%vely associated with various EF measures (p<0.05). These results suggest that higher physical ac%vity is associated with beler EF performance in ADHD children

eﬀect (with variable magnitude) on cogni%ve performance. These eﬀects are not moderated by sex, ADHD symptom level, or BMI

(Change 2012)

Television

¢  Forty children with ADHD were randomly assigned into exercise or control groups. Bar%cipants in the exercise group performed a moderate intensity aerobic exercise for 30 min, whereas the control group watched a running/ exercise-‐related video. Neuropsychological tasks were assessed before and acer each treatment. The results showed that aerobic exercise improved neuropsychological tasks ¢  Exercise helps by alloca%ng alen%on resources, ineuences the dorsolateral prefrontal cortex, and is implicated in exercise-‐induced dopamine release. These ﬁndings support the eAcacy of exercise on execu%ve func%on

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(Christakis 2004) ¢  Authors hypothesized that very early eQposure to television (TV) during cri%cal periods of synap%c development would be associated with subsequent alen%onal problems ¢  Children watched an average of 2.2 hours of TV per day at age 1 and 3.6 hours per week at age 3

¢  A 1-‐SD increase in the number of hours of

Sleep

(Jan 2011)

TV watched at age 1 was associated with a 28% increase in the probability of having alen%onal problems at age Z ¢  Stated diﬀerently -‐ there was a 9% increase in the risk of alen%on problems for each daily hour of television watching

¢  Children with ADHD symptoms: more

night waking, diAculty ini%a%ng sleep, bed%me resistance, and day%me sleepiness compared with normal control subjects

¢  Parent’s report: Children with ADHD were reported to have signiﬁcantly more bed%me resistance, longer sleep onset latency, shorter sleep dura%on, more parasomnias, more night waking, and higher level day%me sleepiness

¢  Comorbidity: Children who have ADHD

comorbid with other disorders reported to have longer sleep dura%on, more diAculty with sleep onset, more bed%me resistance, more diAcul%es awakening in the morning, and more nocturnal ac%vi%es during sleep

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(Noble 2011)

(Lyon 2011)

¢  iTimplementa%on of consistent rou%nes,

¢

especially those related to bed%me, may be a key factor in facilita%ng improved sleep among children who display behaviors consistent with ADHD”

A randomized, double-‐blind, placebo-‐controlled trial was conducted on 98 boys, ages 8-‐12 years, with a diagnosis of ADHD ¢  400 mg daily of L-‐theanine was safe and eﬀec%ve in improving some aspects of sleep quality in boys diagnosed with ADHD. L-‐ theanine may represent a safe and important adjunc%ve therapy in childhood ADHD

(Hoebert 2009)

(Dendz 2010)

Long-‐term melatonin treatment was judged to be eﬀec%ve against sleep onset problems in 88V of the cases. Improvement of behaviour and mood was reported in 71V and 61V respec%vely. We conclude that melatonin remains an eﬀec%ve therapy on the long term for the treatment of chronic sleep-‐onset insomnia in children with ADHD and has no safety concerns regarding serious adverse events or treatment related co-‐morbidity

¢  Studies included children 6-‐14 years old and melatonin doses ranged from 3-‐6 mg administered within a few hours of a scheduled bed%me ¢  In all studies, adverse events were transient and mild ¢  Available data suggest that melatonin is a well-‐ tolerated and eAcacious treatment op%on for paediatric pa%ents with chronic sleep-‐onset insomnia and ADHD

¢

References

A beler approach N#%;+H;#<"#'

N#-%+,5<"#-'

B-‐vitamins (with folic acid and zinc if necessary); micronutrient formula

• Niacinamide (1500-‐3000 mg/day) • Vitamin B6 (300-‐1000 mg/day) • Vitamin B1 (400 mg/day) • Vitamin B5 (500 mg/day) • Best to use op%mal doses of niacinamide in combina%on with a B-‐complex that is high in vitamin B6 (e.g., B-‐Complex #6 by Thorne Research) • Micronutrient formula (e.g., EMP+)

Diet Modiﬁca%ons

¢

• Gluten-‐free (if celiac disease diagnosed) • Reduce or eliminate reﬁned sugars • Elimina%on diet • Elimina%on of ar%ﬁcial food colours

¢

Exercise

• 20-‐minute walk in the park 3-‐5 %mes/week (weather permiled) • 30-‐minutes of moderate-‐to-‐vigorous aerobic ac%vity 3-‐5 %mes/ week

¢

Television

• Limit TV to 20-‐30 minutes/day un%l 7 years of age

¢

Sleep

• Implement consistent bed%me rou%nes • 200 mg of L-‐theanine twice daily • 3-‐6 mg of prolonged-‐release melatonin 60-‐minutes prior to bed

129

Bendz LM, Scates AC: Melatonin treatment for insomnia in pediatric pa%ents with alen%on-‐deficit/hyperac%vity disorder Ann Pharmacother, 2010;44:185-‐191. Brault MC, Lacourse E: Prevalence of prescribed alen%on-‐ deficit hyperac%vity disorder medica%ons and diagnosis among Canadian preschoolers and school-‐age children: 1994-‐2007. Can J Psychiatry, 2012;57:93-‐101. Breggin PR: Psychos%mulants in the treatment of children diagnosed with ADHD: risks and mechanisms of ac%on. Int J Risk Safety Med, 1999;12:3-‐25. Breggin PR: What psychologists and psychotherapists need to know about ADHD and s%mulants. Changes: Inter J Psychol Psychother, 2000;18:13-‐23. Brenner A: The effects of megadoses of selected B complex vitamins on children with hyperkinesis: controlled studies with long-‐term follow-‐up. J Learn Disabil, 1982;15:258-‐264.

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Chang YK, Liu S, Yu HH, et al: Effect of acute exercise on execu%ve func%on in children with alen%on dePcit hyperac%vity disorder. Arch Clin Neuropsychol, 2012;;27::225-‐237. ¢  Charach A, Dash% B, Carson P, Booker L, Lim CG, Lillie E, Yeung E, Ma J, Raina P, Schachar R: Alen%on DePcit Hyperac%vity Disorder: Effec%veness of Treatment in At-‐Risk Preschoolers; Long-‐Term Effec%veness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Oct. Report No.: 12-‐EHC003-‐EF. AHRQ Compara%ve Effec%veness Reviews.

Gapin J, Etnier JL: The rela%onship between physical ac%vity and execu%ve func%on performance in children with alen%on-‐dePcit hyperac%vity disorder. J Sport Exerc Psychol, 2010;32:753-‐763. ¢  Hoebert M, van der Heijden KB, van Geijlswijk IM, et al: Long-‐ term follow-‐up of melatonin treatment in children with ADHD and chronic sleep onset insomnia. J Pineal Res, 2009;47:1-‐7. ¢  Hoﬀer A: Vitamin B3 dependent child. Schizophrenia, 1971;3:107-‐113. ¢  Hoﬀer A: Healing ChildrenGs AHenIon J Behavior Disorders. Toronto, ON. CCNM Press Inc. 2004;102-‐105, 208-‐221.

¢  Hill LJ, Williams JH, Aucol L, et al: . How does exercise benePt performance on cogni%ve tests in primary-‐school pupils^ Dev Med Child Neurol, 2011;;53:630-‐635. ¢  Jan YW, Yang CM, Huang YS: Comorbidity and confounding factors in alen%on-‐dePcitahyperac%vity disorder and sleep disorders in children. Psychol Res Behav Manag, 2011;4:139-‐150. ¢  Johnson RJ, Gold MS, Johnson DR, et al: Alen%on-‐dePcita hyperac%vity disorder: is it %me to reappraise the role of sugar consump%on^ Postgrad Med, 2011;123:39-‐49. ¢  Kaplan BJ, Fisher JE, Crawford SG, et al: Improved mood and behavior during treatment with a mineral-‐vitamin supplement: an open-‐label case series of children. J Child Adolesc Psychopharmacol, 2004;14:115-‐122. ¢  Kim Y, Chang H: Correla%on between alen%on dePcit hyperac%vity disorder and sugar consump%on, `uality of diet, and dietary behavior in school children. Nutr Res Pract, 2011;5:236-‐245.

¢  Lyon MR, Kapoor MP, Juneja LR: The effects of L-‐theanine (Suntheanine~) on objec%ve sleep ùality in boys with alen%on dePcit hyperac%vity disorder (ADHD): a randomized, double-‐blind, placebo-‐controlled clinical trial. Altern Med Rev, 2011;16:348-‐354. ¢  Niederhofer H:Associa%on of alen%on-‐dePcitahyperac%vity disorder and celiac disease: a brief report. Prim Care Companion CNS Disord, 2011;13(3). ¢  Nigg JT, Lewis K, Edinger T, et al: Meta-‐analysis of alen%on-‐ dePcitahyperac%vity disorder or alen%on-‐dePcitahyperac%vity disorder symptoms, restric%on diet, and synthe%c food color addi%ves. J Am Acad Child Adolesc Psychiatry, 2012 ;51:86-‐97.e8. Noble GS, O Laughlin L, Brubaker B: Alen%on dePcit hyperac%vity disorder and sleep disturbances: considera%on of parental influence. Behav Sleep Med, 2011;10:41-‐53.

¢

Pelsser LM, Frankena K, Toorman J, et al: Eﬀects of a restricted elimina%on diet on the behaviour of children with alen%on-‐ dePcit hyperac%vity disorder (INCA study): a randomised controlled trial. Lancet, 2011;377:494-‐503. ¢  Polanczyk G, de Lima MS, Horta BL, et al: The worldwide prevalence of ADHD: a systema%c review and metaregression analysis. Am J Psychiatry, 2007;164:942-‐948. Rucklidge JJ, Gately D, Kaplan BJ: Database analysis of children and adolescents with bipolar disorder consumujng a micronutrient formula. BMC Psychiatry, 2010;10:74. ¢  Schnoll R, Burshteyn D, Cea-‐Aravena J: Nutri%on in the treatment of alen%on-‐dePcit hyperac%vity disorder: a neglected but important aspect. Appl Psychophysiol Biofeedback, 2003;28:63-‐75.

¢

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Shaw I, Rucklidge JJ, Hughes RN: A possible biological mechanism for the B Vitamins altering behaviour in ADHD. PharmaceuIcal Medicine, 2010;24:1-‐6. ¢  Swanson JM, Volkow ND: Serum and brain concentra%ons of methylphenidate: implica%ons for use and abuse. Neurosci Biobehav Rev, 2003;27:615-‐621. Taylor AF, Kuo FE: Children with alen%on dePcits concentrate beler acer walk in the park. J AHen Disord, 2009;12:402-‐409. ¢  Timimi S, Radcliﬀe N: The rise and rise of alen%on dePcit hyperac%vity disorder. Journal of Public Mental Health, 2005;4:9-‐13. Lancet. 2011 Feb 5;377(9764):494-‐503.

Dr. Rogers Prize Lecture Evidence Based Medicine: Beyond Classical RCTs

12-‐03-‐26

Marja Verhoef Objectives   To discuss:   The challenges of evaluating complex CAM (Complementary and Alternative Medicine) and Orthomolecular Medicine interventions using RCTs   Suitable outcomes research designs to deal with these challenges:

Evidence Based Medicine: Beyond Classical RTCs 2012 Orthomolecular Medicine Today April 27-29

  Variations of RCTs   Comparative Effectiveness Research (CER)   Qualitative research/Mixed methods research

Marja J.Verhoef, PhD University of Calgary

  Clinical practice guidelines   The need for a whole systems perspective

Complex interventions or systems…   Consist of multiple interacting components which

Using Randomized Clinical trials to study complex interventions

include treatments, process and context   Eg integrative care, naturopathic medicine, orthomolecular medicine   Are dynamic and non-linear and evolve over time (adaptive)   This implies that the treatment system that evolves is not equal to the sum of its parts and cannot be understood by understanding the individual parts

Randomized Controlled Trials to study complex interventions

Randomized Controlled Trials: The GOLD standard

  An RCT is a good design, if the intervention   Consists of standardized treatment   All patients are willing to be randomized   A suitable placebo treatment is available   Blinding is possible   However..

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Marja Verhoef RCTs are not designed to evaluate complex CAM interventions (1):

RCTs are not designed to evaluate CAM interventions as a complex intervention (2):

  Multi-component individualized CAM systems cannot

  Blinding is impossible for holistic and individualized

easily be standardized, and   Specific interactions and synergy cannot easily be measured in an RCT   Randomization may be difficult as

systems such as Integrative care, naturopathic medicine, TCM, Traditional Chinese Medicine, etc.

  Placebo control is not useful as RCTs   aim at excluding non-specific effects that are crucial for TCM to

work optimally, such as patient expectations and beliefs, the patient-provider relationship, etc.

  Patient (and practitioner) preferences/expectations are an

important part of individualized care and preclude randomization

RCTs are not designed to evaluate CAM interventions as a complex intervention (3):   Results of RCTs apply to the treatment group and, thus, to

‘average’ patients, and

Evidence Based Medicine

  Are not intended to assess individual participants’ outcomes or

outcomes of subgroups of participants (for example patients who received similar treatment regimens).   So we will NOT know for whom the intervention worked and WHAT it is about the intervention that made it work

Evidence Based Medicine (Sackett et all, 2000) is

Clinical expertise:   The skills and judgment that clinicians obtain through clinical

  Is the integration of   the best research evidence (using the best design), AND   clinical expertise and   patient values   All factors are important to assess what the best care is in real life

experience and clinical practice. This includes

  Knowledge of the individual patient over a period of time   Experience treating similar patients

  Best care would provide better evidence

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Dr. Rogers Prize Lecture Evidence Based Medicine: Beyond Classical RCTs

12-‐03-‐26

Marja Verhoef Patient values:

Even in times of EBM…

The patient may   Want treatments that have been helpful in the past   Know intuitively what sort of interventions are helpful   Have strong treatment preferences based upon personal beliefs and values

  The evaluation of complex interventions needs to take into

account the best evidence, clinical expertise and patient values – to provide real life evidence…

  “a large part of complex clinical decision making still relies more

on personal experience and group consensus about clinical experience, traditions and belief systems than on results of efficacy oriented phase III and effectiveness-oriented phase IV clinical studies”

Möller HJ. Is evidence sufficient for evidence-based medicine? Eur Arch Psychiatry Clin Neurosci (2009)259 (Suppl 2): S167-S172

Evidence Hierarchy What is the best research design to achieve optimal evidence related to CAM/Orthomolecular Medicine?

The highest level of evidence   The highest level of evidence - Randomized Controlled

Outcomes Research

Trials - ignores the impact of many real life variables (eg. clinical expertise and patient values and beliefs, patient provider relationship, context and process, etc.) and its results. and   may not represent the effects of the intervention that is being studied adequately

133

Dr. Rogers Prize Lecture Evidence Based Medicine: Beyond Classical RCTs

12-‐03-‐26

Marja Verhoef Outcomes research (1)

Outcomes research (2)

  Seeks to understand the quality and effectiveness of

  Assesses health care practices by using a wide range of

particular health care practices   Takes patients' experiences, preferences, and values into account   Focuses on

specific outcome measures

  often focuses on individual outcomes (eg. functional ability,

preferences, access) but also on

  system outcomes (eg. cost effectiveness, health status, disease

burden, quality of care)

  effectiveness: how well a treatment works in practice, NOT on

  Directly links the care/treatment people get in real life with

  efficacy: how well it works in clinical trials or laboratory studies

the outcomes they experience (not what they received under ideal circumstances)

(under ideal circumstances)

Outcomes Research results facilitate decisionmaking

Outcomes research approaches may include:

  For clinicians and patients, it provides evidence about

  Variations on the RCT (no placebo control and no blinding)

benefits, risks, and results of treatments so they can make more informed treatment decisions.   Such evidence can assist in

  Comparative effectiveness research (CER)   Qualitative research/ mixed methods research

  Improving the quality and value of care, and

  Of note: several of these designs overlap even though they have a

  Informing policy decisions

different name

Preference Trials   Participants with no treatment preferences are randomized as

usual but those with preferences receive their preferred treatment, allowing for the assessment of the interaction between treatment preference and treatment outcome.

Variations on the RCT

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Marja Verhoef Cluster Trials   Randomization of interventions to groups of patients (e.g.,

Comparative Effectiveness Research

families, medical practices) rather than to individual patients, allowing for the assessment of the impact of the context.

Comparative Effectiveness Research (CER)

Comparative Effectiveness Research includes:

  CER is the direct comparison of existing (effective)

  Effectiveness rather than efficacy trials (Pragmatic trials – no

placebo control, no standardization)

interventions in order to determine which work best for which patients and which pose the greatest benefits and harms.   The core question is which treatment works best, for whom and under what circumstances. This is the type of evidence we need.

  Patient-Centered Outcomes Research   Practice-based evidence for clinical practice improvement   Existing data: Charts, large databases (ie insurance or disease

registries), systematic reviews   Lend themselves to identifying patterns and outcomes of care   Observational prospective studies

Example: Ritenbaugh et al (2008): TCM and Naturopathic Medicine for Temporomandibular Disorders (TMD)

Advantages CER

  Pilot trial of TCM, naturopathic medicine (NM) and state of

  Provides direct practical real life information

the art specialty care (SC) provided by dentists who specialize in TMD   Patients randomized to each of the 3 arms   Interventions were individualized   Outcomes: Facial pain and interference with activities   Measurements at end of treatment at 3 month intervals   Results: TCM and NM resulted in greater reduction of pain and interferences with activities than standard special care

  Assists policy makers in identifying subpopulations of

patients that are more likely to benefit from one intervention than another   It asks the right question: ‘is A better than B’, rather than ‘does this work?’

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Dr. Rogers Prize Lecture Evidence Based Medicine: Beyond Classical RCTs

12-‐03-‐26

Marja Verhoef Qualitative Research   The investigation of phenomena (or interventions), in a

Qualitative Research

holistic fashion, through the collection of rich narrative materials (ie personal interviews)   Its Purpose is exploration and obtaining in-depth understanding of participants’ motives, goals, how they choose treatments, what outcomes are important, etc.   This is often a first step before doing comparative research

Qualitative Research

Qualitative research helps to

  In-depth, open ended interviews, focus groups, observation

  Understand the meaning of interventions, such as:   How practitioners and patients make treatment choices   Why they do so   Whether and why they change treatment over time   What factors are impacting on this

and participant observation   Thematic analysis:

  inductively summarizing and classifying elements or parts of text

material (or interview data),

  assigning labels or categories to them, and then   searching for meaningful events and relationships between these