45th Orthomolecular Medicine Today Conference by Journal of Orthomolecular Medicine

Vancouver

Conference Syllabus

TH Annual International Conference

April 29 â&#x20AC;&#x201C; May 1

Fairmont Hotel Vancouver

International Society for Orthomolecular Medicine

2016 Experience the best education in many areas of orthomolecular medicine at our 45th Annual International Conference. Twelve internationally known physicians and researchers will present five sessions on current advances in orthomolecular psychiatry, pediatrics, oncology, and general medicine.

International Society for Orthomolecular Medicine April 29, 2016 Dear Delegates, Welcome to our 45th 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 12 speakers, 25 exhibitors and 175 delegates and guests from countries around the world, including Algeria, Australia, Canada, Japan, Mexico, Nigeria, Norway, Spain, Sweden, Switzerland, the United Kingdom and the United States of America. We are celebrating the 22nd anniversary of the founding of the International Society for Orthomolecular Medicine, which now has 21 country members representing over 30,000 individual members. The ISOM was established in 1994 to unite existing societies and to foster the growth of Orthomolecular Medicine through education, communication and advocacy. 2016 marks the 13 anniversary of the Orthomolecular Medicine Hall of Fame, as we induct three pioneers: Thomas Levy, MD, JD; Michael Gonzalez, PhD; and Jorge Miranda-Massari, DPharm. th

We thank you for your continued dedication to Orthomolecular Medicine and wish you a most memorable Conference. With best regards,

Atsuo Yanagisawa, President

Steven Carter, Founding Director

ISOM Meeting Sunday, May 1 8:30 am â&#x20AC;&#x201C; 10:00 am Please join us to hear reports on activities in education, communication and advocacy from Canada, Japan, Mexico, Spain, Sweden, Algeria, USA and others among the countries in attendance at the Orthomolecular Medicine Today Conference. Donâ&#x20AC;&#x2122;t miss this opportunity to gain an international perspective on Orthomolecular Medicine.

“Often copied, but never equalled.”

Contents

Conference Schedule...............................................................................................................................................4 Exhibitors.....................................................................................................................................................................5 Exhibitor Floor Plan..................................................................................................................................................6 Speaker’s Biographies..............................................................................................................................................7

Session One • Orthomolecular Psychiatry Robert Whitaker Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care......................................8 Ron Hunninghake, MD Optimal Kids: Improving Children’s Mood, Behaviour and Learning..............................................................19

Session Two • Orthomolecular Psychiatry Felice Jacka, PhD The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan..................................................................................................................................................27 Bonnie Kaplan, PhD Why Treating Mental Illness with Minerals and Vitamins Makes Sense..............................................42 Judith Pentz, MD Searching for Orthomolecular Wholeness in a Broken World: One Woman Psychiatrist’s Journey..............................................................................................................................................52

Session Three • Orthomolecular Psychiaty Kazuhiko Kono, MD Orthomolecular Therapy for Dementia: The Kono Method.............................................................................65 Laurie Mischley, ND, MSc Positive Deviants with Parkinson’s Disease...........................................................................................................80

Session Four • Orthomolecular Medicine Michael Gerber, MD Integrative Oncology Patient Support ..................................................................................................................87 Walter Lemmo, ND Oncology: Low-Dose IV Vitamin C and Promising Technologies.....................................................................94 Thomas Levy, MD, JD Oral Pathogens as a Common Cause of Chronic Disease............................................................................... 109

Session Five • Orthomolecular Oncology Michael Gonzalez, PhD Mitochondria and Cancer: The Bioenergetic Theory of Carcinogenesis........................................................... 125 Jorge Miranda-Massari, PharmD Improving Vitamin C in Cancer............................................................................................................................. 136

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

Friday April 29

12:30 PM Lunch - Visit Exhibits

8:00 AM Registration 8:30 AM Exhibits open

2:00 PM Walter Lemmo, ND – Oncology: Low-Dose IV Vitamin C and Promising Technologies

Session One • Orthomolecular Psychiatry

3:00 PM Break - Visit Exhibits

9:00 AM Welcome – Steven Carter, OMT Chair Atsuo Yanagisawa, MD, ISOM President 9:15 AM

3:30 PM 5:00 PM

Robert Whitaker Annual Abram Hoffer Memorial Lecture Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care

Thomas Levy, MD, JD Annual Evan Shute Memorial Lecture Oral Pathogens as a Common Cause of Chronic Disease End of Session Four

5:30 PM Exhibits Close

10:30 AM Break - Visit Exhibits 13th Annual

11:00 AM Ron Hunninghake, MD Optimal Kids: Improving Children’s Mood, Behaviour and Learning

Orthomolecular Medicine Hall of Fame 7:00 pm Reception 7:30 pm Dinner and Induction

12:30 PM Lunch - Visit Exhibits

Sunday May 1

Session Two • Orthomolecular Psychiatry 2:00 PM

Felice Jacka, PhD Dr Rogers Prize Lecture The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

8:30 AM Registration – Exhibits open 8:30 AM ISOM Annual Meeting

Session Five • Orthomolecular Oncology 10:00 AM Break - Visit Exhibits

3:00 PM Bonnie Kaplan, PhD – Why Treating Mental Illness with Minerals and Vitamins Makes Sense

10:30 AM Michael Gonzalez, PhD – Mitochondria and Cancer: The Bioenergetic Theory of Carcinogenesis

4:00 PM Break – Visit Exhibits

11:30 AM Jorge Miranda-Massari, PharmD Improving Vitamin C in Cancer

4:30 PM Judith Pentz, MD – Searching for Orthomo- lecular Wholeness in a Broken World: One Woman Psychiatrist’s Journey

12:30 PM Conference Ends

Saturday April 30

1:00 PM Exhibits Close

8:30 AM Registration – Exhibits open

2:00 – 4:00 pm Optimizing Kids: Managing Behavioural Public Workshop Challenges in Children Through Nutrition, Diet & Lifestyle

Session Three • Orthomolecular Psychiaty 9:00 AM Kazuhiko Kono, MD – Orthomolecular Therapy for Dementia: The Kono Method

Led by a panel of Canadian and International speakers

10:00 AM Laurie Mischley, ND, MSc – Positive Deviants with Parkinson’s Disease

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

11:00 AM Break - Visit Exhibits

Thanks to our generous sponsors

Session Four • Orthomolecular Medicine 11:30 AM Michael Gerber, MD – Integrative Oncology Patient Support

43rd Orthomolecular Medicine Today Conference Exhibitors

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45th Orthomolecular Medicine Today Conference Exhibitors *Floor plan subject to change

Podium

5 4 3 2

Nutrition Break

6 10 Exhibit Area

Nutrition Break

Exhibit Area

Entrance

Foyer Exhibit Area

Reception

1. Canadian Society for Orthomolecular Medicine/JOM 9. Metagenics Canada 2. Cyto-Matrix Inc. 10. Health Care Prevention Alliance 3. Finlandia Pharmacy & Health Centre 11. Douglas Laboratories/ Pure Encapsulations 4. Doctors Data Inc. 12. Boucher Institute of Naturopathic Medicine 1.5.Metagenics Inc. Inc. 11. Finlandia Pharmacy & Health Centre Acquired Canada Intelligence 13. College Pharmacy US BioTek Laboratoires 14.INT Nutritional Fundamentals for Health 2.6.LivLong (LivOn Labs) 12. BDR Inc. 7. True Balance 15. Rocky Mountain Analytical 3.8.Xymogen Canada 13. The Great Plains Laboratory Inc. Seroyal International 16. York Downs Pharmacy

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4. York Downs Chemists

14. Designs for Health Canada

5. Acquired Intelligence Inc.

15. Truehope EMP

6. Douglas Laboratories Canada /

16. Vita Aid Professional Therapeutics

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5 17. College Pharmacy

Pure Encapsulations 7. Pure Integrative Pharmacy

18. Nutritional Fundamentals for Health (NFH)

8. Genuine Health

19. Canada RNA Biochemical Inc.

9. Cyto-Matrix Inc.

20. Canadian Society for Orthomolecular Medicine

10. Seroyal International Inc.

21. Boucher Institute of Naturopathic Medicine ■

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45th Orthomolecular Medicine Today Conference Please Visit Our Exhibitors Acquired Intelligence Inc. 205 -1095 McKenzie Avenue Victoria, BC V8P 2L5 Canada 250 483 3640 sales@salvestrol.ca www.salvestrol.ca

LivLong (LivOn Labs) 601 Montgomery Close SE High River, AB T1V 0B7 Canada 844 246 5997 www.livlong.ca

BDR INT Inc. 11 Glen Avenue Smiths Falls, ON K7A 1S1 Canada 866 634 8075 bdrint@gmail.com www.nanovitamins.ca

Metagenics Canada Inc. 15 - 3250 Ridgeway Drive Mississauga, ON L5L 5Y6 Canada 800 268 6200 brendaparsons@metagenics.com www.metagenics.com

Boucher Institute of Naturopathic Medicine 200 - 435 Columbia Street New Westminster, BC V3L 5N8 Canada info@binm.org www.binm.org

Nutritional Fundamentals for Health (NFH) 3405 F.X. Tessier  Vaudreuil-Dorion, QC J7V 5V5 Canada 866 510 3123 info@nfh.ca www.nfh.ca

Canadian Society for Orthomolecular Medicine 16 Florence Avenue Toronto, ON M2N 1E9 Canada 416 519 2153 info@csom.ca www.csom.ca

Pure Integrative Pharmacy 238 Robson Street Vancouver BC V6B 6A1 Canada 604 809 6948 bob.mehr@purepharmacy.com www.purepharmacy.com

Canada RNA Biochemical Inc. 680 - 4400 Hazelbridge Way Richmond, BC V6X 3R8 Canada 866 287 4986 / 604 273 2233 info@canadarna.com www.canadarna.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

College Pharmacy 3505 Austin Bluffs Parkway Colorado Springs, CO 80918 USA 800 888 9358 / 719 262 0022 info@collegepharmacy.com www.collegepharmacy.com

The Great Plains Laboratory Inc. 11813 West 77th Street  Lenexa, KS 66214 USA 800 288 0383 customerservice@gpl4u.com www.greatplainslaboratory.com

Cyto-Matrix Inc. 300 March Road, Suite 103 Kanata, ON K2K 2E2 Canada 866 783 7504 info@cyto-matrix.com www.cyto-matrix.com

Truehope EMP 680 North 300 East, P.O. Box 888 Raymond, AB T0K 2S0 Canada 866 397 3121 shelly@truehope.com www.truehopeemp.ca

Designs for Health Canada 980 South Street Suffield, CT 06078 USA 877 414 9388 canadaorders@designsforhealth.com www.designsforhealth.ca

Vita Aid Professional Therapeutics 302 - 20285 Stewart Crescent Maple Ridge, BC V2X 8G1 800 490 1738 / 604 465 1688 info@vitaaid.com www.vitaaid.com

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

York Downs Chemists 3910 Bathurst Street Toronto, ON M3H 5Z3 Canada 800 564 5020 416 633 2244 info@yorkdownsrx.com www.yorkdownsrx.com

Finlandia Pharmacy & Health Centre 1111 W Broadway Vancouver, BC V6H 3X5 Canada 604 733 5323 / 800 363 4372 www.finlaniapharmacy.com

Xymogen Canada 14 - 1825 Dundas Street East Mississauga, ON L4X 2X1 Canada 888 511 5035 canada@xymogen.com www.xymogen.ca

Genuine Health 501 - 317 Adelaide Street West Toronto, ON M5V 1P9 Canada 877 500 7888 / 416 977 3505 customerservice@genuinehealth.com www.genuinehealth.com

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conference speakers Michael Gerber, MD, graduated from the Kansas University School of Medicine in 1972. He completed his internal medicine internship at Oakland County Hospital with additional training in Zaire, Africa. He also trained in a psychiatric externship at the crisis intervention ward at the University of California, San Francisco Medical School, and performed psychopharmacology research at the Stanford Research Ward of the Palo Alto, California, Veterans Administration Hospital and Menlo Park Veterans Administration Hospital. Dr. Michael Gerber has always been drawn to natural approaches to medicine, and early in his practice he studied with many well-known medical pioneers such as Dr. John Christopher, Dr. Paavo Airola, and two-time Nobel Prize Laureate Dr. Linus Pauling. He has been a chelating physician since 1976 and has been a diplomate of the American Board of Chelation Therapy since 1984.

Walter Lemmo, ND, is the medical director and founder of LEMMO Integrated Cancer Care Inc. in Vancouver, BC., the longest running naturopathic medical clinic focused in cancer care in Canada servicing patients locally and internationally since 1999. In addition to his practice, in 2011 Dr. Lemmo co-founded Thrive Alive Foundation, a charitable organization committed to providing resources and assistance to people in need for cancer treatments and services not covered by government or health plans. Thrive Alive Foundation began operating its Thrive Support Program in 2012 and has supported patient treatments from various health practitioners, cancer agencies, including lodging support across Canada.

Dr. Michael J. Gonzalez is Professor of Nutrition at the University of Puerto Rico Medical Sciences Campus and Adjunct faculty at the University of Western States. Dr. Gonzalez is a Fellow of the American College of Nutrition, and has authored over 200 scientific publications. He and his colleague, Dr. Miranda -Massari have developed many new scientific concepts, such as the Bioenergetic theory of carcinogenesis, the systemic saturation phenomenon of intravenous vitamin C, the metabolic correction concept for disease treatment and prevention. Doctor Gonzalez is a coauthor of two books, I Have Cancer What Should I do: The Orthomolecular Guide to Cancer Management and New Insights Vitamin C and Cancer.

Thomas Levy, MD, JD, is a board-certified cardiologist and a bar-certified attorney. He has written ten books, with several addressing the wide-ranging properties of vitamin C in neutralizing all tested toxins and resolving most infections, as well as its vital role in the effective treatment of heart disease and cancer. Others address the important roles of dental toxicity and nutrition in disease and health. Currently, Dr. Levy continues to research the impact of the orthomolecular application of vitamin C and antioxidants in general on chronic degenerative diseases. His ongoing research involves documenting that all diseases are different forms of focal scurvy, arising from increased oxidative stress, and that they all benefit from protocols that optimize the antioxidant levels in the body.

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).

Laurie Mischley, ND, MPH, has been specializing in nutrition and neurological disorders for over a decade. She received a BSc in Nutrition Science in 1997 from Pennsylvania State University, a Doctorate of Naturopathic Medicine (ND) from Bastyr University in 2001, and completed a MPH in Epidemiology from the University of Washington in 2013. In 2010, she was awarded an NIH/NCCAM Bernard Osher Career Development Award and with the support of this award she is conducting trials on nutritional strategies for neuroprotection. Dr. Mischley maintains a private practice at Seattle Integrative Medicine in Seattle’s University District. She is author of the book, Natural Therapies for Parkinson’s Disease.

Felice Jacka is a Principal Research Fellow within the Deakin University School of Medicine based at Barwon Health in Geelong. She is also an honorary Research Fellow with the Department of Psychiatry at the University of Melbourne. Over the last seven years, Professor Jacka has been developing an innovative program of research that examines how individuals’ diets interact with the risk for mental health problems. This research is being carried out with the ultimate goal of developing an evidence-based public health message for the primary prevention of common mental disorders. Professor Jacka’s ongoing program of research incorporates a broad range of epidemiological and public health investigations, with extensive partnerships and collaborations in Australia and elsewhere involving the acknowledged experts in the field of psychiatry and public health.

Jorge R. Miranda-Massari has a doctorate in pharmacy from the Philadelphia University of the Sciences. He also completed a post-doctorate in pharmacokinetics clinical of the University of North Carolina. He is the author of above 100 scientific publications in peer-reviewed journals. He is also co-author of two books; I have Cancer What Should I do and New Insight of Vitamin C and Cancer published by Springer Verlag. He is director of project RECNAC 2 Cancer clinical research. He is co-founder of the continuing education program for professionals of the Institute of Metabolic Correction. He was elected into the Academy of Arts and Sciences of Puerto Rico in 2014. He is co-founder of the Institute of Metabolic Correction, a continuing education program for professionals..

Bonnie J. Kaplan, PhD, is a Professor in the Cumming School of Medicine, Univ of Calgary, Alberta, Canada. Originally from Ohio, her training was in the U.S. (Univ of Chicago, Brandeis Univ) in experimental and physiological psychology. Her interest in the biological basis of behavior led to postdoctoral training and then faculty research in neurophysiology at the West Haven (CT) VA Hospital Neuropsychology Laboratory, and Yale University Department of Neurology, until moving to Canada. Her nutritionrelated studies have focused on broad-spectrum micronutrient treatments for mental disorders, and the effect of intra-uterine nutrition on brain development and maternal mental health.

Judith E. Pentz, MD, has been in practice for over 25 years. She is an assistant professor in the department of psychiatry at the University of New Mexico. Dr. Pentz began to include orthomolecular interventions along with other holistic therapies in the early 2000s. Her latest contribution is a chapter on Botanicals for Depression in Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention just released in December 2015.

Robert Whitaker is the author of five books, three of which tell of the history of psychiatry. His first, Mad in America: Bad Science, Bad Medicine and the Enduring Mistreatment of the Mentally Ill was named by Discover magazine as one of the best science books of 2002. His second book on this topic, Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America, won the Investigative Reporters and Editors book award for best investigative journalism in 2010, and has been translated into nine foreign languages. His latest book, which he co-wrote with Lisa Cosgrove, is Psychiatry Under the Influence: Institutional Corruption, Social Injury, and Prescriptions for Reform. He is the founder of madinamerica.com, a website that features research news and blogs from an international group of writers interested in “rethinking psychiatry.”

Kazuhiko Kono, MD, graduated from the Kinki University School of Medicine in 1982, and acquired a doctor’s degree, studying vitamin C deficiencies in rats in the Nagoya University graduate school in Nagoya, Japan. Dr. Kono served as chief of geriatric department of Kainan Hospital and Kyowa Hospital until 2009. From 2007, Dr. Kono began to develop the Kono Method, an original therapeutic system for treating dementia, an intractable neurologic and mental disease, with intravenous glutathione and a ferulic acid supplement. About 330 doctors currently practice the Kono Method. Dr. Kono opened Nagoya Forest Clinic in 2009 and has been vice-President/organizer of the Japanese society of dementia therapy since 2015. He has published 35 books about dementia.

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker

Anatomy of an Epidemic: The History and Science of a Failed Paradigm of Care

DSM III was the “book that changed everything.”

Robert Whitaker April 2016

—Jeffrey Lieberman American Psychiatric Association President

Validating the Disease Model: The Chemical Imbalance Theory of Mental Disorders

The Disease Model

1981: “Researchers believe clinical depression is caused by a chemical imbalance in the brain.” University of Chicago psychiatrist Herbert Meltzer, in interview with Associated Press.

“The major psychiatric illnesses are diseases. They should be considered medical illnesses, just as diabetes, heart disease, and cancer are.” The thought was that each “different illness has a different speciﬁc cause . . . There are many hints that mental illness is due to chemical imbalances in the brain and that treatment involves correcting these chemical imbalances.”

1988. Antidepressants “restore the chemical imbalance scientists have linked to many depressions.” John Talbott, former president of the American Psychiatric Association (APA), in interview with the St. Petersburg Times. 2001: “We now know that mental illnesses--such as depression or schizophrenia--are not ‘moral weaknesses’ or ‘imagined’ but real diseases caused by abnormalities of brain structure and imbalances of chemicals in the brain.” -- APA President Richard Harding, in article in Family Circle magazine.

Nancy Andreasen Editor-in-Chief of the American Journal of Psychiatry The Broken Brain, 1984

The Public Believes

. 2001: Antidepressants “restore brain chemistry to normal.” Future APA President Nada Stotland, in Family Circle magazine.

In a 2006 survey: 2005: A psychiatrist is a “specialist speciﬁcally trained to diagnose and treat chemical imbalances.”--APA press release.

• 87

percent of Americans said they now knew that schizophrenia was caused by a chemical imbalance.

2005: “Antidepressants may be prescribed to correct imbalances in the levels of chemicals in the brain.” APA’s “Let’s Talk Facts About Depression” brochure.

• 80

percent of Americans said they now knew that depression was caused by a chemical imbalance.

2014: “Research has shown that imbalance in neurotransmitters like serotonin, dopamine and norepinephrine can be corrected with antidepressants.” --National Alliance on Mental Illness.

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker

What Science Revealed About the Low Serotonin Theory of Depression

“There is no clear and convincing evidence that a monoamine deﬁciency accounts for depression; that is, there is no real monoamine deﬁcit.”

“Elevations or decrements in the functioning of serotonergic systems per se are not likely to be associated with depression.”

--Stephen Stahl, Essential Psychopharmacology, 2000

--NIMH, 1984 J. Maas, “Pretreatment neurotransmitter metabolite levels and response to tricyclic antidepressant drugs.” Am J Psychiatry 141 (1984): 1159–71.

The Scientiﬁc Conclusion

And Now for the Rest of the Story: Drug-Induced Oppositional Tolerance

“We have hunted for big simple neurochemical explanations for psychiatric disorders and have not found them.”

--Kenneth Kendler, Psychological Medicine, 2005

Dopamine function after exposure to antipsychotics

Dopamine function before exposure to antipsychotics

Presynaptic neuron

Dopamine

Antipsychotic blocks receptors

Dopamine receptors

Dopamine

Postsynaptic neuron Postsynaptic neuron

Brain increases receptors to compensate for drug blockade

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker A Paradigm for Understanding Psychotropic Drugs

The Possible Consequences of “Oppositional Tolerance”

Stephen Hyman, former director of the NIMH, 1996:

“Continued drug treatment may induce processes that are the opposite of what the medication originally produced.” This may !“cause a worsening of the illness, continue for a period of time after discontinuation of the medication, and may not be reversible.”

• Psychiatric medications “create perturbations in neurotransmitter functions.” • In response, the brain goes through a series of compensatory adaptations in order “to maintain their equilibrium in the face of alterations in the environment or changes in the internal milieu.” • The “chronic administration” of the drugs then cause “substantial and longlasting alterations in neural function.”

-Rif El-Mallakh, University of Louisville, 2011

• After a few weeks, the person’s brain is now functioning in a manner that is

“qualitatively as well as quantitatively different from the normal state.”

Source: El-Mallakh, R. “Tardive dysphoria: The role of long-term antidepressant use in inducing chronic depression. Medical Hypotheses 76 (2011): 769-773.

Source: Hyman, S. “Initiation and adaptation: A paradigm for understanding psychotropic drug action.” Am J Psychiatry 153 (1996):151-61.

The Testing of Xanax for Panic Disorder (1980s)

The Conclusion in the Literature

The Xanax Investigators Used This Data to Report Efficacy 7

The study provides a “demonstration of the efﬁcacy of alprazolam compared with placebo in the short-term treatment of panic disorder.”

Number of Panic Attacks

6 5 4 Placebo

3 2

—Gerald Klerman Archives of General Psychiatry

Xanex

1 0 Baseline

Week 1

G. Klerman. “Overview of the cross-national collaborative panic study.” Arch Gen Psychiatry 45 (1988): 407–412.

Week 4

The study of Xanax was designed to measure the efficacy of the drug versus placebo at the end of eight weeks. However, the investigators emphasized the results at the end of four weeks, when the drug provided a statistically significant benefit. Source: C. Ballenger, “Alprazolam in panic disorder and agoraphobia,” Archives of General Psychiatry 45 (1988):413-22.

Here Are the Actual Study Results

Here is What the Press Reported

The Xanax Study 9 8

Number of Panic Attacks

Headline in Newspaper: “In a Panic? Help Is On the Way.” Xanax, the paper reported, works for “70 percent to 90 percent” of those who suffer from the illness. St. Louis Post-Dispatch, October 7, 1990

5 4 3 2 1 0

Xanax

Placebo

Baseline Week 1

Week 4

Off drug

Drug taper

Active treatment

Week 8

Week 9

Week 12

Week 13

Week 14

InSource: Upjohn’s studyC. of“Alprazolam Xanax, patients were treated the drugArch or placebo for eight weeks. Then Ballenger, in panic disorder andwith agoraphobia.” Gen Psychiatry 45 (1988):413-22. Pecknold, C. “Alprazolam in withdrawn panic disorder and agoraphobia.” Archand Gen during Psychiatry 45last (1988):429-36. this treatment was slowly (weeks 9 through 12), the two weeks patients didn’t receive any treatment. The Xanax patients fared better during the first four weeks, which is the result that the Upjohn investigators focused on in their journal articles. However, once the Xanax patients began withdrawing from the the drug, they suffered many more panic attacks than the placebo patients, and at the end of the study were much more symptomatic. Source: Ballenger, C. “Alprazolam in panic disorder and agoraphobia.” Archives of General Psychiatry 45 (1988):413-22. Pecknold, C. “Alprazolam in panic disorder and agoraphobia.” Archives of General Psychiatry 45 (1988):429-36.

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker

The Hippocratic Oath The Long-term Effects of Antidepressants

In order for a treatment to do no harm, it must improve on natural recovery rates.

Long-term Outcomes in the Pre-Antidepressant Era “Assurance can be given to a patient and to his family that subsequent episodes of illness after a ﬁrst mania or even a ﬁrst depression will not tend toward a more chronic course.”

• Emil Kraepelin, 1921. Sixty percent of 450 patients hospitalized for an initial bout of depression experienced but a single bout of the illness, and only 13% had three or more episodes in their lives. • Horatio Pollock, New York State, 1931. In a long-term study of 2700 ﬁrst-episode depressed patients, more than half never had another bout of depression that required hospitalization, and only 13% had three or more episodes.

--George Winokur, Washington University, Manic Depressive Illness, 1969

• Gunnar Lundquist, Sweden, 1945. In an 18-year study of 216 patients, 49% had only a single episode, and another 21% had only one other episode.

The Chronicity Worry is Tested

Clinical Perceptions in Early Years of Antidepressant Use

J.D.Van Scheyen, Dutch psychiatry, 1973: After conducting a study of 94 depressed patients, he concluded that “it was evident, particularly in the female patients, that more systematic long-term antidepressant medication, with or without ECT [electronconvulsive therapy], exerts a paradoxical effect on the recurrent nature of the vital depression. In other words, this therapeutic approach was associated with an increase in recurrent rate and a decrease in cycle duration . . . Should [this increase] be regarded as an untoward longterm side effect of treatment with tricyclic antidepressants?”

•

H.P. Hoheisel, German physician, 1966: Exposure to antidepressants appeared to be “shortening the intervals” between depressive episodes.

• Nikola Schipkowensky, Bulgarian psychiatrist, 1970: The antidepressants were inducing “a change to a more chronic course.” Source: Van Scheyen, J.D. “Recurrent vital depressions,” Psychiatria, Neurologia, Neurochirurgia 76 (1973):93-112.

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker High-Relapse Rates Following Antidepressant Use

An Episodic Illness Turns Chronic in the Antidepressant Era

In a 1997 meta-analysis, Harvard researchers report that 50% of all drug-withdrawn patients relapsed within 14 months. They also noted that the longer the patient had been on an antidepressant prior to drug withdrawal, the higher the relapse rate.

National Institute of Mental Health Panel on mood disorders, 1985:

“Improved approaches to the description and classiﬁcation of [mood] disorders and new epidemiologic studies [have] demonstrated the recurrent and chronic nature of these illnesses, and the extent to which they represent a continual source of distress and dysfunction for affected individuals.”

(In the pre-antidepressant era, this was the relapse rate seen in studies that lasted 15 years or more.) Source: Viguera, A. “Discontinuing antidepressant treatment in major depression,” Harvard Review of Psychiatry 5 (1998):293-305.

Depression Runs a Chronic Course Today

The APA Acknowledges Change in Course of Depression in Modern Era

One-year outcomes from STAR*D Trial Number of patients

5000

American Psychiatric Association’s Textbook of Psychiatry, 1999:

4000

4041

3933

3000

It used to be believed that “most patients would eventually recover from a major depressive episode. However, more extensive studies have disproved this assumption.” It was now known that “depression is a highly recurrent and pernicious disorder.”

2000

1518

1000 108

0 Enrolled

Remitted

Stayed well at one year

Never remitted/ relapsed/dropped out

Source: Pigott, E. “Efﬁcacy and effectiveness of antidepressants.” Psychother Psychosom 79 (2010):267-79.

Outcomes in Real-World Patients In a 2004, NIMH-funded study:

•126 patients were treated with antidepressants and given emotional

“These ﬁndings reveal remarkably low

and clinical support “speciﬁcally designed to maximize clinical outcomes.”

response and remission rates.”

• Only 26% responded to antidepressants (50% reduction in

--John Rush, 2004

symptoms).

• Only half of those who responded stayed better for a signiﬁcant period of time

• Only 6% remitted and then remained in remission at the end of one year.

Source: J. Rush. “One-year clinical outcomes of depressed public sector outpatients,” Biological Psychiatry 56 (2004):46-53.

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker The Course of Medicated Depression Today

Outcomes in Minnesota

According to mainstream texts:

• One-third of all unipolar patients are non-responders to antidepressants. This group goes on to have a chronic course.

In 2009, only 1,131 of 23,887 patients treated for major depression or dysthmia were in remission at the end of one year.

• Another third are partial responders. However, “resolution of major depressive episode with residual subthreshold depressive symptoms, even the first lifetime episode, appears to be the first step of a more severe, relapsing, and chronic future course.” • The final third of patients see their symptoms remit over the short term. About half of this group, when maintained on an antidepressant, stay well for long periods of time.

Source: MN Community Measures, 2010 Health Care Quality Report

Are Antidepressants Depressogenic Over the Long-Term? “Only 15% of people with unipolar depression experience a single bout of the illness,” and for the remaining 85%, with each new episode, remissions become “less complete and new recurrences develop with less provocation.”

“Antidepressant drugs in depression might be beneﬁcial in the short term, but worsen the progression of the disease in the long term, by increasing the biochemical vulnerability to depression . . . Use of antidepressant drugs may propel the illness to a more malignant and treatment unresponsive course.”

--American Psychiatric Association Textbook, 1999

--Giovanni Fava, Psychotherapy and Psychosomatics, 1995

Five-Year Outcomes in Canada

Depression in the Netherlands (Over the course of ten years)

Number of Weeks Depressed Each Year

First episode treated with drug First episode treated without drug

20 19

80%

76%

70% 60% 50% 40%

50%

30%

31%

20%

19%

10% 0%

N = 9,508

11%

Only one episode

Two episodes

4 13%

More than two episodes

On Medication

Off Medication

Source: S. Patten, “The Impact of antidepressant treatment on population health.” Population Health Metrics 2 (2004): 9.

Source: E. Weel-Baumgarten, “Treatment of depression related to recurrence,” J Clin Psychiatry & Therapeutics 25 (2000):61-66.

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker One-Year Outcomes in WHO Screening Study for Depression Continuing Depression

These ﬁndings are consistent with Giovanni Fava’s hypothesis that “antidepressant treatment may lead to a deterioration in the long-term course of mood disorders.” --Scott Patten

Diagnosed/Antidepressants Undiagnosed/no drug

Diagnosed/Sedatives Diagnosed/No drug

60% 50%

51.6% 44.9%

40% 30%

28.3%

20%

25.2%

10% 0%

Continuing Depression

Source: D. Goldberg. “The effects of detection and treatment of major depression in primary care.” British Journal of General Practice 48 (1998):1840-44.

Antidepressants Lessen the Long-Term Beneﬁts of Exercise

“Patients not given drugs had milder illnesses but did signiﬁcantly better than those receiving drugs, both in terms of symptoms lost and their diagnostic status.” This was so “even after adjustment for initial scores on each instrument.” --D. Goldberg

Treatment during ﬁrst 16 weeks

Percentage of patients in remission at end of 16 weeks

Percentage of patents who relapsed in following six months

Percentage of all patients depressed at end of ten months

Zoloft alone

69%

38%

52%

Zoloft plus exercise

66%

31%

55%

Exercise alone

60%

30%

Source: Babyak, M. “Exercise treatment for major depression.” Psychosomatic Medicine 62 (2000):633-8.

Canadian Study of Risk of Long-term Disability for Depressed Workers Medicated 90% 80% 70% 60% 50% 40%

“Does the lack of antidepressant use reﬂect a resistance to adopting a sick role and consequently a more rapid return to work?”

84% 73%

--Carolyn Dewa

30% 20% 10% 0%

Unmedicated

19% 9%

Returned to work

Long-term disability

Quit/retiredﬁred

Source: C Dewa. “Pattern of antidepressant use and duration of depression-related absence from work.” British Journal of Psychiatry 183 (2003):507-13.

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker One-Year Recovery Rates in NIMH-Funded Study of Unmedicated Depression

NIMH’s Study of Untreated Depression Treated

Untreated

N = 84

Recovered 100%

40%

85%

80% 30%

32.3% 67%

60% 20% 10% 0%

40% 9.8%

20%

8.6%

1.3%

Cessation of role function

23%

One month

Became Incapacitated

Six Months

Twelve Months

Source: M. Posternak, “The naturalistic course of unipolar major depression in the absence of somatic therapy.” Journal of Nervous and Mental Disease 194 (2006):324-349.

Source: W. Coryell. “Characteristics and signiﬁcance of untreated major depressive disorder.” American Journal of Psychiatry 152 (1995):1124-29.

A Biological Explanation for Why Antidepressants May Be Depressogenic Agents Over the Long-Term The Problem

• Over time, antidepressants induce brain changes that “are the opposite of what the the medication originally produced.” Rather than raise serotonin levels, the drugs over the long-term impair serotonergic pathways in the brain.

“If as many as 85% of depressed individuals who go without somatic treatment spontaneously recover within one year, it would be extremely difﬁcult for any intervention to demonstrate a superior result to this.” --Michael Posternak

Animal Evidence

• In studies with rats, long-term treatment with an SSRI led to markedly reduced serotonin in “nine areas of the brain.” In addition, treatment with an SSRI leads to a reduced density of receptors for serotonin in the brain. • In experiments with animals, such impairments in serotonergic functions are “associated with increased depressive and anxious behaviors.” Source: El-Mallakh, R. “Tardive dysphoria: The role of long-term antidepressant use in inducing chronic depression. Medical Hypotheses 76 (2011): 769-773.

Three-Month Risk of Relapse After Initial Remission: Placebo vs. SSRI-Withdrawn Patients “When we prolong treatment over 6-9 months, we may recruit processes that oppose the initial acute effects of antidepressant drugs (loss of clinical effects) . . . We may also propel the illness to a

50% 43%

40%

malignant and treatment-unresponsive course that may take the form of resistance or episode acceleration. When drug treatment

30%

ends, these processes may be unopposed and yield withdrawal symptoms and increased vulnerability to relapse. Such processes are

20%

not necessarily reversible.”

10% 0%

Giovanni Fava, 2011

21%

Remission on Placebo

Remission On SSRI

P. Andrews: “Primum non nocere: an evolutionary analysis of whether antidepressants do more harm than good.” Frontiers in Psychology 3 (2012): 1-18.

Source: G. Fava. “The mechanisms of tolerance in antidepressant action.” Progress in NeuroPsychopharmacology & Biological Psychiatry 35 (2011): 1593-1602.

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker Two-Year Relapse Rates for Remitted Patients in the Netherlands “The more antidepressants perturb monamine levels in the brain, the more the brain appears to push back, which increases the risk of relapse when the drug is discontinued . . . antidepressant use appears to increase [biological] susceptibility to depression.”

70% 60%

60%

64%

50% 40% 30% 26%

20% 10%

--Paul Andrews, 2012

Continual AD Use Intermittent AD Use

No AD Use

Source: C. Bockting. “Continuation and maintenance use of antidepressants in recurrent depression.” Psychotherapy and Psychosomatics 77 (2008): 17-26.

Tardive Dysphoria “A chronic and treatment-resistant depressive state is proposed to occur in individuals who are exposed to potent antagonists of serotonin reuptake pumps (i.e. SSRIs) for prolonged time periods. Due to the delay in the onset of this chronic depressive state, it is labeled tardive dysphoria. Tardive dysphoria manifests as a chronic dysphoric state that is initially transiently relieved by -- but ultimately becomes unresponsive to !-- antidepressant medication. Serotonergic antidepressants may be of particular importance in the development of tardive dysphoria.”

“Continued antidepressant treatment may oppose the initial acute effects of [the] antidepressant . . . neurobiological mechanism(s) may be involved in increasing vulnerability” to relapse. --C. Bockting, 2008

-- Rif El-Mallakh, 2011 Source: El-Mallakh, R. “Tardive dysphoria: The role of long-term antidepressant use in inducing chronic depression. Medical Hypotheses 76 (2011): 769-773.

The Antidepressant Pathway to Bipolar Fred Goodwin, former director of the National Institute of Mental Health, 2005:

In 2004, Yale University investigators reviewed the records of 87,290 patients diagnosed with depression or anxiety between 1997 and 2001, and those treated with an antidepressant converted to bipolar at the rate of 7.7% per year, which was three times greater than those not exposed to the drugs. As a result, 20 to 40% of unipolar depressed patients in the U.S. who stay on antidepressants long-term convert to bipolar illness.

“If you create iatrogenically a bipolar patient, that patient is likely to have recurrences of bipolar illness even if the offending antidepressant is discontinued. The evidence shows that once a patient has had a manic episode, he or she is more likely to have another one, even without the antidepressant stimulation.”

Source: A. Martin. “Age effects on antidepressant-induced manic conversion,” Arch of Pediatrics & Adolescent Medicine 158 (2002):773-80.

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker Acknowledgement That Bipolar Outcomes Have Worsened in Modern Era

Long-term Recovery Rates for Schizophrenia Patients

Carlos Zarate, head of NIMH Mood Disorders Program, 2000: “In the era prior to pharmacotherapy, poor outcome in mania was considered a relatively rare occurrence. However, modern outcome studies have found that a majority of bipolar patients evidence high rates of functional impairment.”

50% 40%

Off Antipsychotics

Ross Baldessarini, Harvard Medical School, 2007. 30%

“Prognosis for bipolar disorder was once considered relatively favorable, but contemporary ﬁndings suggest that disability and poor outcomes are prevalent, despite major therapeutic advances.”

20% 10%

Fred Goodwin, 2008

On Antipsychotics

“The illness has been altered. Today we have a lot more rapid cycling than we described in the first edition [of his book, Manic Depressive Illness], a lot more mixed states than we described in the first edition, a lot more lithium resistance, and a lot more lithium treatment failure than we described in the first edition. The illness is not what Kraepelin described any more.”

0% 2 years

4.5 years

7.5 years

10 years

15 years

Source: Harrow M. “Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications.” Journal of Nervous and Mental Disease 195 (2007):406-14.

Results from NIMH’s Long-term Study of ADHD At three years

“I conclude that patients with schizophrenia not

“Medication use was a signiﬁcant marker not of beneﬁcial outcome, but of deterioration. That is, participants using medication in the 24-to-36 month period actually showed increased symptomatology during that interval relative to those not taking medication.” Medicated children were also slightly smaller, and had higher delinquency scores.

on antipsychotic medication for a long period of time have signiﬁcantly better global functioning than those on antipsychotics.” --Martin Harrow,

At six years Medication use was “associated with worse hyperactivity-impulsivity and oppositional deﬁant disorder symptoms,” and with greater “overall functional impairment.”

American Psychiatric

Association annual meeting, 2008

Source: Jensen, “A 3-year follow-up of the NIMH MTA study,” J Amer Academy of Child & Adolescent Psychiatry 46 (200&):989-1002. Molina,“MTA at 8 years,” J Amer Academy of Child & Adolescent Psychiatry 48 (2009): 484-500.

From the Co-founder of the Cochrane Collaboration:

U.S. Disability in the Prozac Era

“I know some excellent psychiatrists who help their patients a lot . . .I also know that some drugs can be helpful sometimes for some patients. And I am not ‘antipsychiatry’ in any way. But my studies in this area lead me to a very uncomfortable conclusion:

Millions of adults, 18 to 66 years old 5 4

Our citizens would be far better off if we removed all the psychotropic drugs from the market, as doctors are unable to handle them. It is inescapable that their availability creates more harm than good.”

3 2 1

--Peter C. Gøtzsche, 2013! Co-founder of the Cochrane Collaboration! Director of the Nordic Cochrane Center

0 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 Source: U.S. Social Security Administration Reports, 1987-2010

Anatomy of an Epidemic – The History and Science of a Failed Paradigm of Care Robert Whitaker Disability Due to Psychiatric Disorders in New Zealand, 1991-2010

Disability Due to Psychiatric Disorders in Australia, 1990-2010 Adults

Adults

250000

50000 40000

200000

30000 150000 20000 100000

10000 0

1991

1993

1995

1997

1999

2001

2003

2005

2007

50000

2009

1990

Source: Statistics New Zealand, Annual reports, 1999-2010

1992

1994

1996

1998

2000

2002

2004

2006

2008

2010

Source: Australian Government, “Characteristics of Disability Support Pension Recipients, June 2011.”

Percentage of All New Disability Cases in Sweden That Are Due to Mental Illness

New Cases of Disability in Denmark Due to Mental Illness

60% 50% 9000

40%

6750

30%

4500

20% 10%

2250

0% 1992

0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

1994

1996 1998

2000 2002

2004 2006

2008 2010

Source: OECD. Mental Health and Work: Sweden, 2013.

Source: Danish government, The Appeals Board, Statistics on Early Retirement.

Anatomy of a Failed Paradigm of Care

And Finally, a Diagnostic Manual that Lacks Validity

• •

“When I graduated a generation ago, I accepted DSM IV as if it were the truth. I trusted that my elders would put the truth ﬁrst, and then compromise for practical purposes where they had no truths to follow. It took me two decades to realize a painful truth, spoken now frankly by those who gave us DSM III when Ronald Reagan

• •

was elected, and by those who gave us DSM IV when Bill Clinton was president: the leaders of those DSMs don’t believe there are scientiﬁc truths in psychiatric diagnosis —only mutually agreed upon falsehoods. They call it reliability.”

•

—Nassir Ghaemi, Tufts Medical School Department of Psychiatry, 2013.

•

The biology of mental disorders remains unknown. Psychiatric drugs induce the very abnormalities hypothesized to cause mental disorders (oppositional tolerance). Over the long-term, antidepressants and other psychiatric drugs increase the chronicity of the disorders they are supposed to treat. Antidepressants and stimulants increase the risk that a person will turn “bipolar,” which is fueling the increase in the number of disabled mentally ill. Since the publication of DSM III, the number of people disabled by mental illness in the United States and other developed countries has soared. The DSM categories lack “validity”.

Optimal Kids: Improving Childrenâ&#x20AC;&#x2122;s Mood, Behaviour and Learning !"#$%#$&' Ron Hunninghake, MD

Optimal Kids

Anne Zauderer, DC Ron Hunninghake, MD

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Hypothesis: a Unifying Mechanism for Nutrition and Chemicals as Lifelong Modulators of DNA Hypomethylation'

Duk-Hee Lee,1 David R. Jacobs Jr.,2,3 Miquel Porta4 Environ Health Perspect; DOI:10.1289/ehp.0900741

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Outcome incident depression (CES-D)

Outcome incident depression

OR = 0.84 (0.76, 0.92) Am J Clin Nutr 2013

Adherence to the Mediterranean diet and risk for depression

ADOLESCENTS

RR = 0.68 (0.54–0.86) Psaltopoulou et al. 2013

The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD Healthy Neighbourhoods Study n ! 7000 - Murdoch Children's Research Institute Lowest intake of Healthy foods

Age Gender

Parental work status

Parental education level SEIFA score (SES) Family conﬂict

Poor family Management

Highest intake of Unhealthy foods

Physical activity Smoking

Adolescent dieting scale

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Highest intake of UNhealthy foods

Highest intake of Healthy foods

“Cross-sectional relationship between unhealthy dietary patterns and poorer mental health in children and adolescents”

O’Neil et al. Am J Pub Health 2014

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WHAT IS THE POSSIBLE CONTRIBUTION OF EARLY LIFE NUTRITIONAL EXPOSURES TO THE MENTAL HEALTH OF CHILDREN?

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The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD

F<%%/(.!)9!a+6&+7-! ?&7#$(!&+0/_$-!)9!=>?@AB"?C!MLL2F!*.!%)0#$(-!6<(&+7! 3($7+/+'.!/($!($8/0$6!0)!&+'($/-$6!$^0$(+/8&-&+7!*$#/4&)<(-!&+! '#&86($+! Impact of early life nutritional exposures extends from physical to mental health

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PREVENTION

The Microbiome in Psychiatry:Â Diet as a Prevention and Treatment Strategy Across the Lifespan Felice Jacka, PhD

The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

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Effect of one-day HFD feeding on inﬂammatory gene expression Waise et al. Biochemical and Biophysical Research Communications 2015

BDNF and brain plasticity •! Chronic intake (4 months) of high fat and/or high sugar diets increases free radical generation, protein oxidation & neuroinﬂammation and reduces BDNF in the hippocampus (Morrison 2010; Pistell

•! Adults 65+

2010)

•! Cognitive deﬁcits (place recognition memory) apparent within ONE WEEK (Beilharz 2013)

•! Dietary patterns predicted depression over time •! Not explained by detailed measures of SES or other health behaviours

•! Healthy adults who ate a high fat diet for one week performed worse on tasks measuring attention and speed of retrieval than they had prior to the diet (Edwards et al. 2011 FASEB)

The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD Hippocampal volume in older adults IVGG!

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r = 0.74

www.motherjones.com

The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD

2&$0!/+6!7<0!%&'()*&)0/!

•! In 98 individuals, enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides ) versus carbohydrates (Prevotella ). •! A controlled-feeding study of 10 subjects showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/low-ﬁber or low-fat/ high-ﬁber diet, but that enterotype identity remained stable during the 10-day study

•! Animal proteins and fats 2-3 times higher in Western diet •! Carbohydrates and fibre far higher in African diet •! Profound differences in gut microbiota composition African Americans switched to a high fibre/low fat diet for 2 weeks = significant reductions in mucosal inflammation and biomarkers of cancer risk (Africans switched to Western diet showed the opposite)

‘LEAKY GUT’

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Burcelin et al. Acta Diabetol (2011)

The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD ?&7#!9/0!6&$0!/+6!%&'()*&/8!0(/+-8)'/5)+!

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Live commensal intestinal bacteria present in large numbers in adipose tissue (MAT), mesenteric lymph nodes (MLN) and blood after only one week on a high-fat diet (HFD)

Amar J et al. EMBO Mol Med 2011;13:559-572

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The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD

•! Disruptions in cognitive and exploratory behaviours •! Associated neuroinﬂammation •! Absence of differences in body weight

•! Serum IgM and IgA against LPS of gram-negative Enterobacteria:

Hafnia alvei, Pseudomonas aeruginosa, Morganella morganii, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae measured in 112 depressed patients and 28 normal controls.

•! Signiﬁcantly elevated in acute and chronic depression •! Signiﬁcantly correlated with gastro-intestinal symptoms HFD = high fat diet

•! Germ free mice – showed that gut bacteria are necessary and sufﬁcient to cause antipsychotic-induced weight gain

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•! Antipsychotics shift microbiota towards an ‘obesegenic’ proﬁle •! Antipsychotic had antimicrobial action in vitro

Dash et al. Curr Opin Psychiatry (2015) Jan;28(1):1-6

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PNAS | February 15, 2011 | vol. 108 | no. 7 | 3047–3052

The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD

E)6$!)9!6$8&4$(.! •! E)6$!)9!6$8&4$(.!#/-!/+!&+f<$+'$!)+!0#$!$/(8.! ')8)+&l/5)+!)9!0#$!7<0!%&'()f)(/!&+!+$`*)(+-!! •! >$`*)(+-!6$8&4$($6!*.!'/$-/($/+!-$'5)+!-#)`!! 6&e$($+'$-!&+!')8)+&l&+7!%&'()*&)0/!9)(!4/7&+/88.!/+6! '/$-/($/+!6$8&4$($6!'#&86($+!0#/0!3$(-&-0!`$88!&+0)! '#&86#))6!/+6!/($!/--)'&/0$6!`&0#!&+'($/-$6!*)6.!%/--! /+6!'#&86#))6!)*$-&0.!XF/8%&+$+Z!FH!j<0!VGGPn!W8<-0$&+Z!mH! D+!m!L*$-!VGNI[! "#<-Z!c/7&+/8!%&'()f)(/!&%3)(0/+0rr!

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Jasarevic et al. Neurobiology of Stress (2014)

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Male and female mice either received LDP from birth or did not receive antibiotics.

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All mice were started on a NC diet, and then half were maintained on normal chow and half switched to a HFD at week 17

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Low dose penicillin delivered in early life results in lasting effects on body composition via transient changes to the microbiota

Jasarevic et al. Neurobiology of Stress (2014)!

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The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD ?$/80#.!,/($+0-Z!?$/80#.!u&6-!d!! /!3($7+/+'.!-0<6.! ! Collaboration MCRI, APC! and Deakin University Two groups (mothers third trimester) Two half day workshops, followed up with monthly phone support for health behaviour change “… the potential of dietary manipulation in the periconception and perinatal period as a key strategy for improving health outcomes in children”

Diet (gut focused)

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Dietary improvement as a treatment strategy in major depression: RCT#

Recruitment completed in April 2015

“…. clinicians should advocate dietary improvement for their patients with depression and should not be pessimistic about the likelihood of adherence to such recommendations” O'Neil A…Jacka F. A randomised, controlled trial of a dietary intervention for adults with major depression (the SMILES trial): study protocol BMC Psychiatry 2013 13:114

The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD ! !"#$%&,-.$/"/-.0&! !

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whole of diet approach

“There can be no health without mental health” (WHO)! ! ! Opposite also true! ! !

INTERNATIONAL SOCIETY FOR NUTRITIONAL PSYCHIATRY RESEARCH WWW.ISNPR.ORG info@isnpr.org www.facebook.com/ISNPR

The Microbiome in Psychiatry: Diet as a Prevention and Treatment Strategy Across the Lifespan

16-04-01

Felice Jacka, PhD

It is both compelling and

LANCET PSYCHIATRY (published online Jan 26th 2015)

daunting to consider that dietary intervention at an

“Nutritional medicine should now be considered as a mainstream element of psychiatric practice, with research, education, policy, and health promotion supporting this new framework”

individual or population level could reduce rates of psychiatric disorders.

AJP 2010

Why Treating Mental Illness with Minerals and Vitamins Makes Sense Bonnie Kaplan, PhD

Disclosure

Micronutrients and Mental Health

No commercial interest in any company or sale of any product Bonnie J. Kaplan, PhD Professor, Cumming School of Medicine University of Calgary, Alberta, Canada April 2016, ISOM, Vancouver Kaplan@ucalgary.ca

Disclaimer There are other causes of mental challenges, other than nutrition!

Nutrition: there are 2 sides to this coin

What are we NOT eating enough of

What we eat that maybe we should not eat

Gluten

Minerals vitamins

Casein/ dairy

Phytonutrients

Omega-3 fatty acids

Artificial additives

EARLY 20TH CENTURY

My topics 1.! A bit of history

!!1910 People’s Home Library: 500-page source of in-depth practical knowledge for North American homesteaders

2.! Review some evidence on micronutrient treatment (minerals & vitamins) in pill form

!!General guide: treatments for everything from minor burns up to tuberculosis and heart disease

3.! Show you how our societies can save $$$ (and suffering)

!!The number one cause of acquired insanity was “imperfect nutrition”

Why Treating Mental Illness with Minerals and Vitamins Makes Sense Bonnie Kaplan, PhD

The obvious solution? This was the compendium of “Common Knowledge”

Teach everyone to eat better

100 years ago! (It would have been in Clinical Practice Guidelines)

Paxton s Start the Conversation

An important digression:

What all clinicians can do

1.! How many times a week do you eat fast food meals or snacks

•! Start the conversation! •! Here’s something every clinician could say to every patient/client:

2. How many regular sodas or glasses of sweet tea do you drink each day? 3. How many servings of fruit do you eat each day? 4. How many servings of vegetables do you eat each day?

There is an increasing amount of scientific data showing that what we eat influences how we feel. Let s talk about your diet.

Single nutrient research

re: The obvious solution

Began in earnest, scientifically, in the 1920s

Teach everyone to eat better Difficult to do, and may not be sufficient for everyone

Why Treating Mental Illness with Minerals and Vitamins Makes Sense Bonnie Kaplan, PhD

One small portion of serotonin pathway 5-Hydroxyindole-acetyaldehyde 6-Hydroxykynurenate

Vit. B6

5-Hydroxyindolepyruvate

!!Review of nutrient treatment research 1920s-present --for mental health

3-Formylaminobenzaldehyde

!!Some correlational data; some treatment studies !!Strongest evidence in single nutrient studies: iron, copper, zinc, vitamins B1, B6, B12, D, E and folate

5-Hydroxy-N-formylkyunrenine Molybdenum

Vit. B6 Indole

Copper

Vit. B6 Iron

!!Better clinical efficacy from multi-ingredient treatments

Serotonin

5-Hydroxy-L-tryptophan Vit. B6

Iron

Tryptophan

3-Indole-glycolaldehyde

Take-away messages

At least 25% of teen consumption

1.! Variety of micronutrients needed 2.! How could you choose only one for a treatment study? 3.! Are mental disorders equivalent to inborn errors of metabolism? (re: Ames 2002, J Clin Nutr) 4.! Do our diets provide sufficient micronutrients for optimal brain metabolism? For everyone?

Whatâ&#x20AC;&#x2122;s the evidence for taking nutrients in pill form? !! Since 2000, multinutrient treatment: !! ~25 RCTs with multi-nutrient and broad-spectrum formulas â&#x20AC;˘! All trials on clinical samples -POSITIVE

Why Treating Mental Illness with Minerals and Vitamins Makes Sense Bonnie Kaplan, PhD

Micronutrients & Psychiatric Symptoms: Evidence of Benefit

OSU Case Study: EMPowerplus

Frazier, Fristad & Arnold, 2009, J Ch Adol Psychopharm

•! Boy diagnosed at age 5 yrs, 11 mos with BP-NOS –! severe mood cycling, sadness, irritability, selfharming behaviors, sleep disturbance, severe tantrums, elevated mood, poor peer relations, low frustration tolerance, flight of ideas, aggressive behavior, hyperactivity and impulsive negative behaviors

•! Case studies •! Case series, and reversals •! Case series of hundreds (databases)

•! By age 8: BP-I, GAD, learning and communication disorders

•! Case controls

–! impairing anxiety and worsening mood symptom intensity and cycling, increased destructive behavior, transient suicidal ideation, and increased global impairment

•! RCTs

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

By ages 10-11: psychotic features (auditory hallucinations), obsessions and compulsions –!increasingly aggressive. –!Intrusive, command hallucinations when anxious, told him to act on his compulsions, do things he did not want to –!threatened him ~100X/wk telling him If you don t do this you ll surely die. and Don t listen to [parents and other adults] . –!removed from his private school and was home schooled

•! Medication+psychoeducational psychotherapy •! Many medication trials •! No medication combination maintained symptom amelioration and adequate global functioning over an extended period of time

•! Spring 2008: micronutrients (EMPowerplus)

Progression of Evidence on Micronutrients & Psychiatric Symptoms

•! Fall 2008: Began regular public school (for the first time), on a school soccer team, friendships, parents report improvements in functioning while taking EMP+ are greater than those made in the past on medications

•! Case studies

•! His only additional intervention: whey protein (1/2 C) mixed in milk when very active. According to his mother, helps keep him clear, slowed down, peaceful, settled and happy

•! Case series, and reversals

•! Summer 2009: Continues to remain stable, a normal teenager

•! Case controls

•! Summer 2011: Needed to increase dose

•! RCTs

•! Case series of hundreds (databases)

•! Summer 2013: parents divorcing, having adjustment issues but completing HS, sports

Why Treating Mental Illness with Minerals and Vitamins Makes Sense Bonnie Kaplan, PhD

Symptom reduction in adults with bipolar disorder

First case series, with adults with bipolar disorder Kaplan et al., 2001, J Clin Psychiatry

- 11 pts aged 29-46 yrs -! Assessed at baseline with SCID by psychiatrist

Bipolar Mixed 9%

-!Took a broad-spectrum formula This was an unselected sample

Total Score

Bipolar NOS 9%

Bipolar I 46%

Bipolar II 36%

45 40 35 30 25 20 15 10 5 0

Ham-D

YMRS

Pre-intervention

BPRS

** p<.01 * p<.05

Post-intervention

Open Label Childhood Mood Dysregulation Frazier, Fristad, Arnold, 2012, J Comp Alt Med

Side effects?

â&#x20AC;˘! N=10, 2-month open label trial of EMP+ â&#x20AC;˘! Participants had to remain off all psychotropic meds for 11 wks (3 wks prior to EMP+ and 8 wks of EMP+) "! 10 children age 6-12; M = 8.9, SD = 2.0

minor and transitory

Compliance?

good but not perfect

**Large effect size (>.8) >2 year follow-up

ITT (N=10) Depression Scores Over Time, p<.06

Study Completers (n=7) Depression Scores Over Time p<.05 12

Mean KDRS Score

Mean ITT KDRS Score

8 8

4 4

0 visit 1

visit 2

visit 3

visit 4

visit 5

visit 6

visit 7

visit 1

Timepoint

visit 2

visit 3

visit 4

visit 5

visit 6

visit 7

Timepoint

Why Treating Mental Illness with Minerals and Vitamins Makes Sense Bonnie Kaplan, PhD

Micronutrient supplementation in 231 young adult prisoners Ratio of rate of disciplinary incidents supplementation/baseline

Gesch et al. 2002, Br J Psychiatry

!! RCT in 231 young offenders â&#x20AC;&#x201C;average length in RCT: 142 days !! Supplement with a broad array of minerals, vitamins, and some EFAs (26 ingredients at RDA levels)

Active supplement

26.3% fewer rule infractions 35.1% fewer violent acts

Replication in a Dutch sample

Active

Placebo

1 0.8

0.6

!6.7%

0.4

!35%

0.2 0

Before Supplementation

During Supplementation

Stress, Natural"#$$%&'! Disasters

Zaalberg et al. 2010, Aggressive Behavior

!!8 RCTs have shown that micronutrients:

Incident ratios

!! decrease stress/anxiety in both stressed and nonstressed populations !! Carroll et al., 2000, Psychopharmacology; Gruenwald et al., 2002, AT; Schlebusch et al., 2000, SAMJ; Kennedy et al., 2010, Psychopharmacology; Stough et al., 2011, Hum Psychopharmacol; Long & Benton, 2013, Hum Psychopharmacol ; Rucklidge et al., 2012, Hum Psychopharmacol ; Kaplan et al., 2015, Psychiatry Res

14%

!! 1 RCT found no benefit of micronutrients over placebo in a normal population on anxiety/stress measures (Harris et al., 2011, Hum Psychopharmacol)

!34%

7.1 earthquake in Christchurch,NZ occurred during active trials of multinutrient treatment 7%/,%-<%+)=,>)?@A@)=BCD'-)

185 people died, 7000 injured Dr. Julia Rucklidge and her research team were evaluating broad spectrum mineral/ vitamin formulas in the treatment of ADHD symptoms in a group of adults

Why Treating Mental Illness with Minerals and Vitamins Makes Sense Bonnie Kaplan, PhD

Still protective one year later

% who would have met criteria for probable PTSD

*!" )!" (!" '!" &!" %!" $!" #!" !"

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!"#$%"&'(#)*+, -.%"//0'(#)12, 3456'''(#)17, 3458'''(#)12, Control B complex BSM low BSM

-09.&:#. hi 6';..<9 Rucklidge et al., 2014, Human Psychopharmacology

AB-NZ collaboration"

Kaplan et al., Psychiatry Research, 2015 $"

F(2,52)=3.81, p<.05; ES=0.76-0.88

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3 studies (post-earthquake, postﬂood) now show the same thing that has been shown in experimental models

–!Two RCTs •!one showed no additional benefit of nutrients above effect of omega 3s but used low dose (below RDA) of micronutrients (Sinn & Bryan, 2010, JDBP) •!one positive with broad spectrum micronutrients (Rucklidge et al., 2014, BJP)

HUMANS ARE ALSO more resilient to stress when they are better nourished

Why Treating Mental Illness with Minerals and Vitamins Makes Sense Bonnie Kaplan, PhD

Micronutrients for adults with ADHD: RCT evidence

Improvement in self rated ADHD symptoms

Rucklidge et al., 2014, Brit J Psychiatry

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"! 80 participants with ADHD (med free)

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"! Mean age: 35 years

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"! 8 weeks RCT: 42 received micronutrients, 38 received placebo

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Which commercial broad spectrum formulas have any evidence of benefit with mental symptoms?

23&4$3(531

Commercial vs research products: Are they the same? Rucklidge, Harris & Shaw, 2014, NZMJ

))))))))))))))E%0%'+F>)08//(%-%#,0))))))))))9$%+G,>%GF"8#,%+)08//(%-%#,0

“Andrew”

Nutrition above the neck

!! Middle child of 3; intact Calgary family !! Age 10: “stressed” and “overwhelmed”

1.! Importance of nutrition for mental health 2.! Review some evidence on micronutrient treatment (minerals & vitamins) 3.! Show you how our societies can save $$$ (and suffering)

!! Disturbances in sleep, concentration, behaviour !! Auditory hallucinations, paranoid ideation !! Symptoms of Obsessive Compulsive Disorder !! 6 months inpatient med trials: no change

Why Treating Mental Illness with Minerals and Vitamins Makes Sense Bonnie Kaplan, PhD

“Andrew” by spring 2009 (and still in 2016)

Hallucinations Visual hallucinations

Auditory hallucinations

$! No clinically significant anxiety $! No psychotic symptoms $! Enjoys school, has friends $! Normal relationship with sibs $! No adverse events, No safety concerns $! Graduated high school May 2015 M Rodway, A Vance, A Watters, H Lee, E Bos, B Kaplan, Efficacy of micronutrient treatment of childhood psychosis, BMJ Case Reports, Nov 9, 2012

The new model of mental health in terms of brain metabolism is an optimistic message

Micronutrients cost <2% of conventional treatment

•! Good nutrition is foundational to mental health --- and it is a modifiable risk factor •! It is a model that will eliminate most of the stigma: –! does Andrew suffer from mental illness? Cost of conventional inpatient treatment

–! or imperfect nutrition?

Cost of micronutrient outpatient treatment

‘But aren’t psychiatric problems mostly genetic?’

kaplan@ucalgary.ca !! For questions or comments

“The genes for mental illness

!! To join my email update list

are likely

!! To learn about the 3-part webinar series !! To get links to TEDx talk

the genes that regulate brain metabolism of essential nutrients.”

!! To learn about how you can support research on multinutrient treatment of mental disorders with tax-deductible donations

Pauling (1974)

Searching for Orthomolecular Wholeness in a Broken World: One Woman Psychiatrist’s Journey

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Integrative Oncology Patient Support

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Integrative Oncology Patient Support

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Michael Gerber, MD

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Cervical Lymphatic Drainage Points

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Integrative Oncology Patient Support

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Michael Gerber, MD

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Integrative Oncology Patient Support

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Michael Gerber, MD

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Integrative Oncology Patient Support

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Michael Gerber, MD

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Reference Checking

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

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Prominent Promoters of Chronic Degenerative Diseases %%

Prominent Promoters of Chronic Degenerative Diseases&

1. Infections (endotoxins, exotoxins, aerobic and anaerobic metabolic byproducts, dental); documented to strongly promote oxidative stress and lessen antioxidant capacity 2. Known exogenous toxin exposures (heavy metal, pesticides, etc.) 3. Toxic iron status (most people in “normal” range are toxic) 4. Toxic calcium status (the rule in all adults) 5. Dietary toxin exposures (constipated gut, Clostridium); inadequate/poor nutrition and/or poor digestion; poor digestion is worse than poor nutrition in terms of impact on the antioxidant capacity of the body 6. Low sex hormone levels; low or elevated thyroid hormone levels; low thyroid especially important in promoting infection

All promoters of chronic degenerative diseases share one common denominator: they cause/ promote/result in:

Increased Oxidative Stress

Increased Oxidative Stress&

Toxins and Infections: Common Denominator

A state existing when the production of free radicals (highly reactive pro-oxidants) in the human body exceeds the body's antioxidant capacity to neutralize them, or to prevent their production in the first place. Oxidative stress always results when there is a deficiency of antioxidants and/or there is an excess of free radicals. Halliwell, 2006 [16760481]

& Question: What do all toxins and infections have in common?

Increased oxidative stress can also be characterized as existing when excess levels of previously oxidized biomolecules (RNA, DNA, enzymes, structural proteins, lipids, sugars) are present.

Answer: All infections and all toxins cause cell/tissue damage and produce symptoms by increasing oxidative stress. No exceptions.

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Increased Oxidative Stress and Disease

Redox Physiology: How Does It Work? Nutrient/Toxin Relationship

Increased oxidative stress (intracellular and/or

extracellular) causes all diseases and causes all disease symptoms The many variations in clinical disease expression pertain to: 1. The intracellular organelles, cells, tissues, and/or areas the body with increased oxidative stress 2. The biochemical properties of the molecules (toxins) directly causing the increased oxidative stress 3. The genetic predispositions (susceptibilities) present 4. The chronicity of the increased oxidative stress 5. The degree of increased oxidative stress

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The defining property of a nutrient is to metabolize into one or more substances that have the ability to donate electrons (REDUCTION):

Antioxidant = Nutrient Nutrient = Antioxidant

& &

Redox Physiology: How Does It Work?

Nutrient/Toxin Relationship

Even though there is a tremendous variety of molecular structure among all of the known toxins, they ALL SHARE the property of taking, or causing to take, electrons from other molecules, oxidizing them and causing a state of increased oxidative stress. They also share the property of HOLDING ON to those electrons, and not allowing themselves to be readily oxidized again, as is seen with an antioxidant molecule like vitamin C. If a molecule does not cause the loss of one or more electrons from another molecule it IS NOT TOXIC, and it CANNOT BE TOXIC. Toxicity and any symptoms of toxicity cannot exist unless electrons are being taken from other molecules (oxidation) and retained by the toxin.

The defining property of a toxin, directly or indirectly, is its ability to take electrons (OXIDATION): Pro-oxidant = Toxin Toxin = Pro-oxidant

The Basic Laws of Redox Physiology

Toxins: Basic Principles Factors determining the clinical expression of toxins:

1. Electrons are literally the fuel of life. The “combustion” of this fuel is nothing more than the flow (exchange or relay) of electrons between and among biomolecules (reduction/ oxidation)

1. Solubility characteristics (water- or fat-soluble; a determinant as to where toxin accumulation occurs) 2. Molecular size (access, permeability) 3. Ionic charge (access, permeability) 4. Physical mass of accumulation 5. Access of intrinsic chelators to sites of toxin accumulation (for example, glutathione transferases) 6. Were intrinsic chelators or other molecules of detoxification among the molecules oxidized? 7. Whether the chemical nature of toxin initiates oxidative chain reactions, massively upregulating oxidative stress

2. All increased oxidative stress causes electron depletion and inhibits optimal electron flow 3. All toxic effects are caused by increased oxidative stress. 4. Increased oxidative stress IS all disease.

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Toxins: Basic Principles

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Toxins: Basic Principles Factors determining the clinical expression of toxins:

Factors determining the clinical expression of toxins: 8. The chemical nature of a toxin prevents redonation of the electrons taken (basic difference between an antioxidant and a reduced toxin); an antioxidant readily gives up electrons, and a reduced toxin does not. This is why antioxidant molecules molecules PROMOTE electron exchange and flow, while toxin BLOCK electron exchange and flow. This is also why an antioxidant can repair an oxidized biomolecule, while a toxin cannot, even though both the antioxidant and the toxin are replete with electrons; the chemical nature of the toxin only allows it to repeatedly take and keep electrons, while the antioxidant can take and give electrons. After toxins acquire electrons, they are in their most stable chemical configuration, and they are unable to donate electrons as an antioxidant would. & &

9. Physical accumulation, above and beyond the oxidation of nearby biomolecules, can further impair normal tissue function by physically interfering with the ability of biomolecules, enzymes, and antioxidants to interact. It is this physical accumulation that effective chelation and/or excretion can greatly lessen over time. Even if a toxin has already oxidized a biomolecule and is relatively nonreactive, it can further impair cellular function by making it more difficult for vital cellular molecules to physically interact and/or react with one another, as long as it is not mobilized and excreted.

Toxins: Basic Principles

Increased Oxidative Stress and Redox Physiology&

Factors determining the clinical expression of toxins:

The biomolecules of the body (enzymes, proteins, fats, sugars, structural molecules, etc.) exist in either a reduced or an oxidized state. Rarely, a biomolecule might be chemically inert and not be technically oxidizable, although it would still be technically in a reduced state, with a full contingent of elections. When reduced, the biomolecules have their optimal state of electron repletion/saturation; oxidized biomolecules are in a state of electron depletion. Reduced biomolecules are in a state of optimal physiological function; oxidized biomolecules are in a state of decreased to absent physiological function.

10. Toxins can be directly pro-oxidant by oxidizing the biomolecules near to them. Toxins can also be predominantly indirectly pro-oxidant, such as when they inactivate any of a number of antioxidants or antioxidant enzymes (for example, superoxide dismutase or catalase), which then results in the secondary upregulation of oxidative stress. An example would be the binding of a heavy metal like mercury to the sulfhydryl groups in various enzymes, amino acids, and antioxidants such as glutathione and N-acetylcysteine.

Increased Oxidative Stress and Redox Physiology&

Furthermore, as oxidative stress increases and the redox balance ratio decreases, there is less effective electron flow in a given tissue, organ, multicellular, or cellular microenvironment. Redox molecules, like vitamin C, promote these vital microcurrents and facilitate the maintenance of healthy transmembrane electrical potentials. The health of any area of the body is directly related to its ability to permit electron flow through the tissues. Oxidized biomolecules block this flow, or severely impede it, depending on their prominence (concentration) in a given area of the body.

The degree to which a tissue, organ, or a specific microenvironment in the body is optimally functional (wellness) versus being decreased in, or devoid of, function is directly related to the ratio of how many biomolecules are reduced to how many biomolecules are oxidized (redox ratio: reduction/oxidation) in that area of the body. A higher redox ratio reflects better physiological function and health; a lower ratio reflects different degrees of disease.

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Oral Pathogens as a Common Cause of Chronic Disease Thomas Levy, MD, JD

Treatment Principles for All Chronic Degenerative Diseases

Treatment Principles for All Chronic Degenerative Diseases&

1. Prevent/minimize new daily toxin exposure (environmental, dental, dietary, digestive) 2. Neutralize existing toxins present in body 3. Excrete toxin stores in a non-toxic, or minimally toxic, manner 4. Resolve infections, and eliminate the reasons for contracting new infections 5. Supplement optimally to maximize the antioxidant/ nutrient status of the body as completely as possible 6. Address hormone imbalance, typically deficiencies of testosterone, estrogen, and/or thyroid hormone &

Dental infections and non-infectious sources of dental toxicity are involved in all six of these treatment principles, as will be discussed. Very, very few people (none??) with any significant chronic degenerative disease(s) have a healthy mouth. Even the “healthy” mouth is filled with pathogens, and pathogens are the most reliable source of new, ongoing, and highly potent toxins. When the pathogens in the mouth are allowed and helped to magnify, substantial chronic disease can then ensue, lead prominently by heart disease, cancer, and autoimmune disease.

Primary Sources of Oral Infection/Toxicity&

The Root Canal Procedure&

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1. Root canal-treated teeth (most impactful, along with painful, acutely abscessed teeth) 2. Other chronically infected teeth (typically asymptomatic) 3. Chronic periodontal (gum) infection/inflammation 4. Cavitational gangrene (old extractions and around root tips of root canal-treated teeth) 5. Chronically infected tonsils (draining root canals and other infected teeth) 6. Infected dental implants 7. Toxic metals (mercury, nickel, etc.)

The Root CanalTreated Tooth&

Over 5000 consecutive extracted root canal-treated teeth were examined and analyzed. 100% had pathogens and highly potent pathogen-related toxins. If there does exist a nontoxic root canal-treated tooth, it remains to be found and reported. Of note, “normal” teeth extracted for orthodontic purposes and analyzed showed no toxins or pathogens. All root canal-treated teeth continually produce endogenous toxins as the pathogens proliferate. Root canals that have been “identified” as infected have been found to have fungi, viruses, and over 460 different types of bacteria. (Siqueira, 2009 [19828883]) Any combination from this array of microbes and pathogens, however, represents what can be found in all root canal-treated teeth.

Once it is realized that all root canals are chronically infected, the mainstream dental literature provides the evidence clearly showing the wide array of pathogens and microbes that are present in these treated teeth. (Vidana 2011 [21155997]; Nobrega 2013 [23408792]; Siqueira 2013 [23554416]) Furthermore, this literature also documents the presence of endotoxins in these teeth. On the teeth that the researchers “acknowledged” to be infected, endotoxins were found to be present in 30 of 30 such teeth (Gomes 2012 [22794210]) A similar study found endotoxins in 21 of 21 root canals acknowledged to be infected. (Martinho 2011 [21238796]) Another study that looked at “asymptomatic” and symptomatic root canals, the DNA of bacterial pathogens was seen in 34 of 34 patients. (Rocas 2011 [21846535]) Finding a sterile root canal-treated tooth would be as amazing as finding a sterile mouth; either finding simply does not exist, as it is the mouth that “feeds” the remaining pulp and apex with microbes and pathogens.

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Root CanalTreated Tooth&

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Root CanalTreated Tooth& 6. For the molars and larger teeth, a perfect endogenous delivery system of pathogens and toxins into the venous blood and lymphatic drainage 7. From the draining veins, first high-pressure blood vessels to receive the pathogens/toxins: coronary arteries (and then the cerebral arteries) 8. From the draining lymphatics, a chronic to-andfro sharing of the pathogens/toxins with the lymphatic circulation of the breast(s)

1. Fatally-flawed procedure, assuring chronic infection 100% of the time 2. Immune system no longer has access to much of the tooth, or to the dentinal tubules 3. Fluid flow reversal post-procedure 4. Anaerobic environment—enormous toxicity 5. “Successful” procedure results in a pain-free, albeit still infected, tooth

Root CanalTreated Tooth&

Regular X-ray vs. 3D Digital X-ray&

Always highly toxic, but variably toxic, depending on:

In root canal-treated teeth, which are 100% infected, regular X-ray shows clear periapical pathology (radiolucencies from bone resorption secondary to infection) between 40 and 70% of the time, largely dependent on the quality of the X-ray and the experience of the interpreting dentist. DeMoor, 2000 [11307451]; Saunders, 1998 [9744239]; Gunduz, 2011 [21689415]; Weiger, 1997 [9550033]

1. Unique pathogen flora (bacteria, viruses, fungi, protozoa) 2. The tooth involved (small incisor versus large molar) 3. Containment; the degree to which the supporting bone becomes cavitated, further facilitating dissemination 4. Genetic predisposition to different diseases 5. How long the root canal has been present 6. The quality and quantity of nutrition and supplementation 7. Hormonal status, especially thyroid, directly and strongly affecting the likelihood and degree to which focal infection can spread and re-situate, as in the coronary and cerebral artery endothelial layers 8. Age and general health of the patient (significant osteopenia, osteoporosis elsewhere in the body?; immunocompromised?)

Regular X-ray vs. 3D Digital X-ray&

Root Canal and Periapical Infection&

In one study a careful examination was made of the same 46 root canal-treated teeth with regular X-rays and then with the 3D Digital X-rays. Periapical pathology (infection) was seen on 70% of the 2D exams and on 91% of the 3D exams. Lofthag-Hansen, 2007 [17178504] While infection is always present in root canals, pathology is clearly very often missed by regular X-rays, especially with less critically interpreted studies. Even though the root canal-treated tooth is always infected, radiolucencies at the root tip can more easily convince the otherwise reluctant dentist to extract the tooth.

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Infectious Periapical Pathology&

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Inflammation and Coronary Artery Disease& Inflammation is now accepted as the primary cause for initiating and evolving atherosclerosis. [Rosenfeld (2013), 23357128] Furthermore, atherosclerosis is now considered a chronic inflammatory disease [Legein (2013), 23430000]

But What Causes the Chronic Inflammation?&

But What Causes the Chronic Inflammation?& Pathogens, along with their associated toxins, are now accepted as a major (perhaps nearly entire?) reason for chronic inflammation at all stages of atherosclerosis [Bzowska (2012), 22556042]

Inflammation requires a pro-oxidant presence; for coronary artery disease, this is the seeding of pathogens and associated toxins from oral infectious sources into the coronary endothelium. When the seeding does not stop, the immune inflammatory response becomes chronic, and it becomes the disease it was designed to prevent.

Periodontal disease has long been clearly “linked” to the presence and evolution of atherosclerosis [Andriankaja (2011), 21375559; Shrihari (2012), 22313976].

As Hal A. Huggins, DDS, MS put it:

Periodontal disease (gum infection) has also been recognized as an independent risk factor for coronary artery disease [Humphrey (2008), 18807098]. &

“You can’t dry off while you are still in the shower.”

Root CanalTreated Tooth&

Root Canals and Heart Attacks: The DNA of oral pathogens typical for root canal and gum infection flora has consistently been identified in coronary atherosclerotic plaque [Haraszthy (2000), 11063387; Mattila (2005), 16277580; Mahendra (2010), 20657096] Also consistent with this poly-pathogen oral presence, a bacterial diversity of >50 different species has been identified in atherosclerotic lesions obtained via atherectomy. [Ott (2006), 16490835]

Root Canals and Heart Attacks: DNA of pathogens typical for periodontal infection and endodontic (root canal) origin were present in the blood clots aspirated from patients with acute myocardial infarction. [Pessi (2013), 23418311] 101 patients: endodontic (root canal-treated tooth) origin— 78%; periodontal origin—35% Total amount of DNA found in the clots was 16 times higher than was present in just the arterial blood

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Root CanalTreated Tooth&

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Root CanalTreated Tooth& In an extraordinarily surprising study from a mainstream dental journal, it was stated that individuals who reported having had two or more root canal-treated teeth were statistically more likely to have coronary artery disease. (Caplan 2009 [19654253]). Either no one was paying attention or no one wanted to pay attention. Regardless, all dental patients should be made aware of this study (and a summary of the rest of the data already cited) in their informed consent before receiving a root canal procedure.

Root Canals and Heart Attacks: Pessi’s study now finally converts the “link, association, correlation, risk factor” etc. conclusions of so many previous studies examining the mouth-heart disease connection to the now clear and inescapable conclusion: Root canal-treated teeth and periodontal disease have cause-and-effect relationships to coronary artery disease and heart attacks. Another study reported that “incident lesions” (aka, radiolucencies from chronic infection) of root canal origin on the X-rays of a group of individuals were associated with the more rapid development of coronary artery disease. (Caplan 2006 [17062738]) Similar findings have been seen more recently. (Pasqualini 2012 [23146639]; Willershausen 2013 [23604464])

Inflammation, Focal Infection, and Pathogens&

Inflammation, Focal Infection, and Pathogens& The same group that looked at root canal/ periodontal pathogens accumulating in acute MI thrombi also looked at the pericardial fluid postmortem of coronary artery disease patients. A sizeable majority of the fluid specimens had oral pathogen-specific DNA detectable by PCR (polymerase chain reaction) testing, and the worse the coronary artery disease was, the greater the total amount of DNA was found in the fluid. [Louhelainen (2014), 25412607]

Consistent with the seeding of coronary atheromas with oral pathogens of root canal and periodontal origin, strong evidence also indicates the same thing occurs in cerebrovascular arteries. Root canal-related bacteria were found in a majority of patients with ruptured and unruptured intracranial aneurysms. [Pyysalo (2013), 23761916; Pyysalo (2016), 26777430]

Root CanalTreated Tooth&

In addition to the cause-and-effect relationship that is now established between root canals and atherosclerosis, a strong link has also been long-noted between root canals and cancer. In the 1950s when very few root canals were being done, relative to today, Dr. Josef Issels found that 98% of his adult advanced cancer patients had, in Issels’ words, “between two and ten dead teeth.” Dr. Issels categorized a root canal as a dead tooth. [Issels (2005) Cancer: A Second Opinion, Garden City Park, NY: Square One Publishers, Inc.] Issels always extracted these teeth first, and his cancer survival rates were quite phenomenal.

The draining lymphatics and veins of the jaw and mandible make significant antioxidant depletion (increased oxidative stress) most likely to occur to the greatest degree in the head, neck, and chest (lymphatics) and the coronary/cerebral arteries (venous drainage). Once the pathogens and toxins enter the venous drainage, the first artery to be encountered is the coronary artery, with the attendant high pressure and shear force facilitating their endothelial localization/implantation.

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Root Canals and Other Infected Teeth&

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Root Canals and Other Infected Teeth& A regular Panorex mouth X-ray misses a lot of pathology. 3D digital X-rays of the mouth need to become an integral part of the routine baseline evaluation of any chronic degenerative disease patient, especially heart disease and cancer. The patient does not have to have chronic sinusitis for a chronically infected tooth to be present. And you will never know such a tooth is present if you don’t look for it. You don’t know someone has diabetes until you measure their blood sugar.

A minority of chronically infected teeth are symptomatic. An acutely abscessed, very painful tooth, relative to other infected teeth is the exception and not the rule. However, both types of infected tooth are highly toxic. Therefore, it is essential to look for such infected teeth proactively in the asymptomatic mouth, as their removal can end up being the most beneficial intervention you can offer your patient.

Chronically Infected Teeth and Sinus Infection&

Panorex X-Ray (2D)&

In addition to all the other reasons for looking proactively for asymptomatic infected teeth, you should also always do a thorough 3D examination of the teeth in any patient with chronic or unresolving sinusitis problems, or even chronic rhinitis. Anyone who tells you they have any trouble at all getting a good night’s sleep due to nasal stuffiness should be evaluated in this fashion. Kulacz et al. (2004) “An unsuccessful sinus surgery caused by dental involvement within the floor of the maxillary sinus” Operative Techniques in Otolaryngology—Head and Neck Surgery 15:2-3.

Maxillary Root Canal and Chronic Sinus Infection (3D)&

Non-Root Canal Infected Teeth and Chronic Sinus Pathology (3D)&

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Lymphatics, Neck and Chest&

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Lymphatics, Neck and Chest& While the lymphatic system is designed to flow in only one direction, disease, inflammation (as would be seen with the chronic presence of oral pathogen toxins in the lymph), enlarged lymph nodes, and other conditions can result in retrograde lymphatic flow as well. This effective “sharing” of lymphatically-drained pathogens and toxins makes the head, neck, and chest especially sensitive to the antioxidant depletion caused by root canals, and it is a major factor in the causation of cancer in the head, neck, and chest. Any treatment plan in a patient with a brain tumor or breast cancer that does not include a proper extraction of root canals and other infected teeth is missing the most consistent way to both get a tumor remission and a maintenance of that remission, without relapse or the appearance of a new malignancy. The cause of a cancer must be eliminated along with the cancer itself in any complete cancer treatment protocol.

Root CanalTreated Tooth&

Root Canals and Tonsils&

The root canal-treated tooth, due to its extraordinary ability to deplete antioxidants and promote chronic inflammation in affected tissues and organs, can be considered:

The root canal and other infected teeth “trash” the tonsils. Tonsils “manage” dental infections, but chronic infections like root canals overwhelm the tonsil, especially the ipsilateral one, and it morphs from an infection “manager” to a site of chronic infection than remains unresolved until surgically removed. Quite often, such infected tonsils continue to inflict a significant degree of chronic toxicity indefinitely after the root canal(s) or other infected teeth are gone, harboring many of the pathogens previously contained in the root canal (or the infected gums). Issels routinely removed the tonsils in his cancer patients, and he commented that nearly all of them were abscessed and chronically infected, even when appearing normal on examination. As a practical point, keep the option of tonsillectomy open for a patient who is not properly responding to what appears to otherwise be a complete and comprehensive treatment protocol. Tonsillectomy in adults is major surgery but of vital importance if indicated.

1. The single most important cause of cancer of the head, neck, and chest, and 2. The single most important cause of atherosclerosis and heart attacks. Currently, about 25 million root canal procedures are performed every year.

Periodontal Disease&

Periodontal (gum) disease is very common in the population today. The presence of this condition has now been wellestablished to be an independent risk factor for coronary artery disease. (Humphrey 2008, [18807098]; Kshirsagar 2009 [19165177]; Dorn 2010 [20367093]; Ameet 2013 [23730671]; Hanaoka 2013 [23676848]; Kodovazenitis 2013 [23713486])

Any infection and/or inflammation in the gums (even advanced conditions) is usually very effectively treated by daily, warm water irrigation (as with a Waterpik): 1 to 2 large cupfuls with one to two tablespoons of 3% hydrogen peroxide and a splash of preferred mouthwash for taste. Response is typically rapid, with initial significant gum bleeding at lower pressure levels improving to no bleeding at the highest pressure levels within a few weeks or much sooner. Never floss unless you have impacted food that water irrigation cannot reach, which is almost never the case, or you simply do not have the availability of water irrigation. A regular Waterpik treatment as described above would prevent most gum disease from ever developing, and would completely resolve a large amount of existing gum disease.

Not surprisingly, periodontal disease features the same array of pathogens and toxins, and the anaerobic environment, as root canal-treated teeth. Advanced periodontal disease and advanced tooth decay are often the reasons that a tooth becomes infected and leads to the root canal procedure being performed in the first place.

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Cavitational Osteonecrosis “Cavitations”&

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Cavitations&

A source of dental toxicity that remains little-appreciated, although it is extremely common, especially in older individuals. Depending on a number of factors, cavitations can be a source of extraordinary ongoing toxicity in some individuals, while representing a relatively minor toxic immune challenge in others. “Modern” dentistry not only does not appreciate the regular occurrence of cavitations, it shows little to no interest in conducting any meaningful research on it, or to even acknowledging its existence, except in “rare” circumstances.

Simply put, a cavitation is the residual hole resulting from the incomplete healing of the jawbone after a tooth is extracted. And while the hole can sometimes be large enough to compromise the integrity of the jawbone (traumatic fracture), it is the contents of these cavitations that present the real danger.

Cavitation&

Cavitation, Pathology and Schematic&

Cavitation, Extensive, Edentulous&

Cavitation Physiology& Every tooth is seated in the jawbone in a dense encasement of connective tissue known as the periodontal ligament. It serves to both anchor the tooth in its socket, as well as serving as a natural “shock absorber” for the impact of the tooth on the jaw and socket during chewing. It would be like the difference between sleeping on a mattress or a concrete slab.

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Cavitation Physiology&

In the course of the “routine” tooth extraction, no separate attempt is made to remove or clean out the ligament after the tooth is removed. Much of the time a bit of the ligament stays adhered to the tooth, and a variable amount of the ligament ends up gets inadvertently removed as well. It would appear that leaving the ligament in place is the primary reason that a cavitation forms, supported by an pre-existing poor ability to heal, as in a patient with significant osteoporosis elsewhere in the body.

Hypothesis When all or a significant portion of the periodontal ligament remains in the vacant tooth socket (typical extraction), the surrounding bone cells in the jawbone have no “physiological awareness” that the tooth is gone, since they are still abutting the dense ligament that normally separates them from the tooth. It is only when the ligament has been removed that the physical barrier and restraint that it normally presents to the bone has been removed, and the natural stimulus for osteoblast activity is present. Bone cells have never been known to grow “through” a periodontal ligament and form a direct bony encasement of the tooth. The loss of the ligament is the natural trigger for new bone growth.

Cavitation Physiology&

Cavitation Pathology&

It would appear that the actual size of the resulting cavitation depends on both the percentage of the ligament extracted and the strength of the patient’s immune system and basic healing ability. How well a blood clot forms, along with its not being disrupted until it naturally resorbs, also plays a big role in what healing does take place. At the upper edges of the socket, above which the periodontal ligament does not extend, the ligament inhibition to bone growth is never present, and the bone edges are free to gradually grow over the top of the hole, resulting in a typically thin cap of bone, usually complete by about 6 months or so. Direct intra-cavitation ozone injection can sometimes help grow new bone; using ozone at the time of cavitation cleaning should be even more effective in reducing/eliminating post-surgery residual cavitation.

Cavitation Contents The same variety of toxins and pathogens are seen in the cavitation as in the apex of the root canaltreated tooth. The pathogen population is generally more sparse, however, and there is only a minimal presence of immune cells. All cavitations contain a necrotic content, typically very foul-smelling, that is pathologically and chemically indistinguishable from wet gangrene.

Cavitations: Clinical Consequences&

The clinical consequences of cavitations are highly variable, depending on one or more of the following factors: 1. Size; larger with more necrotic contents 2. Socket site; molar sites more impactful 3. Presence of adjacent cavitations, promoting extending tunneling and large “channel-like” cavitations 4. Underlying health of patient, relating directly to how much cavitations spread or stay put; spread can be totally unpredictable and ameba-like; older edentulous patients can have cavitations that extend the length of the jawbone and down into the deeply seated alveolar nerves

Generally, chewing exerts relatively little, or no, pressure over a cavitation site in the same manner as an opposing tooth grinding against a root canal-treated tooth. Also, the cavitation is not directly “linked” to natural venous and lymphatic drainage like the root canal. As such, this major factor of toxin/pathogen dissemination with root canals plays no significant role in expressing the contents of a cavitation. Unless the cavitation is very large and extending outside of the original extraction site area, most of the gangrene stays put. Many people with medical problems secondary to root canals can completely resolve with the proper extraction of such teeth, and without addressing sites of cavitation. But not always.

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Cavitations: Clinical Consequences&

When the cavitation process expands deep into the bone and begins to surround the alveolar nerves with its progressive necrosis, the myelin sheath of the nerves can degenerate as well, and intense pain syndromes can develop. This pain can potentially be felt directly in the jaw or anywhere in the face, other teeth, mouth, and nasal cavities supplied by the trigeminal nerves. When a pain syndrome is present with cavitation, it is known as Neuralgia-Inducing Cavitational Osteonecrosis (NICO). However, the vast majority of cavitations in the jaw are not directly associated with any pain syndrome. The presence of pain, however, is an indicator of likely greater systemic toxic impact by the gangrenous cavitational contents.

Without even really knowing about cavitations and their clinical impact, some mainstream dental researchers have inadvertently documented their toxicity: The presence of fewer teeth, a state that is always accompanied by more cavitational necrosis, is related to a greater risk of all-cause mortality, including cardiovascular mortality. (Elter 2004 [15295942]; Holmlund 2010 [20350152]) Furthermore, less teeth were also associated with a greater incidence of the metabolic syndrome and laboratory markers of inflammation, important factors in the causation of atherosclerosis. (Holmlund 2007 [17722439])

Cavitations: Clinical Consequences&

It is always desirable to attempt the surgical repair of cavitations, as the long-term impact of these pockets of wet gangrene are inevitably bad for the health. When large cavitations are surgically explored with the contents and surrounding necrotic bone removed, this often does not result in a complete healing in of the jawbone hole/deficit. However, even a partial resolution of such a cavitation is always desirable, as smaller holes not only contain less necrosis, they also shrink progressively further away from the nerves and apical blood/lymphatic drainage of the socket and become of less long-term clinical consequence.

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Whenever possible, the residual extraction site after surgical cleaning should be allowed to fill with blood and clot normally, with some closure of the overlying gum tissue to keep the clot from becoming dislodged later. In addition to the basic health of the individual’s immune system and bone metabolism, how well a cavitation heals in healthy bone relates to how well the initial blood clot sets, as it provides a physical matrix that facilitates the gradual ingrowth of new bone cells over time.

Cavitations&

Dental Implants&

Nearly 90% of the time a very minimal exploration by a dental drill will find cavitations at the sites of healed-over wisdom teeth extractions, commonly decades after the extractions. [Levy & Huggins (1996) Routine dental extractions routinely produce cavitations. Journal of Advancement in Medicine 9:235-249.] Time alone cannot be expected to “heal” such cavitations and fill them in with good bone. They are always permanent unless and until they are properly addressed surgically, and appropriate measures are take to support new bone growth. Repeated surgeries are often required, but it should be realized that the toxin exposure gets smaller and of less consequence with smaller residual cavitations, especially when surrounded by new bone growth.

Dental implants are another source of variable degrees of toxin exposures, somewhat like cavitations. In any given patient, the toxic impact can be minimal to massive. A dental implant involves the insertion of a dental material (post or anchor) at the site of a missing tooth. This post allows the subsequent attachment of a prosthetic tooth or even to anchor a bridge. Unfortunately, the implant procedure is usually initiated relatively shortly after the tooth extraction takes place. When the extraction was done in a typical fashion, without the proper removal of the periodontal ligament, the implant is being initiated in an area of developing cavitation, which seeds its infectious contents deeper into the bone.

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Dental Implants&

When implanted into solid, healthy bone, with no developing osteonecrosis, a dental implant can be stable, strong, and often an inconsequentially toxic procedure, although some patients can still develop autoimmune reactions due to the foreign material being directly implanted into bone. However, these factors are rarely taken into consideration, and the implant is more often put into an area of developing necrosis, with pathogens and toxins already present, in a socket with a poor blood supply, and in an older person with a variable degree of preexisting immune system compromise.

When an implant is performed in its typical fashion, some cavitation in and around the implanted post is largely assured. Nevertheless, since the original roots of the extracted tooth are now absent, the effective delivery upon chewing of the toxins and pathogens that are present is impaired to some degree, relative to the degree to which chewing on a root canal can effectively extrude them into the draining veins and lymphatics.

Dental Implant&

Dental Implants&

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While the toxicity of an implant can potentially be minimal, most dental implants in most older individuals placed without regard to the factors mentioned present significant immune challenges to those patients and are very strong contributors to all chronic degenerative diseases. A properly performed dental implant is best maintained and prevented from becoming infected by diligent and meticulous gum care, as previously mentioned (Waterpik), as the gum contact point against the prosthesis is the major barrier preventing pathogens from reaching the prothesisbone interface over time.

Thyroid Hormone and Atherosclerosis&

Thyroid Hormone and Atherosclerosis& Although 90%+ of all patients with CAD and heart attacks have dental infection/toxicity, maintaining a EUTHYROID status strongly protects against sustaining a myocardial infarction, seemingly regardless of dental status and other heart disease risk factors.

& Very amazingly, no one was asked to stop smoking or modify any of their dietary or exercise habits during this period of time. 62% of the men in the study group were smokers. Barnes also noted that at least 30 fatal heart attacks occurred in those who stopped thyroid therapy and dropped out of the study. (Barnes and Galton, 1976, Hypothyroidism: The Unsuspected Illness)

Broda Barnes reported on 1,569 patients that he treated with dessicated thyroid, most over a 20-year period. Only four men had heart attacks during this period. For a group of this size and age, the Framingham study established that 72 individuals should have sustained heart attacks during a comparable period of time.

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Intracellular Hypothyroidism&

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Thyroid Status and Infections&

Most adults are at least mildly hypothyroid; standard thyroid blood tests do not reliably reflect this. Rather, they reflect hyperthyroidism fairly well, as well as severe hypothyroidism. Much of the reason for this is that most mildly hypothyroid individuals have intracellular rather than glandular hypothyroidism. Roughly 80% of the T4 produced by the thyroid is converted to T3 outside of the thyroid gland throughout the cells of the body, making many cells de facto “mini-thyroid glands.” Routine blood testing reflects the normalcy of thyroid gland activity but not the ability of the cells in the body to effectively convert T4 to T3, which is where most of the functional thyroid hormone metabolism takes place.

Thyroid Hormone While it is reasonable to try to correct a low thyroid status in anyone, it would appear especially important to do so in the patient with known cardiac disease. Many individuals have cellular hypothyroidism, and a proper ratio of free T3 to reverse T3 (18 to 21/1) needs to be achieved to have proper thyroid function clinically. As with sex hormone replacement, thyroid administration should be low and slow.

General Protocol for Chronic Degenerative Disease&

Primary goals:

1. Minimize new toxins A. No calcium, iron, or copper supplementation B. Address dental toxins/infections a. Root canals (Number one cause of heart attacks) b. Gums c. Cavitations d. Dental implants (usually improperly placed) e. Toxic dental materials (mercury, nickel)

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

General Protocol for Chronic Degenerative Disease&

1. Minimize new toxins

2. Eradicate infections Most infections significantly lowering antioxidant stores through the body will be found in dental sources. However, for many individuals, chronically infected tonsils will significantly impair or even block the recovery from many different chronic diseases. Usually tonsils that need extracting will be on the same side of the body as an existing or even previously extracted root canal-treated tooth. Generally, once a tonsil has drained a root canal for any significant length of time, it cannot recover even if the root canal is extracted. Rather, it becomes a source of chronic focal infection, seeding pathogens and toxins throughout the body. The protector becomes the infector. (Issels, 2005, Cancer, A Second Opinion)

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

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Thomas Levy, MD, JD

General Protocol for Chronic Degenerative Disease&

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

4. Correct critical hormone deficiencies Testosterone, estrogen, and thyroid deficiencies affect all the cells of the body. All three play prominent roles in calcium metabolism, in the bone and elsewhere Replacement must be low dose, slow to increase dose, and target lab should be low to mid-range normal, no more, and even a lower target for the person over age 70. Other critical laboratory tests, such as metabolic syndrome parameters, should be stable or improving during the treatment period. Bioidentical is preferable.

General Protocol for Chronic Degenerative Disease&

5. Optimize antioxidant levels A. Vitamin C, regular form as tolerated; liposome-encapsulated, 1 to 2 grams daily; ascorbyl palmitate, 500 to 1,000 mg daily B. Lysine, 1,000 to 2,500 mg daily and proline, 250 to 500 mg daily (2x more for known CAD) C. Vitamin D3: aim for blood level of 60 to 80 ng/cc D. Vitamin K2, 3 to 6 mg daily E. Magnesium glycinate, 200 to 400 mg daily F. Omega-3 EFA, fish oil source, 2,000 to 4,000 mg daily G. Vitamin E as mixed tocopherols, 400 IU twice daily H. Beta carotene, 25,000 to 50,000 IU daily I. Vitamin B complex, one daily

6. Appropriate prescription medications Only really to be utilized when a satisfactory clinical response is not seen with the rest of the protocol. This needs to be considered in the context that vitamin C, vitamin D, vitamin K, magnesium, EFAs, and properly adjusted hormone levels all individually decrease the chances of death from all causes. The prescription meds typically have side effects and only rarely positively impact longevity, except for such drugs as long-acting calcium channel blockers.

Recap&

Recap& 2. Because of the incredibly large role played by oral infections in virtually all diseases, it is essential that the practicing physician form alliances with the dentists in their area of the country. Some of the most impactful forces on the general health (asymptomatic chronically infected teeth) simply will never be discovered without specific testing. Full mouth 3D digital X-rays should be a routine part of the evaluation of all chronic disease patients, right along with the glucose, electrolyes, CBC, and biochemistry panel.

1. All chronic degenerative diseases are caused or worsened by chronic infections and the increased oxidative stress that they inflict throughout the body. Many significant diseases, such as coronary artery disease, are primarily caused by dental infections and toxins. Many cancers, especially of the breast, are also directly due to this same source of infection and toxicity.

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In the Words of Mark Twain

Recap& &

3. While there are many facets to a successful therapeutic protocol, it cannot be overstated how important it is to effectively diagnose and properly manage the increasingly large epidemic of low-grade hypothyroidism seen today. Many infections, with their enormous resultant toxicity, simply do not take “hold” in the face of normal thyroid status throughout the body (not just inside the thyroid gland).

“Be careful in reading health books. You may die of a misprint.” or, perhaps more accurately, and NOT in the words of the venerable Mark Twain:

“Be careful in reading health books. You may die from something printed as intended.”

G2,#$%H)'+& I appreciate very much the opportunity to present to this distinguished audience the concepts and ideas contained in this presentation. Your comments, questions, or thoughts regarding what was presented are welcome. Please feel free to contact me at: televymd@yahoo.com www.peakenergy.com Thank You. Thomas E. Levy, MD, JD

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Mitochondria'

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126

!"#$%#$&' Mitochondria and Cancer: The Bioenergetic Theory of Carcinogenesis

Michael Gonzalez, PhD

Cancer Biochemistry'

Cancer Biochemistry (cont)'

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Abnormalities in Nutrient Metabolism (Cancer)'

Changes in Metabolism (Cancer)'

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Changes in Metabolism (Cancer)'

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127

!"#$%#$&' Mitochondria and Cancer: The Bioenergetic Theory of Carcinogenesis

Michael Gonzalez, PhD

Metabolic !eories of Cancer'

Bioenergetic !eory Carcinogenesis" Energy, Cell membrane and Cancer' •! •! •! •! •! •! •!

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Metabolic !eories of Cancer (cont)'

RECNAC 2"

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RECNAC 2" Bio-Energetic !eory Carcinogenesis'

RECNAC 2"

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•! •! •! •!

128

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Mitochondria and Cancer: The Bioenergetic Theory of Carcinogenesis !"#$%#$&' Michael Gonzalez, PhD

Bio-Energetic !eory Carcinogenesis'

Cancer as a Metabolic Energy Disease' •! ]/657-9*,'8/052</N/26+'O0/,/8/'C/2/Q,' ,452</+=' •! 'C/2/Q,',452</+'O0-N-6/'528'O/0O/6:56/'64/' N59*<2526'+656/='

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Change the Conditions that Encourage Abnormal Growth'

RECNAC 2' (I4/0/'*+'5'7/b/0'351s'a*2/'*6t>' ' ' '#'I4-N5+'@='F8*+-2'

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Fig. 2 Schematic representation of the differences between oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis (Warburg effect).

M G Vander Heiden et al. Science 2009;324:1029-1033

Published by AAAS

129

!"#$%#$&' Mitochondria and Cancer: The Bioenergetic Theory of Carcinogenesis

Michael Gonzalez, PhD

Mito Diets'

Mitochondrial Optimization' •! •! •! •! •! •! •!

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RECNAC 2'

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130

!"#$%#$&' Mitochondria and Cancer: The Bioenergetic Theory of Carcinogenesis

Michael Gonzalez, PhD

Oxygen'

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131

!"#$%#$&' Mitochondria and Cancer: The Bioenergetic Theory of Carcinogenesis

Michael Gonzalez, PhD

Co-Q10'

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Vitamin C' •! •! •! •! •!

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Michael Gonzalez, PhD

Phospholipids'

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Nicolson GL & Ash ME. Lipid Replacement Therapy: a natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function. Biochim Biophys Acta. 2014 Jun; 1838(6):1657-79.

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Mito Health' •! •! •! •! •! •! •! •! •! •! •! •!

General Recommendations'

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!"#$%#$&' Mitochondria and Cancer: The Bioenergetic Theory of Carcinogenesis

Michael Gonzalez, PhD

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Jorge Miranda-Massari, PharmD

Change in the U.S. Death Rates* by Case: 1950 & 2005

High Dose Intravenous Vitamin C and Cancer: Improving its Effectiveness Jorge R Miranda-Massari Michael J Gonzalez Pharmacy Practice and Departments of Human Development RECNAC 2 Project, University of Puerto Rico Medical Sciences Campus, San Juan, PR Metabolic Correction Institute

May 1st, 2016, 45th Orthomolecular Medicine Today

Cancer Biochemistry

Chemotherapy and Survival

"!Radiation forms ROS - superoxide radicals from oxygen and increases its cell killing effect. "!Rapid growth of cancer cells promote hypoxic environment in spite of angiogenesis,

!! Study on Chemo and survival. Authors: 1 medical oncologist and 2 radiation oncologist. !! Analyzed randomized clinical trials in U.S. and Australia that reported a statistically significant increase in 5 year survival with Cytotoxic Chemotherapy (1990-2004). !! Contribution to 5 year survival Australia = 2.3% !! Contribution to 5 year survival US = 2.1%

"!Poor blood supply precludes adequate drug delivery and resistance to radiation –reduces ROS. "!Hypoxic cells are resistant to radiation to a great extent. "!The cancer cells survive by switching to fermentation of sugars (glycolysis) for energy.

Morgan G, Ward R, Barton M. The contribution of cytotoxic chemotherapy to 5year survival in adult malignancies. Clin Oncol (R Coll Radiol). 2004;16:549-60.

Ascorbate and Cancer

Cancer Biochemistry !! Warburg effect - most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid formation in the cytosol !! Cancer cells develop overexpression of GLUT1 and/or GLUT3 !! Vitamin C enters through Glut !! Vitamin C enters mitochondria via facilitative Glut1 and confers mitochondrial protection against oxidative injury.

Ideal Cancer Therapy: •! Non-toxic •! Prevents cell proliferation •! Induces cancer cell death •! Improves quality of life •! Synergistic to other therapies •! Strengthens the immune system •! Kill cancer cells but not normal cells

! ! Macheda ML et al, J Cell Physiol. 2005 Mar;202(3):654-62. Agus DB et al. Cancer Research. 1999:59:4555-4558. KC S ey al. FASEB J. 2005 Oct;19(12):1657-67.

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USDA Agricultural Research Service

Glucose & Vitamin C

General guideline for interpretation of Plasma AA Plasma Adequate

> 23 µM (0.023 mM)

Low

11.1 -23 µM

Deficient

<11.1 µM (0.011 mM)

Jacob and Sotoudeh. Nutr Clin Care 2002:5:66-74.

Introduction

Ascorbate and Cancer Vitamin C:

!! Vitamin C deficiency in Cancer Patients !! 50 pts (28! 22" ) with Advanced cancer

!! at low doses a powerful AO (free radical scavenger)

!! Average age 65.2 yrs

!! at high doses it presents oxidative capabilities.

!! Estimated dietary intake of 40 mg of AA !! 30% AA deficient

< 11 µM

!! 42% AA low

11.1 -23 µM

!! It is possible to give much higher doses of Vitamin C intravenously than it is by mouth, thus achieving very high levels in the bloodstream. !! IV Vitamin C is an extremely safe form of treatment.

!! Low plasma vitamin C significantly associated with low albumin, low PLT, high CRP, shorter survival

!! It is much safer than most drugs made by pharmaceutical companies.

Mayland er al. Palliative Medicine 2005

Ascorbate as an anti-tumor agent

Introduction

#! Initial published case reports demonstrated potential benefit from high dose ascorbate treatment. #! Subsequent reports documented the results of 100 patients with terminal cancer, in whom conventional therapy was no longer considered useful and were given intravenous and oral ascorbate.

•! IVC considered by the medical community to be an unconventional treatment •! Has been given in high doses to many thousands of people in many countries over the last forty years. •! Pharmacological concentrations of ascorbate easily achieved in humans are effective in cancer therapeutics.

#! Patients who received ascorbate survived 300 days longer than controls. A prospective study was then conducted randomizing patients to ascorbate treatment or palliative therapy. #! Treated patients had a median survival of 343 days vs. 180 days for controls. Cameron E, Pauling L. Proc Natl Acad Sci U S A 1976;73:3685-9. Cameron E, Pauling L. Proc Natl Acad Sci U S A 1978;75:4538-42. Cameron E, Campbell A. Med Hypotheses. 1991 Nov;36(3):185-9.

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Pkin Ascorbate

Ascorbate as an anti-tumor agent

Predicted plasma Vitamin C concentrations in healthy persons after oral (top) or intravenous (bottom) administration of Vitamin C.

"! To test whether ascorbate was effective, Moertel conducted two randomized placebo controlled studies with oral ascorbate (10 g) and neither study showed any benefit. "! Because Moertel’s studies were taken as definitive, ascorbate treatment was considered useless. "! However Moertel’s results were not comparable to those previous studies because ascorbate was given orally and not intravenously.

Creagan ET, Moertel CG, O’Fallon JR, et al. N Engl J Med 1979;301:687-90. Moertel CG, Fleming TR, Creagan ET, et al. N Engl J Med 1985;312:137-41. Padayatty. Annals of Internal Medicine 140:533, 2004

Pkin Ascorbate and Cancer

Ascorbate’s Pro-oxidant action !! Chen et al. measured cell death in 10 cancer and 4 normal cell types using 1 hour exposures to ascorbate. !! Normal cells were unaffected by 20 mM ascorbate whereas 5 cancer cell lines had EC50 values of < 4 mM, a concentration achievable by intravenous administration.

"! Consumption of 5-to 9 servings of fruits and vegetables daily, steady-state plasma concentrations are 80 mol/L "! Oral vit C q 3 g 6 times daily peak values do not exceed 220 mol/L. "! Intravenous vit C may produce 1- 15 000 mol/L. "! Greater than 1000 mol/L, vit C is toxic to cancer cells "! Ascorbyl radical may form only when plasma concentrations are greater than 1000 mol/L "! In-vitro, in-vivo, the pharmacokinetic data and the clinical reports and studies all suggest a role of vit C in cancer.

!! H2O2 generation was dependent on ascorbate concentration, incubation time, and displayed a linear relationship with ascorbate radical formation. !! intravenous injection of ascorbate increased baseline concentrations of ascorbate in blood and extracellular fluid to > 8 mM and increased formation H2O2. !! These studies provide a foundation for pursuing pharmacologic ascorbate as a prooxidant agent in cancer therapy. Chen Q et al. Proc Natl Acad Sci U S A. 2005;102(38):13604-9.

Padayatty. Annals of Internal Medicine 140:533, 2004

Intravenous Vitamin C- Safety

IV Vitamin C IV vitamin C plays a role in cancer treatment in the following ways:

$! Vitamin C has no known toxic dosage in patients without preexisting kidney disease.

1.! IV vitamin C can enhance the effectiveness of conventional cancer treatment such as chemotherapy and radiotherapy. 2.! IV vitamin C can reduce the severity of cancer symptoms and the unpleasant side-effects of chemotherapy and radiotherapy. 3.! IVC use increased quality of life in cancer patients. 4.! IV vitamin C can be used in those people who cannot receive or have chosen to not have conventional cancer treatment.

$! “…194,054 g, or 427 lbs of IV vitamin C” were “administered to 275 patients with no sign of kidney disease, or any other significant side effects over a 16-year period.” ! ! ! Jackson et al. (2002) http://www.riordanclinic.org/research/articles/ 89023765_jom.pdf

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Jorge Miranda-Massari, PharmD Intravenous Vitamin C- Safety

Intravenous Vitamin C- Safety !! 172 practitioners administered IV vitamin C to 11,233 patients in 2006 and 8876 patients in 2008.

#!Safe administration of i.v. vitamin C for > 30 years #!Treatment 1-3 infusions/week #!No serious adverse events

!! Average dose was 28 grams every 4 days, with 22 total treatments per patient. !! High dose IV vitamin C is in unexpectedly wide use by CAM practitioners. !! known complications of IVC in renal impairment or glucose 6 phosphate dehydrogenase deficiency !! High dose IVC appears to be remarkably safe.

! Padayatty SJ, et al. PLoS One. 2010 Jul 7;5(7):e11414. Kawada H et al. Tokai J Exp Clin Med. 2014;39(3):111-5.

Padayatty SJ et al. PLoS One. 2010 ;5(7):e11414

Intravenous Vitamin C- Safety

Vitamin C- Safety

$! Kidney stones

$! Relative safety well documented in the medical literature. $! Predominantly minor side effects (thirst, nausea). $! To improve tolerability monitor osmolarity and pH

$! In a Harvard study on 85,557 women with no history of kidney stones, vitamin C intake was not associated with risk of developing kidney stones. $! The Harvard researchers advised that “routine restriction of vitamin C to prevent stone formation appears unwarranted.”

$! Contraindications: glucose-6-phosphate dehydrogenase deficiency, hemochromatosis. $! Precautions: Renal impairment or renal failure.

Curhan (1999) J Am Soc Nephrol.10:840-5

Vitamin C- Safety

Intravenous Vitamin C- Safety $! Phase I clinical trial of intravenous ascorbic acid in advanced cancer $! 11 men and 5 women $! IVC in doses from 0.2 to 1.5 g/kg body weight. $! Less than 0.5% of a very large IVC is recovered as urinary oxalic acid in people with normal renal function. $! The present data indicate a remarkable lack of severe hyperoxaluria after massive IVC in people with normal renal function.

$! Another large study, the Harvard Prospective Health Professional Follow-Up Study: $! “The intake of high doses of vitamin C does not increase the risk of calcium oxalate kidney stones…” $! The members of the group with the highest vitamin C intake “had a lower risk of kidney stones” than those with the lowest intake. Gerster (1997) Ann Nutr Metab.(5):269-82

Robitaille L et al. Oxalic acid excretion after intravenous ascorbic acid administration. Metabolism. 2009 Feb;58(2):263-9.

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Ascorbate and Cancer

Intravenous AA Protocols

AA Saturation:

What is the most effective dosing regimen? (After clearing the G6PD test)

!!GI absorption saturation !!Renal reabsorption saturation !!Tissue saturation (interstitial and cellularâ&#x20AC;Śnot just leukocytes) !!Systemic saturation â&#x20AC;&#x201C; When the concentration in plasma and tissues in the body is high enough to disturb biochemical parameters.

#!Start at 25 gm and titrate #!Shorter infusions are more convenient #!Longer infusions are probably better #!Synergize (Lipoic and others: Mitochondrial Enhancers)

Ascorbate and Cancer

Intravenous AA Protocols

Synergistic Nutrients/molecules: "! Oxygen "! Co-Q10 "! R-Lipoic acid "! ALCAR "! Phospholipids "! Mg "! Iodine "! Vitamin D

Duration: 6-12 months; years? Depends on objective: #! Quality of life #! Survival time #! Tumor marker response #! Tumor growth response #! Metastasis inhibition

Therapeutic benefits of IV Vitamin C

1. Improving quality of life:

2. Reducing complications of the disease: a. b. c. d.

a.! Decreasing adverse effects of standard cancer treatments. b.! Reducing pain. c.! Increasing energy. d.! Increasing appetite.

Ascorbate insufficiency in the cancer patient. Combating infections (viral, bacterial, fungi). Cancer-associated inflammation. Prevention of cancer associated sepsis.

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Therapeutic benefits of IV Vitamin C

3. Pharmacological doses have cytostatic or cytotoxic

4. Sustain and improve the effect of standard antineoplastic agents.

action in cancer cells through a variety of mechanisms: a. Malignant fuel control by glucose antagonism b. Electron donor for the energy problem c.! Other mechanisms previously discussed

(peroxide, HIF, ROS dependent- downregulation of specificity protein (Sp) transcription factors and Sp-regulated genes involved in cancer progression). Abdel-Latif MM, et al. J Chemother. 2005;17(5):539-49. Santos RV et al. Clin Exp Pharmacol Physiol. 2007;34(12):1294-9.

Chen Q, et al. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-9. Knowles HJ et al. Cancer Res. 2003;63(8):1764-8 Pathi SS et al. Nutr Cancer. 2011;63(7):1133-42.

Variables affecting IV Vitamin C Therapy

IV Vitamin C and Cancer

â&#x20AC;˘! Consistent improvement cancer patient outcomes requires

!! Many patients have shown impressive responses in tumor reduction, !! improvement in pain control, !! increased energy levels and appetite !! but the success of the use of intravenous vitamin C has been somewhat variable. !! This may be due to a number of direct interacting variables.

â&#x20AC;˘! Comprehensive evaluation that allows identifying contributing factors to health deterioration and the barriers to heal.

Oxygen

Co-Q10 !! Coenzyme for at least three mitochondrial enzymes. !! Accepts electrons in the aerobic reactions of energy production. !! Essential in aerobic respiration. !! Stimulate the immune system and to protect the heart from damage caused by certain chemotherapy drugs. !! Low blood levels of coenzyme Q10 have been detected in patients with some types of cancer.

"! Normal cells require O2 but not cancer cells. "! Significant decrease in metastases in HBO group (85 patients, head & neck cancer). VandenBrenk HAS, et al. Clin Radiol 1967;18:54-61.

"! HIF-1 over-expression has been associated with an increased patient mortality rate in many cancer types. Clottes E. Bull Cancer. 2005;92:119-27.

"! HIF is a mammalian protein that that is activated when oxygen levels fall.

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Co-Q10

Lipoic Acid ! Recycles and extends the metabolic function of:

$!Pilot study - period of 9 years, $!41 patients who had end-stage cancer were included. $!Primary cancers -breast, brain, lungs, kidneys, pancreas, oesophagus, stomach, colon, prostate, ovaries and skin. $!coenzyme Q(10) 300 mg and a mixture of other antioxidants (e.g. vitamin C, selenium, folic acid and beta-carotene $!Mean actual survival was 28.8 months versus 11.9 months for mean predicted survival.

$!vitamin C (AA) $!Glutathione $!coenzyme Q10 $!indirectly renews vitamin E.

! Potentiates AA antitumor effect ! Enhances insulin function Packer L, Witt EH, Tritschler HJ. Free Radic Biol Med. 1995;19(2):227-50. Silvestri S. J Clin Biochem Nutr. 2015 Jul;57(1):21-6 Singh U, Jialal I. Nutr Rev. 2008 Nov;66(11):646-57.

Hertz N & Lister RE. J Int Med Res. 2009;37(6):1961-71.

ALCAR

Lipoic Acid

"! Acetyl-L-Carnitine is derivative on the amino acid lysine and methionine. "! Helps in conversion fatty acids into energy. "! Can help repair the mitochondria. "! Boost levels of glutathione and CoQ10 and work synergistically with lipoic acid. "! In Cancer improved QoL, tolerance to chemotx and facilitates aerobic respiration leading to redifferentiation or apoptosis.

#!Potentiates AA antitumor effect #!Lipoic acid synergistically enhanced ascorbate cytotoxicity, reducing the 2-day LC(50)in hollow fibre tumours from 34 mM to 4 mM.

Casciari et al. Br J Cancer. 2001 Jun 1;84(11):1544-50. Fan JP et.al. Amino Acids. 2008;36:365-72.

Phospholipids!

Magnesium

Lipid Replacement Therapy

!! Over 300 enzymes systems rely upon Mg to facilitate their catalytic action

!! Phospholipids and glycolipids can repair cellular membranes by increasing cell membrane fluidity. !! Improves mitochondria nutrient uptake so that the mitochondria may produce more ATP. !! Also mitochondria itself can be repaired with the phospholipids.

!! Required for DNA and RNA synthesis and protein synthesis. !! including ATP metabolism, creatine-kinase activation, adenylate-cyclase, and sodium-potassium-ATPase. !! Has a role in fatty acid and phospholipids acid metabolism affecting permeability and stability of membranes.

Nicolson and Ellithorpe (2006) J Chronic Fatigue Syn 13: 57-68.

Grรถber U, Schmidt J, Kisters K. Nutrients. 2015;7(9):8199-226. Long S, Romani AM. Austin J Nutr Food Sci. 2014;2(10).

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Iodine

!! Iodine-deficient breast tissue exhibits chemical markers of elevated lipid peroxidation. !! This is an early factor in cancer development. !! Coupled with iodine deficiency-induced increases in circulating estrogen levels, these changes can substantially increase the risk of breast cancer in women with low iodine levels. !! Iodine also helps regulate levels of cortisol and contributes to normal immune function !! Abnormal cortisol levels and deficient immune function are significant contributors to the risks of breast cancer

!! Every cell in the body needs and requires iodine to function optimally. !! Iodine’s main job is to maintain a normal architecture of thyroid, the ovaries, the uterus, breasts, and prostate. !! Deficiency causes cystic formation, nodes and hyperplasia !! In the presence of chemicals and enzymes found in breast tissue, iodine has been shown to exert a powerful antioxidant effect equivalent to vitamin C.

Venturi S et al. Adv Clin Path. 2000 Jan;4(1):11-7. Nolan LA, et al. J Neuroendocrinol. 2000 Dec;12(12):1149-59. Stadel BV Lancet. 1976;1(7965):890-1

Patrick L. Altern Med Rev. 2008 Jun;13(2):116-27 Smyth PP. Biofactors. 2003;19(3-4):121-30.

Vitamin D

!! Low levels of vitamin D in the blood are strongly associated with elevated cancer risk. !! Persons with lower levels have an 83 to 150% increased risk of developing cancer. !! Vitamin D receptors, regulate a number of signaling pathways involved in inflammation, tumor growth, and immune system surveillance for cancer— !! Especially in the epithelial cells of the skin, breast, prostate, and colon.

#! Cancer cells, the vitamin D receptor is dramatically decreased, leaving cells unregulated and prone to reproduce in an out-of-control fashion.57 #! Treating cancer cells in culture with vitamin D, however, produces a number of actions that help fight against cancer: it decreases tumor cell proliferation, quells inflammation, reduces invasiveness, and increases tumor cell death (apoptosis).

Bilinski K et al Breast Cancer Res Treat. 2013;137(2):599-607. Hopkins MH, et al. Cancer Prev Res (Phila). 2011 Oct;4(10):1645-54. Dormoy V et al. Carcinogenesis. 2012;33(11):2084-93.

Krishnan AV, et al. J Steroid Biochem Mol Biol. 2013 Jul;136:289-95 Krishnan AV et al. Steroids. 2012;77(11):1107-12.

Cancer Management

Therapeutic Strategies

Laboratory testing

Detoxification "! Hydration

"! Environmental toxins $! Heavy metals $! Pesticides

!!Water (abundant, pure)

"! Circulation/mobilization

"! Infection panel

!!Exercise (promote circulation and sweat) !!Heat (Sauna/whirlpool)

$! EDTA $! DMPS

•! Chelation

"! Nutrient Panel "! Organic acid testing "! Hormones

!!EDTA and others

$! Adrenal $! Thyroid $! Sexual

#!Vitamin C #!Glutathione

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Improving IVC in Cancer

Therapeutic Strategies

"! Individualized nutrient repletion "! Chelation "! Oxidative treatments "! Antimicrobial therapy "! Hormone support

"! Elimination: $!Urine -Hydration $!Feces -Hydration, magnesium, fiber 25-50 grams/d $!Sweat -Heat and Exercise $!Breath -Exercise

RECNAC 2 Cancer Protocol

Liquids:

Solid Nutrition:

!!Abundance of Pure water !!Limited amount of natural juices (without added sugar) !!No milk, Almond milk and yogurt OK !!No sodas

"! Abundance of multicolored Vegetables (Organic). "! Abundance of sprouted grains (organic). "! Fruits: papaya/pineapple/pomegranate/goji and berries (organic). "! No candy or sugar. "! Modest amount of organic, Free range poultry, Wild caught fish, grass fed meat.

RECNAC 2 Cancer Protocol

The Ketogenic Diet

Solid Nutrition

!! A treatment option for epilepsy and cancer. !! A very strict diet that involves fluid restriction, high fat and low carbohydrate + protein intake. !! The goal: alter the bodyâ&#x20AC;&#x2122;s fuel source from glucose to fat.

Fats: "! No margarine or other partially hydrogenated oils (trans fatty acids). "! No corn oil. "! Extra virgin, cold press, organic Olive oil, Avocado oil, organic Coconut oil.

Branco AF et al. Eur J Clin Invest. 2016 Mar;46(3):285-98.

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Improving Vitamin C in Cancer Jorge Miranda-Massari, PharmD

RECNAC 2 Cancer Management Protocol

Physiology behind the Keto diet

Basic:

"! Glucose ! Fat (as the primary fuel source) "! Ketone bodies – the acidic products formed from excessive breakdown of fat. "! Calorie restriction and restricted ketogenic diets which reduce circulating glucose levels and elevate ketone levels, are anti-invasive, anti-angiogenic, and pro-apoptotic towards cancer. "! Useful in mitochondrial disease and cancer

•! Multivitamin HP •! Vitamin C 500-1000

1-2 tab. BID, PC 1-2 caps TID, PC

Mitochondrial Correctors •! CoQ10 100 mg

1 cap TID

•! Lipoic acid 300 mg

1 cap BID

•! ALCAR

1cap BID

500 mg

•! Magnesium 500 mg

1 cap BID

Branco AF. Eur J Clin Invest. 2016;46(3):285-98.

RECNAC 2 Cancer Management Protocol

Sodium Bicarbonate •! Oral administration of sodium bicarbonate, by normalizing the extracellular pH of tumors •! Has the potential to boost the activity of SCTV2 in tumor cells, thereby promoting increased ascorbate uptake. •! The utility of oral sodium bicarbonate for suppressing metastasis formation in nude mice with a human breast cancer has been reported.

Other: "! Probiotic

1-2 tab. BID, AC

"! High potency Omega 3-fatty acids caps TID, PC "! Vitamin D

1-2

10,000IU daily

McCarty MF. 2013 Med Hypotheses 81:664-70. Robey IF, Baggett BK, Kirkpatrick ND, et al. 2009 Cancer Res;69(6):2260–8.

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Jorge Miranda-Massari, PharmD Variables affecting IV Vitamin C Therapy

Variables affecting IV Vitamin C Therapy! 1.!

! ! Cell energy related metabolic derangements.

4.! Hormonal imbalances/endocrine disruptors. Distorted metabolism. 5.! Excessive inflammation. Cancer promotion (increased ROS). 6.! Infectious agents and unbalance body flora. Immune disruption. 7.! Excessive psychological stress. Physiological disruption. 8.! Excessive exposure to radiation. 10% of invasive cancers are related to radiation exposure.

Cancer as a Metabolic Disease. Mitochondrial damage. 2.! Toxicities (tobacco, alcohol, pesticides, heavy metals, hydrocarbons, food nitrosamines). 3.! Medications a.! Impair immune responses – (Steroids , opioids) b.! Increase angiogenesis and may even act directly on tumor cells to encourage their growth and spread. (opiods) c.! Mitochondrial dysfunction i.! ii.! iii.! iv.!

Membrane permeability Oxidative Phosphorylation impairment Inhibition of Fatty acid oxidation Tamoxifen. AZT, VPA, ibuprofen, antibiotics

Improving IVC Therapy

Improving IVC Therapy Oxidative Medicine:

•! Separation of B Vitamins and Glutathione from the Oxidative IVC Therapy. •! Hydration •! Oral sodium bicarbonate:

"! Therapies that uses oxidants. "! Oxidants are electron receptors. "! Oxygen is typically the final electron receptor of oxidants, which facilitate and stimulate body processes. –! –! –! –!

Ozone therapy Ultraviolet blood irradiation therapy Intravenous hydrogen peroxide therapy HD IVC is also OM because stimulates the production of hydrogen peroxide in the tissues –! HBOT

By normalizing the extracellular pH of tumors, has the potential to boost the activity of SCTV2 in tumor cells, thereby promoting increased ascorbate uptake.

Chen P et al Free Radic Biol Med. 2011 Aug 1;51(3):681-7

Improving IVC Therapy

Improving IVC Therapy Ozone MOA •! Inactivation of bacteria, viruses, fungi, yeast and protozoa: Ozone therapy disrupts the integrity of the bacterial cell envelope through oxidation of the phospholipids and lipoproteins. •! Stimulation of oxygen metabolism: Ozone therapy causes an increase in the red blood cell glycolysis rate. •! Ozone activates the Krebs cycle by enhancing oxidative carboxylation of pyruvate, stimulating production of ATP.

Increased oxygen HBOT: "! HIF-1 signaling and oxygen pressure, and shows a strong epigenetic signature "! alteration of DNA-methylation and induction of tumorsuppressing microRNAs In cancer cell. "! ROS-induced, HIF-1!- and O2 -dependent cytotoxicity of ascorbate on 60 different cancer cells. "! This suggests that for clinical application, cancer patients should additionally be oxygenized to increase the cytotoxic efficacy of ascorbate. Venturelli S et al. Wien Med Wochenschr. 2015;165(11-12):251-7. Sinnberg T et al. J Cell Mol Med. 2014 Mar;18(3):530-41

Elvis AM et al. J Nat Sci Biol Med. 2011 Jan-Jun; 2(1): 66–70

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Improving IVC Therapy

Ozone MOA "! Activation of the immune system: "! Ozone administered at a concentration of between 30 and 55 µg/cc causes the greatest increase in the production of

Ozone "! A prolonged cycle of ozonated autohemotherapy may correct tumor hypoxia, lead to less aggressive tumor behavior. "! Improving oxygen levels would be expected to favor the anticancer effect of vitamin C.

–! interferon –! tumor necrosis factor –! interleukin-2

Elvis AM et al. J Nat Sci Biol Med. 2011; 2(1): 66–70.

Bocci V et al. J Altern Complement Med. 2005 ;11(2):257-65.

Activation of the Krebs cycle and increased ATP production

Decreased bacterial/viral load

!! Microbes can produce excess inflammation. !! Since inflammation is known to play a major role in the pathogenesis of cancer, microbial balance can influence tumor progression. !! This can occur by chronic activation of inflammation, alteration of tumor microenvironment !! Induction of genotoxic responses and cytotoxic products that can further damage metabolism. !! This can be dealt with nutritional support of immune system, natural and synthetic antimicrobials, oxidative therapies and detoxification.

"! Restoration of the oxidative phosphorylation mechanisms (Mitochondrial Correction) "! Stimulate the production of energy necessary to achieve cell re-differentiation and eliminate cell malignant behavior and characteristics. "! CoQ10, ALA, ALCAR, PQQ, Shilajit, NADH "! Omega-3, phospholipid replacement "! Mg, B Complex

“People who say it cannot be done should not interrupt those who are doing it.”

Hyperthermia May favor augmentation of oxygen, pH and immune cells to the tumor. $! AA and hyperthermic treatment synergistically inhibits cancer cell growth through G2/M arrest and apoptosis induction via H2O2 generation at lower AA concentrations; $! This carcinostatic effect was not exerted by AA alone.

Saitoh Y et al. Exp Oncol. 2015 ;37(2):94-9.

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Jorge Miranda-Massari, PharmD Just Doing It! Impossible â&#x20AC;ŚNothing

Conclusions $! Pharmacological doses of ascorbate, achievable in humans when given intravenously, have potential for therapy in cancer. $! Vitamin C is safe, very it tolerable, and improves QoL $! Detailed analysis and management of all variables affecting the individual

Books

RECNAC 2 ! Vitamin C and Cancer ! Cancer cell killing effect with minimal toxicity. $! P R Health Sci J. 2004 Jun;23(2):115-8.

! Reduction of side effects due to cancer chemotherapy. $! Cancer Treat Rev. 2007;33(5):407-18.

! Maintains or improves effect of cancer chemotherapy. $! J Am Coll Nutr. 2005 Feb;24(1):16-21.

! Improves quality of life in cancer patients. $! Int J Vitam Nutr Res Suppl. 1982;23:103-13 $! J Korean Med Sci. 2007;22(1):7-11.

! Low cost makes this therapy cost-effective.

In loving Memory of Dr. Hugh D. Riordan

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