Truckee 2010 cut for Charlie's talk slides copy

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  • Thank the OK PPA Dan Smith, Teresa Kolpak , Tony Stephan and David Hardy
  • Slide documetnting of my poverty
  • I will not engage in discussing any government- approved treatments.
  • Good Health Measures make humans healthy and mitigate medical problems, including psychiatric. NUTRITIONAL
  • In addition to nutrition…….
  • Sleep and EXERCISE too are demonstrably….
  • Rest and relaxation are demonstable… At least particular types of relaxation… exemplified in mind-body approaches
  • We will focus on: SPECIFIC TREATMENTS > Bipolar > NUTRIENT ALTERNATIVES TO THE PHARMA APPROACHES.
  • My focus today: The emerging role of vitamins and minerals….. Micronutrients
  • Background / Review: Old news that single vitamin DEFICIENCIES can cause psychiatric symptoms….. More on slides than I will cover in detail…
  • Single MINERAL DEFICIENCIES too. Micronutrient deficiencies cause psychosis and cognitive problems: attention and memory loss…..
  • BUT MICRONUTRIENTS WORK TOGETHER Example: B Vitamins Pyridoxine/B6: Synthesis of dopamine, norepinephrine, serotonin, and GABA. Folates: Catecholamine synthesis. Copper: Dopamine to norepinephrine. Zinc: GABA synthesis
  • BUT MICRONUTRIENTS WORK TOGETHER Example: B Vitamins
  • BUT MICRONUTRIENTS WORK TOGETHER Example: B Vitamins
  • BUT MICRONUTRIENTS WORK TOGETHER Example: B Vitamins
  • BONNIE WILL PRESENT THIS SLIDES IN TRUCKEE
  • These studies follow the standard medical model: Study one variable at time in medicine….
  • You need to understand micronutrients, and you can’t rely on your usual knowledge from medical pharmacology.
  • No physiologically sensible to look at one at a time.
  • These studies follow the standard medical model: Study one variable at time in medicine….
  • To describe the action of N ingredients for the FDA.. • So you’re talking about a lot of money to do this part of the project.
  • BUT micronutrients do not operate like drugs. do not operate in isolation as single agents do operate in concert /complex/symphony Let’s talk about how micronutrients work…..
  • Minerals in virtually every process in biology – Minerals can be pictured as part of the FOUNDATIONAL ORGANIZATION of biology…..
  • Balancing each other
  • What is OPTIMAL nutrition?
  • Various standards have been historically to define good nutrition.
  • But depends on health goal: ?Target heart, muscles, brain, long life? Optimal nutrient needs for heart may not be the same as optimal needs for mental health.
  • But depends on health goal: ?Target heart, muscles, brain, long life? Optimal nutrient needs for heart may not be the same as optimal needs for mental health.
  • Relative balance Relative deficiencies… or functional deficiencies
  • BALANCE
  • Example
  • Contrary to traditional medical school training, extensive data indicate…
  • Contrary to traditional medical school training, extensive data indicate…
  • {Dietary Reference Intake} Not just Vitamin D deficiency, which is endemic in the northern US. But a whole range of nutrient deficiencies.
  • Leading to a VARIETY OF COMMON MICRONUTRIENT DEFICIENCIES…
  • {Dietary Reference Intake} Not just Vitamin D deficiency, which is endemic in the northern US.
  • Show something about multiple deficiencies… David Hardy’s slides… TAKE PRIOR SLIDE, SUPERIMPOSE, AND TURN UPSIDE DOWN.
  • Imagine that each deficiency were a hole in the dam..
  • When you plug one hole When you fix one deficiency…
  • You just get another deficiency
  • And another
  • You have to fix ALL the deficiencies to make the dam work, Not just one… Not just the most severe… But ALL
  • Simplified summary of rationale ….
  • Alternative: Treat with broad-spectrum
  • In nutrition, it makes more sense to look at the symphonic interactions of compounds that make up normal biology:
  • My KENNEDY SLIDE
  • So WHAT ARE the effects of broad-spectrum micronutrient treatments in mental health? Surprisingly little research… But there is some…. Looking at different functions.
  • MCN improves scores on Attention and nonverbal intelligence (formerly performance IQ).
  • Why? In my opinion, the medical model has been hard for psychiatrists to question. More than one ingredient is too much against the usual way of doing things: Too strange. Almost “unscientific.”
  • So how did psychiatry come to look at MCN/bipolar? It came from farms: Pig aggression. Agribusiness: Broad-spectrum micronutrients. Well known and common agricultural intervention.
  • How did this approach migrate to humans with bipolar disorder? STRANGE WEIRD STORY Tony’s Kids - Bipolar, aggressive. Commercial product • Not-for-profit company. Believed in it, wanted research.
  • Other proposed formulas have been proposed, BUT ALL OF THE RESEARCH ON MCN IN BIPOLAR HAS BEEN CONDUCTED WITH ESSENTIALLY ONE PROUCT.
  • Bonnie first, then small but growing cadre of researchers -- all looking at this one product. 6 teams, 650 patients. No RTCs, but interesting open-label findings.
  • Very different from conventional PD and PK.
  • When transitioning these particularly difficult drugs, we prefer for patients to have discontinued benzodiazepines and SSRIs several weeks and preferably months before beginning a transition to MCB36. MCN36 potentiation made it possible to detect the withdrawal syndromes of some drugs prior to the publication of reports on the existence of those drugs’ withdrawal syndromes.
  • Clinically, the withdrawal syndromes from psychiatric drugs presents a MAJOR COMPLICATION in transitioning patients to MCN36: The transition is MUCH HARDER because of these potentiated withdrawal reactions.
  • A different order of magnitude.
  • A different order of magnitude.
  • When transitioning these particularly difficult drugs, we prefer for patients to have discontinued benzodiazepines and SSRIs several weeks and preferably months before beginning a transition to MCB36. MCN36 potentiation made it possible to detect the withdrawal syndromes of some drugs prior to the publication of reports on the existence of those drugs’ withdrawal syndromes.
  • StressTabs ® or stress formula, One-a-Day ® , and Theragran ® or Therapeutic ® . Multivitamins taken once daily were not a problem. PARALLELS FINDINGS WITH ZINC ON PROSTATE CANCER.
  • MCN36 not examined in this study.
  • How might this work to treat a psychiatric illness like bipolar disorder?
  • How might this work to treat a psychiatric illness like bipolar disorder?
  • Lithium works via MANY POSSIBLE WAYS
  • NO ESTABLISHED ENDOGENOUS BIOLOGICAL role. But hints…
  • Do not ASSUME a lithium deficiency… BUT WHO KNOWS? Limited understanding of mineral functions in biology.
  • Do not ASSUME a lithium deficiency… BUT WHO KNOWS? Limited understanding of mineral functions in biology.
  • MANY POSSIBLE WAYS. Single or subset of nutrients vs. broad spectrum?
  • Bruce Ames: Broad systemic effects of optimizing micronutrient intake
  • Metabolic tune-up
  • Optimizing health
  • Optimizing health
  • MOOD STABILIZING MICRONUTRIENTS Li Omega-3 fatty acids MCN36
  • MOOD STABILIZING MICRONUTRIENTS Li Omega-3 fatty acids MCN36
  • MOOD STABILIZING MICRONUTRIENTS Li Omega-3 fatty acids MCN36
  • Re patient preference, possibly fewer side effects, or difficulty of transitioning from conventional treatment to MCN36.
  • Indication or Contraindiction in Pregnancy
  • Natural Mood stabilizers MCN = No lithium or omega-3. OPINION: Omega-3’s are MUCH WEAKER clinically than MCN36.
  • Also possibly youths with conduct disorder.
  • Neuronal injury: Brian Kolb has shown, in rat experiments, that the MCN36 formula can speed recovery from experimentally-indcued CNS lesions. If metabolically “tuned up” nutrition can improve recovery from brain injury , it raises questions about the use of broad- spectrum micronutrients for accelerating recovery from physical injury.
  • FINAL SLIDES
  • I have not used the word “supplements” in referring to micronutrients. I think of micronutrients as primary, fundamental to physiology and health, not supplemental.
  • I do not think of micronutrients “complementary” or “alternative” treatments. Drugs are the supplement. I do not think of them as complementary to our foreign-body drugs. In this picture, the micronutrients are the primary treatment, working and speaking in the language of the chemical workings of the body. It’s the drugs that are the “supplement.”
  • Surgery can be effective, and is the best in certain situations. But it is the introduction of foreign body, like using a drug.
  • And I would not buy into speaking of micronutrient treatments as part of CAM medicine. Many good treatments really are CAM. But, in my book, micronutrients is not one of them.
  • Micronutrients are potential low-cost alternatives to expensive pharmaceuticals.
  • Food consumption: National sugar policy Sugar, corn, junk (minimum nutritional adequacy standards for food). Pesticides, hormones, preservatives. Storage and delivery delays.
  • Food consumption: National sugar policy Sugar, corn, junk (minimum nutritional adequacy standards for food). Pesticides, hormones, preservatives. Storage and delivery delays.
  • Truckee 2010 cut for Charlie's talk slides copy

    1. 1. Workshop on Micronutrient Treatment and Research in Mental Health The Cedar House Sport Hotel Truckee, California May 14 - 16, 2010
    2. 2. Sponsored by <ul><li>Association for </li></ul><ul><li>Micronutrients in Mental Health </li></ul>
    3. 3. Micronutrient Treatment of Psychiatric Disorders Charles Popper, M.D. McLean Hospital Harvard Medical School [email_address]
    4. 4. Charles Popper, M.D. <ul><li>No financial conflicts of interest: </li></ul><ul><li> No stock, financial interest, or leadership roles in any </li></ul><ul><li>pharmaceutical, nutraceutical, or nutritional company. </li></ul><ul><li> No grants or research funding. </li></ul><ul><li> No speaker bureau fees. </li></ul><ul><li> No intellectual property except publications. </li></ul><ul><li> No travel or honoraria except from academic departments and professional societies. </li></ul>
    5. 5. <ul><li>None of the agents discussed in this talk </li></ul><ul><li>have been approved </li></ul><ul><li>for the treatment of mood disorders </li></ul><ul><li>by the U.S. Food and Drug Administration. </li></ul>
    6. 6. Wholesome foods, good cooking practices, sensible meal times. Minimize junk food - Excess fats and sugars, salt loads, corn syrup. Ample fluids. Minimize alcohol, caffeine, and nicotine/smoking. Avoid recreational drugs. Add nutritional support - Multivitamins, omega fatty acids. Managing Psychiatric Disorders: Nutritional “Good Health” Measures
    7. 7. Healthful nutrition, hydration, multivitamins, avoid alcohol/caffeine/etc. Sleep regularity - Regular wake-up times, adequate duration, comfortable bed. Exercise. Rest. Relaxation. Sunlight. Social connection - Conversation, companionship, closeness, moral caring. General hygiene - Personal cleanliness, contagion prevention. Air management - Clean indoor environment. Time management. Stress management. Disease management. Prevention measures, including weight management, medical checkups. Managing Psychiatric Disorders: General “Good Health” Measures
    8. 8. Mead et al., Cochrane Database Syst Rev 2009 25 RCTs Strong clinical effects 3 RCTs with best methods Moderate non-significant effects Insufficient data to assess risks. No data on dysthymia. Exercise for Adults with Major Depression
    9. 9. Evidence supports: Progressive Muscle Relaxation Bowers, Brit J Psychiatry 1990 Massage Hou et al., J Clin Psychiatry 2010 Yoga Pilkington et al., J Affect Disord 2005 Meditation Pilkington et al., Expert Rev Neurotherap 2006 Tai Chi Cho, Med Sport Sci 2008 Evidence does not support: Acupuncture Smith et al, Cochrane Database Syst Rev 2010 Mind-Body Approaches to Major Depression
    10. 10. <ul><li>Psychosocial / Psychotherapeutic </li></ul><ul><li>Psychopharmacological </li></ul><ul><li>Neurostimulation - ECT, TMS, VNS, DBS; neurofeedback; light therapy. </li></ul><ul><li>Nutrient alternatives to pharmaceutical approaches </li></ul><ul><li>Essential fatty acids. </li></ul><ul><li>SAMe, 5HTP, choline, inositol, L-theanine. </li></ul><ul><ul><ul><li>Vitamins and minerals </li></ul></ul></ul>Managing Mood Disorders: Specific Treatments
    11. 11. <ul><li>Vitamins and Minerals = Micronutrients </li></ul>
    12. 12. Single Vitamin Deficiencies Can Cause Psychiatric Symptoms Thiamine B1 Wernicke’s encephalopathy (short-term memory loss, disorientation/confabulation, hallucinations) Beriberi (irritability, emotional lability) Niacin B3 Pellagra (mental confusion, dementia, depression, anxiety, agitation, aggression, hallucinations, paranoia) Pyridoxine B6 Depression, irritability Biotin B7 Anxiety Folate B9 Depression Cobalamin B12 Pernicious anemia (depression, mania, hallucinations, paranoia) OCD Ascorbate C Scurvy (depression, irritability)
    13. 13. Single Mineral Deficiencies Can Cause Psychiatric Symptoms <ul><ul><ul><ul><ul><li>Iodine “Myxedema madness” </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Zinc Attention deficits (ADHD?) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Iron Depression, irritability </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Attention deficits (ADHD?) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Magnesium Attention deficits? </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Boron Attention deficits </li></ul></ul></ul></ul></ul>
    14. 14. Single Micronutrient Deficiencies or Interventions Can Alter Mood Vitamins Vitamin B1 Thiamine Vitamin B3 Niacin Vitamin B6 Pyridoxine Vitamin B7 Biotin Vitamin B9 Folate Vitamin B12 Cobalamin Vitamin C Ascorbic acid Vitamin D Cholecalciferol Vitamin E D-alpha tocopheryl Minerals Magnesium Calcium Iron Copper Zinc Chromium Selenium Kaplan et al., Psychol Bulletin 2007
    15. 15. Single Micronutrient Deficiencies: Folate (Vitamin B9) and Depression Folate deficiency Increased depression (irritability, insomnia, fatigue, inattention, apathy). Increased depression severity. Low CSF 5HIAA and HVA. Slower response to fluoxetine. Weaker response to augmentation (lithium, desipramine). Increased relapse after successful antidepressant treatment Among patients with depression: Low serum folate (in up to 40%) Pretreatment folate levels predict response to fluoxetine (Fava 1997). Low folate: 35% nonresponse. Normal folate: 20% nonresponse. Pretreatment folate levels predict response to ECT. Folate augmentation improves response to antidepressants among normofolemic patients with depression. Correlations may be lower since 1998 folate fortification of grain products.
    16. 16. Single Micronutrient Deficiencies: Cobalamin (Vitamin B12) and Depression Weaker link than folate/depression. Among patients with depression: 56% with folate deficiency, 20% with B12 deficiency. B12 may be more important in older populations.
    17. 17. Single Micronutrient Deficiencies: Cholecalciferol (Vitamin D) and Depression Epidemiological and clinical studies show inconsistent associations, but perhaps correlations for premenstrual syndrome, seasonal affective disorder, and major depression. Jorde et al., J Intern Med 2008 441 overweight and obese adults (BMI 28-47 kg/m 2 ) Serum Vitamin D (25-OH) BDI-Total BDI-Short < 40 nmol/L) 6.0 2.0 ≥ 40 nmol/L 4.5 1.0 Randomized double-blind placebo-controlled trial Vitamin D 20,000-40,000 IU weekly x 1 year. High doses may improve mild depressive symptoms, regardless of pretreatment serum Vitamin D levels.
    18. 18. Single Micronutrients on Mood: Randomized Double-Blind Placebo-Controlled Trials Assembled by Taron Fletcher and Jared Hardy Chromium Magnesium Pyridoxine Calcium Thiamine Selenium Folic acid Lecithin Intervention Davidson 2003 Giannini 2000 Wyatt 1999 Metaanalysis Thys-Jacobs 1998 Benton 1997 Benton 1991 Godfrey 1990 Cohen 1982 Citation Improved symptom scores Atypical depression 15 Adults Improved mania Mania 20 Adults Improved overall, esp. depression Premenstrual syndrome 940 9 RTCs Improved mood Premenstrual syndrome 466 Adults Improved mood Normal volunteers 120 Adults Improved mood Normal volunteers 50 Adults Improved mood Depression-24 Schizophr-17 41 Adults Improved mood Manic episode 6 Adults Outcome Diagnosis Sample
    19. 19. The Medical Model of Pharmacology 1 Drug : 1 Disease : 1 Effect One Dose-Response Curve Insulin : Diabetes : Reduce Blood Sugar
    20. 20. <ul><li>Micronutrients ≠ Drugs </li></ul>
    21. 21. <ul><li>Many micronutrients are present at once. </li></ul><ul><li>Like biological polypharmacy </li></ul>Micronutrients ≠ Drugs
    22. 22. <ul><li>Many micronutrients are present at once. </li></ul><ul><li>Micronutrients interact and work together. </li></ul><ul><li>For example, B vitamins work as a complex. </li></ul>Micronutrients ≠ Drugs
    23. 23. The Medical Model of Pharmacology 1 Drug : 1 Disease : 1 Effect One Dose-Response Curve Insulin : Diabetes : Reduce Blood Sugar
    24. 24. To describe the action of N ingredients….. One drug: 1 dose-response curve, consisting of data points for 5 doses, so 5 1 = 5 data points (a very small DR curve). Two agents: 5 dose-response curves, 5 dose points for each drug, so 5 2 = 25 data points. 7 agents (B complex): 5 7 = 78,125 data points. 36 agents: 5 36 = 150,000,000,000,000,000,000,000,000 data points. [World Economy in US Dollars in 2008: $75,000,000,000,000]
    25. 25. Extremely complex interactions among micronutrients
    26. 26. Many different micronutrients are present at once, working together in complex interactions, acting on numerous biological processes. Micronutrients ≠ Drugs
    27. 27. Short Facile List of Mechanisms of Micronutrient Action Modulate gene expression. Modulate enzyme activity as cofactors. Alter neurotransmitter metabolism. Change drug biotransformation. Transform receptors. Transform ion channels. Modify membrane fluidity and membrane biophysics. Influence second or third messenger systems. Alter the action of other nutrients and other molecules, including medications; e.g., interactions at receptors, ion channels, etc. Vary the absorption of other nutrients.
    28. 28. Many different micronutrients are present at once, acting together and interacting with each other , operating to modulate complex biological processes, with changing needs over time. Micronutrients vs. Drugs
    29. 29. Optimal levels of micronutrient intake vary in each individual across time with: Age Gender Physical activity Stress Pregnancy Alcohol use Smoking Geography - Local soil contents, sun exposure. Cultural cuisine, including vegetarianism, veganism. Cooking methods Dieting Diseases Antibiotic use (by reducing absorption) Other medications (by inducing micronutrient depletion) Genetic polymorphisms / Biochemical individuality
    30. 30. What is Good Nutrition? Recommended Daily Allowance (RDA) = The amount of an individual micronutrient required to prevent frank deficiency diseases. Recommended Daily Intake (RDI) The amount meeting the nutritional needs of 97-98 % of 14 to 70 year old males and females. Dietary Reference Intake (DRI) = A newer set of recommended amounts for optimal physical health.
    31. 31. What is Good Nutrition? Optimal nutrient intake depends on the targeted health goal: Cardiovascular vs. immunological vs. mental vs. longevity
    32. 32. What is Good Nutrition? Optimal nutrient intake depends on the targeted health goal: Cardiovascular vs. immunological vs. mental vs. longevity. Balancing the goals. Balancing the micronutrients.
    33. 33. Conventional medical pharmacology works for single agents, but does not fit for understanding multiple micronutrient actions and interactions at multiple sites. Differences ways of conceptualizing drug action will be needed, emphasizing the relative balances of agents.
    34. 34. Micronutrients must be balanced against each other to optimize their functioning and to minimize adverse effects. Calcium-magnesium-phosphorus balance is critical. E.g, Too much calcium  Constipation Too much magnesium  Diarrhea Zinc-copper balance is strongly influenced by iron, magnesium, and manganese. Complex micronutrients interactions require balanced micronutrient intake. (Think biological polypharmacy) Balancing of Interactions Among Micronutrients
    35. 35. Balance Among Micronutrients Chromium and vanadium can both increase insulin sensitivity. Chromium can counter insulin resistance, but that does not imply a chromium deficiency. Perhaps chromium is making up for a deficiency in vanadium --- or some other micronutrient. So there may be no deficiency at all: Just an imbalance among multiple factors…
    36. 36. Relative or Functional Deficiency No absolute deficiency, but a relative imbalance. (Think biological polypharmacy)
    37. 37. In addition to relative deficiencies…. Absolute nutrient deficiencies in the US population are widespread, even among the wealthy and “well-fed.”
    38. 38. http://www. ba . ars . usda . gov/cnrg/services/cnmapfr .html Percent of U.S. Population Not Meeting the DRI For Specific Nutrients
    39. 39. Widespread Absolute Nutrient Deficiencies in the US Contrary to conventional medical understanding in the 1950’s and 1960’s: Then, normal dietary intake was viewed as generally nutritionally adequate. What changed?
    40. 40. Absolute nutrient deficiencies in the US are common and multi-form. Marked reductions in the mineral content of 20 fruits and 20 vegetables grown between the 1930s and the 1980s. Fruits: Magnesium, iron, copper, and potassium. Vegetables: Calcium, magnesium, copper, and sodium. Nutrient depletion of soil by agricultural methods: A failure of agricultural practices and policy. Mayer AM: Historical changes in the mineral content of fruits and vegetables. British Food Journal 99:207-211, 1997
    41. 41. http://www. ba . ars . usda . gov/cnrg/services/cnmapfr .html Percent of U.S. Population Not Meeting the DRI For Specific Nutrients
    42. 42. David Hardy’s Dam Analogy of Nutrient Deficiency
    43. 48. To correct multiple deficiencies. To make biological systems function normally. To maximize the functioning of each micronutrient. Need a Broad-Spectrum of Micronutrients
    44. 49. <ul><li>Single Vitamins and Single Minerals </li></ul><ul><li>Vs. </li></ul><ul><li>Broad-Spectrum Micronutrient Treatments </li></ul>
    45. 50. Rationale for Broad-Spectrum Micronutrient Treatment - 1 Many vitamins and minerals. Each has multiple physiological functions. Most micronutrients operate in concert with other micronutrients. The balance among micronutrients optimizes their functioning. The balance among micronutrients minimizes their adverse effects.
    46. 51. Rationale for Broad-Spectrum Micronutrient Treatment - 2 Biochemical individuality. Nutrient requirements change over time in individuals. Numerous and varied absolute nutritional deficiencies in the general population, which are clinically difficult to identify . Relative (functional) deficiencies are even more difficult to identify clinically than absolute deficiencies. Physicians do not usually know what nutrients are (absolutely or relatively) deficient in an individual at a particular time, so cannot select replenish.
    47. 52. Rationale for Broad-Spectrum Micronutrient Treatment - 3 Broad-spectrum micronutrient treatments can promote balanced chemical microenvironments in populations of individuals with varying physiological needs and nutritional resources.
    48. 53. Medical Model of Pharmacology vs. Nutritional Model of Pharmacology
    49. 54. A Nutritional Model of Pharmacology Ask not “What are the effects of one or two nutrients at a time?” But “What are the effects of a broad spectrum of nutrients at once?”
    50. 55. Research on Broad-Spectrum Micronutrient Interventions in Mental Health <ul><li>Research on: </li></ul><ul><li>Cognitive Functioning in Normal Volunteers </li></ul><ul><li>Mood and Anxiety in Normal Volunteers </li></ul><ul><li>Violent and Antisocial Behavior in Schools and Prisons </li></ul><ul><li>Bipolar Disorder in Adults and Youth </li></ul>
    51. 56. Attention in Young Adults Benton et al., Psychopharmacol 1995 127 young healthy adult volunteers . Double-blind placebo-controlled trial. Treatment Multivitamins at 10 times RDA level for 12 months . Outcome Females showed improved attentional measures. Nonverbal Intelligence In Children Benton, Neurosci Biobehav Rev 2001 In a review of double-blind placebo-controlled studies of multi- micronutrient use on intelligence in children, 10 of 13 studies showed improved measures of non-verbal intelligence , with benefits observed in a minority of subjects. Broad-Spectrum Micronutrients on Cognitive Functioning
    52. 57. No published rigorously controlled studies document the safety or efficacy of broad-spectrum micronutrient treatment in treating any psychiatric disorder. Broad-Spectrum Micronutrient Research in Psychiatry
    53. 58. Not from universities or NIH or industry. An Unexpected Source: Knowledge developed by agribusiness for reducing destructive aggression among farm animals. Origins of Broad-Spectrum Micronutrient Treatment for Bipolar Disorder
    54. 59. <ul><li>Original Observers of the Broad-Spectrum </li></ul><ul><li>Micronutrient Treatment Effects on Bipolar Disorder </li></ul>David Hardy Tony Stephan Bonnie Kaplan
    55. 60. Hardy and Stephen developed a 36-ingredient product, based on a formula that reduced aggression among farm animals, which helped children and then relatives with bipolar disorder. The product is distributed by Truehope Nutritional Support, a not-for-profit company. Other commercial broad-spectrum micronutrient formulations have been proposed to treat bipolar disorder. However, all of the research to date has been conducted on a single set of formulations (brand name EMPowerPlus ® ), developed by Hardy and Stephan, which we will call MCN36. Broad-Spectrum Micronutrient Treatment Research on Bipolar Disorder
    56. 61. Diagnosis N Letter/Comment Youth Bipolar 1 Popper J Clin Psychiatr 2001 Adult Bipolar 19 Simmons J Clin Psychiatr 2001 Mixed Bipolar 22 Popper J Clin Psychiatr 2001 Case Reports Youth Bipolar 2 Kaplan JCAP 2002 Child Bipolar + Psychosis 1 Frazier JCAP 2010 Adult OCD + Dep + Anx 1 Rucklidge J Anx Disorders 2009 Adult Bipolar + ADHD + Anx 1 Rucklidge CNS Spectrums Case Series Adult Bipolar 11 Kaplan J Clin Psychiatr 2001 Child Bipolar 11 Kaplan JCAP 2004 Adult Bipolar + ADHD 14 Rucklidge J Atten Disord 2010 Mixed Autism + Comorbidity 88 Mehl-Madrona JCAP 2010 Database Analyses Adult Bipolar 358 Gately Clin Med: Psychiatr 2009 Child Bipolar 120 Rucklidge (Submitted) Controlled Trials 0 Number of Subjects 649 Number of Investigative Groups 6 JCAP = J Child Adolesc Psychopharmacol MCN36 Research on Psychiatric Disorders
    57. 62. The MCN36 Formulation
    58. 63. MCN36 Formulation Consists of 36 ingredients, including: A broad range of minerals. All the standard vitamins except for K. A variety of antioxidants, including 3 botanicals: Ginkgo Biloba (leaf), Grape Seed, and Citrus Bioflavonoids. Three amino acids: L-Glutamine, DL-Phenylalanine, L-Methionine Choline and inositol. Contains neither omega fatty acids nor lithium .
    59. 64. Chemical Description of MCN36 Vitamins Standard daily dose 15 capsules (Five capsules three times daily) with food > UL UL/TUIL RDA/AI 15 Capsules # # NE NE, NA 800-1,000 80-100 NE, NA 30-35 mg (niacin) NE, NA NE, NA 800-1,000 2000 1,800-2,000 2,800-3,000* 25-30 2.4 400 1.2-1.7 5 14-16 1.0-1.3 1.0-1.2 15 200-400 65-90 700-900 1,080 µg 900 µg 1,440 µg 36 mg 21.75 mg 90 mg 13.5 mg 18 mg 240 mg 36 µg 600 mg 1,920 µg Vitamin H (biotin) Vitamin B12 (cyancobalamin) Vitamin B9 (folic acid) Vitamin B6 (pyridoxine HCl) Vitamin B5 (d-calcium pantothenate) Vitamin B3 (niacinamide) Vitamin B2 (riboflavin) Vitamin B1 (thiamine mononitrate) Vitamin E (d-alpha tocopheryl succinate) Vitamin D (cholecalciferol) Vitamin C (ascorbic acid) Vitamin A (retinyl palmitate)
    60. 65. Chemical Description of MCN36 Minerals Standard daily dose 15 capsules (Five capsules three times daily) with food > UL UL/TUIL RDA/AI 15 Capsules # # No UL 1,700-2,000 NE 9-11 8-10 400 34-40 350 900-1,100 4000 45 2500 4700 43-45 20-35 1.6-2.3 0.9 55 8-11 310-420 150 700-1,250 8-15 1,000-1,300 240 mg 144 µg 624 µg 9.75 mg 7.1 mg 204 µg 48 mg 600 mg 204 µg 840 mg 13.9 mg 1,320 mg Potassium  Molybdenum  Chromium  Manganese  Copper  Selenium Zinc  Magnesium  Iodine Phosphorous  Iron  Calcium 
    61. 66. Chemical Description of MCN36 Proprietary Ingredients [Quantities Not Published] Minerals Vanadium (as chelate) Nickel (as chelate) Boron (as chelate) Germanium (sesquioxide) Small organic molecules Inositol Choline (bitartrate) Amino acids L-Glutamine DL-Phenylalanine L-Methionine Phytochemicals Ginkgo Biloba (leaf) Grape Seed (Vitis rinitera) Citrus Bioflavonoids
    62. 67. Chemical Description of MCN36 The ratios among ingredients are critical for maintaining a proper balance among components; for example, calcium/magnesium/phosphorus and zinc/copper ratios are particularly critical. Certain ingredients are chelated (mainly vegetable-based) to improve gastrointestinal absorption of certain ingredients. A unique “ micro-grinding ” process is used to obtain small-particulate powder, which improves absorption. These technological advances enhance bioavailability and effectiveness . Routine over-the-counter multivitamin-multimineral products would require an enormous number of pills to match the delivery of MCN36. As is, the usual daily dose of MCN36 is 15 pills daily, with most of the bulk contributed by the chelates.
    63. 68. Chemical Description of MCN36 Four ingredients exceed the Tolerable Upper Intake Limits, but do so for logical reasons. Vitamin B3 (Niacin) UL was set to avoid flushing reaction, which is caused by nicotinic acid. MCN36 contains only niacinamide, which does not cause flushing. Vitamin B9 (Folate) UL was set because of high folate doses can mask B12 deficiency. Not an issue because B12 is present in high doses in formula. Magnesium UL set to avoid diarrhea, but magnesium-induced diarrhea is prevented by proper balancing with calcium. Zinc UL was set to prevent copper imbalance, but presence of copper (along with iron and magnesium) prevents this.
    64. 69. MCN36 Pharmacology Some unusual pharmacological properties of this broad- spectrum micronutrient formula have been observed. It is unclear whether these pharmacological properties are specifically characteristic of MCN36 or, more generally, of broad-spectrum micronutrient formulas. Other commercial broad-spectrum micronutrient formulas may or may not have similar pharmacological or clinical properties.
    65. 70. Pharmacological Characteristics of MCN36 Unexpected pharmacokinetics and pharmacodynamics 1) Micronutrient-induced amplification of the CNS effects of psychiatric medications and other drugs. 2) Potent mineral-mineral interactions.
    66. 71. Unexpected Pharmacologic Phenomenon #1 Nutrient-Drug Interactions
    67. 72. Nutrient-Drug Interactions MCN36 ---> Potentiation of CNS drugs’ therapeutic effects. Potentiation of CNS drugs’ side effects. Potentiation of CNS drugs’ withdrawal effects. Reduced therapeutic effectiveness of MCN36. These effects may operate concurrently.
    68. 73. Nutrient-Drug Interactions MCN36 potentiates (amplifies) the CNS effects of most CNS-active substances: Psychiatric medications. Prescription and OTC drugs that have CNS therapeutic effects or CNS side effects. All recreational drugs, including caffeine, alcohol, nicotine, marijuana. Certain hormones. MCN36 potentiates most CNS-active drugs by a factor of 3-5 fold.
    69. 74. Nutrient-Drug Interactions: Medical Drugs Examples of CNS-active medical drugs to be avoided (or used at lower dose) in combination with MCN36: Cold medications, including dextromethorphan and pseudoephedrine. Some antihistamines, especially ceterizine. Theophylline. Narcotic analgesics. Also, expect these medications to be potentiated when added to an ongoing MCN36 regimen.
    70. 75. Nutrient-Drug Interactions: CNS Drugs Patients starting MCN36 should expect potentiation of nutrient-drug interactions, so may need to stop or reduce: Psychiatric medications Medical medications Alcohol Caffeine (coffee, tea, chocolate) Nicotine (smoking) Recreational drugs Without such dose reductions, expect increased side effects of these agents -- and less effectiveness of MCN36 .
    71. 76. Nutrient-Drug Interactions In transitioning from conventional treatment to MCN36, the doses of psychiatric medications must be lowered – and preferably discontinued – in order to: Avoid increased psychiatric drug side effects AND Avoid decreased MCN36 effectiveness.
    72. 77. Nutrient-Drug Interactions Do prior psychiatric drugs absolutely need to be discontinued? No, MCN36 can be used with lowered doses of psychiatric medications. But continuing low doses of conventional medications will undercut the full effectiveness of micronutrients.
    73. 78. Unexpected Pharmacologic Phenomenon #2 Potentiated and Protracted Drug Withdrawal
    74. 79. Potentiated and Protracted Drug Withdrawal MCN36 potentiates drug withdrawal syndromes in both intensity ( potentiated withdrawal ) and duration ( protracted withdrawal ).
    75. 80. Potentiated and Protracted Drug Withdrawal MCN36 potentiates withdrawal syndromes of: All serotonin reuptake inhibitors, esp. venlafaxine, paroxetine. Benzodiazepines. Pseudobenzodiazepines (zaleplon, zolpidem, eszopiclone). Tramadol (opiate mu receptor agonist, venlafaxine analog). Trazodone. Certain antipsychotics, esp. quetiapine, aripiprazole, pimozide.
    76. 81. Drug Discontinuation Syndromes Serotonergic: Odd head feeling (&quot;headache without the headache”), mental fog. Odd gastrointestinal feeling (&quot;nausea without the nausea&quot;), GI upset. Flu-like symptoms, lightheadedness, dizziness, headache, anorexia, nausea/vomiting, fatigue, malaise, myalgia. Anxiety, irritability, insomnia, agitation, confusion, vertigo, hot and cold flashes, tremors, parathesias, “buzzing all over,” generalized pruritis, “electric shock-like sensations”, visual “jolts.” Cholinergic: Anxiety, agitation, sweating, pupil dilation, tremors, anorexia, hot and cold flashes. Serotonergic plus anticholinergic: Visual trailing, similar to LSD (treatable with donepezil).
    77. 82. Unexpected Pharmacologic Phenomenon #3 Delayed Drug Discontinuation Syndromes
    78. 83. Delayed Drug Discontinuation Syndromes MCN36-potentiated symptoms can appear with a delay of weeks, months (and at times years) after stopping a conventional medication, especially for drugs with long half-lives. Symptoms are triggered by physiological stressors, including exercise, pregnancy, dieting, temperature and climate change, saunas, and body work (including massage, acupuncture, rolfing). These symptoms can mimic psychiatric symptoms (e.g., anxiety, agitation, insomnia) and may appear long after the clinician no longer suspect drug discontinuation to be relevant -- leading to misattribution and incorrect management decisions.
    79. 84. Delayed Drug Discontinuation Syndromes Mechanism is unclear: Are small residues of medication still being cleared from the body, mobilized by stress into circulation from fat or protein bound sites, months or years after last administration? Are activated neuronal network firings, sensitized by multiple prior MCN36-potentiated discontinuation reactions, persistently re-triggered by stressors?
    80. 85. Unexpected Pharmacologic Phenomenon #4 Mineral-Mineral Interactions
    81. 86. Mineral-Mineral Interactions MCN36 potentiates lithium by about 100-fold. Compare to the 3-5 fold potentiation of most CNS drugs. When using lithium in a patient receiving MCN36, the usual dose range is 20 mg (1-5 mg four times) daily. Usual range without MCN36: 600-2000 mg. Beyond 20 mg daily, classical lithium toxic symptoms appear.
    82. 87. Mineral-Mineral Interactions Plasma lithium levels are undetectable, so mineral-mineral potentiation is pharmacodynamic (not pharmacokinetic). Other aspects of routine lithium monitoring (thyroid, renal, etc.) remain necessary with lithium “micro-dosing .” Similarly potent mineral-mineral interactions are described at receptor sites and G proteins.
    83. 88. Clinical Implications of Micronutrient Pharmacology A patient’s clinical transition from conventional treatment to micronutrient treatment can be difficult to navigate: <ul><ul><li>Discontinuing psychiatric drugs, so risk of relapse. </li></ul></ul><ul><ul><li>Increase in psychiatric drug side effects. </li></ul></ul><ul><ul><li>Potential psychiatric drug discontinuation effects potentiated by MCN36. </li></ul></ul><ul><ul><li>All happening concurrently . </li></ul></ul>
    84. 89. Clinical Implications of Micronutrient Pharmacology Transitioning from conventional to MCN36 treatment is tricky: Do not try this on your own without training and available consultation.
    85. 90. When First Learning to Use MCN36…. Start with a “simple” patient with bipolar disorder. Select a patient who has NOT received psychiatric or CNS drugs for at least several weeks or months. And preferably start with a medication-naïve patient .
    86. 91. MCN36 Starting Regimen for Patients with NO Recent CNS Drug Use <ul><li>Day 1 One pill three times daily. </li></ul><ul><li>Day 2 Two pills three times daily. </li></ul><ul><li>Day 3 Three pills three times daily. </li></ul><ul><li>Day 4 Four pills three times daily. </li></ul><ul><li>Day 5 Five pills three times daily. </li></ul><ul><li>Go slower if needed to manage adverse effects. </li></ul>
    87. 92. Basic Dosing Guidelines for MCN36 Modal dose 15 pills daily Taken as 5 pills three times daily . Typical range 12-18 pills daily Same across weights and ages > age 8. Take with food, best sandwiched in the middle of a meal , to aid absorption (and reduce gastrointestinal side effects). Administer no more than 6 pills at a time (calcium absorption is limited). Spread doses through day . Keep at least 2 hours between doses. 4 daily doses might be needed to sustain effect; 2 is rarely adequate. Missed doses can be made up the next day. Available in capsules, pills, or flavored powders for liquid consumption.
    88. 93. Advanced Guidelines: Transitioning from Conventionals to Micronutrients Once you get a feeling for this treatment, then work with a patient who is on a simple pharmacological regimen. For such patients, cross-tapering is typically conducted over a 2-4 week period. Do not attempt to transition a patient recently treated with SSRIs or benzodiazepines until you have a good feel of the transition process in several simpler cases involving patients on “easier” medications.
    89. 94. Advanced Guidelines: Transitioning from Conventionals to Micronutrients “ Difficult” conventional medications include: All serotonin reuptake inhibitors, esp. venlafaxine, paroxetine. Benzodiazepines. Pseudobenzodiazepines (zaleplon, zolpidem, eszopiclone). Tramadol (opiate mu receptor agonist, venlafaxine analog). Trazodone. Certain antipsychotics, esp. quetiapine, aripiprazole, pimozide. Easier: Mood stabilizers. Olanzapine (and risperidone).
    90. 95. Advanced Guidelines: Transitioning from Conventionals to Micronutrients The cross-tapering procedure is especially complex for patients with current/recent use of psychiatric drugs with difficult withdrawal syndromes. Rate of increase in dose of MCN36 is more gradual. Speed of tapering medication dose depends on drug “ difficulty”, duration of drug treatment, other concurrent medications, and the unfolding clinical course. Get training and ongoing consultation.
    91. 96. Advanced Guidelines: Transitioning from Conventionals to Micronutrients Transition process may take days, sometimes weeks . Rarely, a patient can be dysfunctional for some months before discontinuation effects of prior drug treatments resolve. Most people do not miss any work or school. During the transition, most patients experience significant anxiety , due to symptom relapse, potentiated drug overstimulation, potentiated discontinuation, and related situational anxiety. Withdrawal-related symptoms can be managed by natural agents, especially balanced amino acid mixtures.
    92. 97. Advanced Guidelines: Transitioning from Conventionals to Micronutrients Expect benefits to be delayed by the transition complications (return of psychiatric symptoms, potentiated drug side effects, and potentiated withdrawal). Transitional complications may cease gradually or suddenly. Once transitional complications recede, it becomes easier to evaluate treatment effects. From the beginning, and repeatedly through the transition, prepare patients AND families for regression.
    93. 98. Advanced Guidelines: Transitioning from Conventionals to Micronutrients You will need a consultant to help Advise on patient suitability, Guide you through developing a cross-tapering schedule, Judge how quickly to increase MCN36, Decide when and how to lower the psychiatric drug doses, Show what to do if withdrawal effects appear, Inform on how to manage side effects, Help interpret adverse changes in behavior, and Consult on managing concurrent medical problems and selecting suitable drug alternatives to CNS-active medications.
    94. 99. Clinical Response For Patients with NO Recent CNS Drug Use Might see benefits beginning: Mania Within 5 days at full dose. Depression Within 4-8 weeks at full dose (longer if chronic or psychotic). Approximately 80% responders in open-label trials to unmodified MCN36 by 2 months without conventional psychiatric medication. For Patients WITH Recent CNS Drug Use Benefits may be difficult to perceive until transition is complete. Approximately 50% responders in open-label trials. Database (Gately and Kaplan 2009): 53% responders (>50% symptom reduction) at 3 months. Mean symptom reduction 41% at 3 months (45% at 6 mos). Medication use reduced from 78% to 55% at 3 mos (44% at 6) Probably more responders if MCN-experienced clinician.
    95. 100. Safety
    96. 101. Adverse Effects of MCN36 Common Loose stools, semi-formed diarrhea Usually transient. Nausea Take with more food and water. Insomnia Move last dose earlier. Headache Temporarily lower dose. Anxiety, agitation, impulsivity, mania Increase or decrease dose. Candida (yeast) infection MCN36 can induce or aggravate. “ Neon” yellow urine Not a problem (B2 excretion). Uncommon Vomiting Take with more food and water. Flatulence Simethacone. Watery diarrhea Green bananas, or briefly reduce MCN dose.
    97. 102. Adverse Effects of MCN36 In contrast to mild adverse effects of MCN36, there are serious side effects related to individual micronutrient ingredients. Vitamin and mineral toxicities are well-established in medicine.
    98. 103. Micronutrient Toxicities <ul><li>Vitamin C (Ascorbic acid) </li></ul><ul><li>Nausea, abdominal cramps, diarrhea </li></ul><ul><li>Renal stones </li></ul><ul><li>Mobilization of bone minerals </li></ul><ul><li>Abortion </li></ul><ul><li>Hemochromatosis </li></ul><ul><li>Vitamin D (Cholecalciferol) </li></ul><ul><li>Nausea, vomiting </li></ul><ul><li>Anorexia, weight loss </li></ul><ul><li>Constipation </li></ul><ul><li>Muscular weakness </li></ul><ul><li>Joint pain </li></ul><ul><li>Excessive thirst and urination </li></ul><ul><li>Hypercalcemia </li></ul><ul><li>Vitamin E (Tocopherol) </li></ul><ul><li>Gastric upset </li></ul><ul><li>Potassium </li></ul><ul><li>Cardiac arrest </li></ul><ul><li>Calcium </li></ul><ul><li>Anorexia </li></ul><ul><li>Muscle weakness </li></ul><ul><li>Lethargy, apathy </li></ul><ul><li>Confusion, clouded consciosness </li></ul><ul><li>Nausea, vomiting </li></ul><ul><li>Constipation </li></ul><ul><li>Shortened ST segments, arrythymias </li></ul><ul><li>Hypertension </li></ul><ul><li>Muscle weakness </li></ul><ul><li>Myopathy </li></ul><ul><li>Renal stones </li></ul><ul><li>Calcification of heart, lungs, kidneys </li></ul><ul><li>Magnesium </li></ul><ul><li>Diarrhea </li></ul><ul><li>Nausea </li></ul><ul><li>Anorexia </li></ul><ul><li>Mental status changes </li></ul><ul><li>Muscle weakness </li></ul><ul><li>Difficulty in breathing </li></ul><ul><li>Extremely low blood pressure </li></ul><ul><li>Arrhythmias, bradycardia, vasodilation </li></ul>Vitamin A (Retinoic acid) Dry mucous membranes Headache Insomnia Fatigue Hair loss Bone abnormalities - bone and joint pain Anorexia Vomiting Anemia Liver damage, hepatomegaly Hypercalcemia Hyperlipidemia Menstrual irregularities Spontaneous abortions, birth defects Dizziness Blurred vision / diplopia Muscular incoordination Birth defects Vitamin B1 (Thiamine) Gastric upset Vitamin B3 (Niacin) Vascular dilation, flushing Hyperuricemia Liver changes Nausea Heartburn Fatigue Dry hair Sore throat Inability to focus eyes GI irritation Increased muscle glycogen utilization Decreased serum lipids Vitamin B5 (Pantothenic acid) Diarrhea Edema Vitamin B6 (Pyridoxine) Dizziness Nausea Peripheral neuropathy Ataxia Iron Constipation, diarrhea, bloody diarrhea Vomiting Hemosiderosis, hemochromatosis Cirrhosis Increased incidence of hepatoma Diabetes Cardiac failure Zinc Copper deficiency Reduced HDL Reduced immune function Stomach cramps, nausea, and vomiting Pancreas damage Gastrointestinal irritation, vomiting, Microcytic anemia Iodine Goiter, hypothyroidism Selenium Nausea, abdominal pain, diarrhea Fatigue, irritability Hair loss White blotchy nails Peripheral neuropathy Copper Liver damage Weakness Nausea, diarrhea, gastric pain Manganese Psychosis Parkinsonian syndrome Molybdenum Gout Copper deficiency Vanadium GI symptoms Depressed growth Green tongue Nickel GI symptoms
    99. 104. No Known Micronutrient Toxicity at Any Dose: Riboflavin (Vitamin B2) Folate (Vitamin B9) Cyanocobalamin (Vitamin B12) Biotin (Vitamin H)
    100. 105. <ul><ul><ul><li>Negative Health Effects of </li></ul></ul></ul><ul><ul><ul><li>Single-Micronutrient or Two-Micronutrient Treatments </li></ul></ul></ul><ul><li>Vitamin A (as beta-carotene) </li></ul><ul><li>Increase in cardiovascular disease deaths by 26% in smokers. </li></ul><ul><li>Omenn et al. 1996. </li></ul><ul><li>Increase in all-cause mortality by 16%. </li></ul><ul><li>Cochrane Collaboration 2008 </li></ul><ul><li>Increase in new-onset of lung cancer and its cancer mortality. </li></ul><ul><li>Druesne-Pecollo 2009, Satia et al. 2009 </li></ul><ul><li>Vitamin E </li></ul><ul><ul><ul><li>Increase in all-cause mortality by 4%. </li></ul></ul></ul><ul><ul><ul><li>Cochrane Collaboration 2008 </li></ul></ul></ul><ul><li>Vitamin C + E </li></ul><ul><li>Reduce some beneficial effects of physical exercise. </li></ul><ul><li>Ristow et al. 2009 </li></ul>
    101. 106. Micronutrient Toxicity is Not Strictly Ingredient-Dependent or Dose-Dependent Certain forms of micronutrient toxicity can be decreased OR increased by the balance of other micronutrients. That is, toxicity can be adequately countered by a proper balance of other micronutrients, or aggravated by an inappropriate balance.
    102. 107. Micronutrient Toxicity is Not Strictly Ingredient-Dependent or Dose-Dependent Safe levels of intake for various single vitamins and minerals are well studied, and standards are continually updated by governmental agencies. But nutrient-nutrient interactions potentiate the effects of individual micronutrients. The safety of a combination of micronutrients cannot be inferred from the safety data on individual ingredients.
    103. 108. Micronutrient Toxicity Although “multivitamins” are generally presumed safe, even by regulatory government agencies, controlled studies of any micronutrient formulation will be required before safety claims can be made . Despite such uncertainties, micronutrient formulas appear safer than psychiatric drugs, even at relatively high doses, at least in balanced broad- spectrum formulations.
    104. 109. Other Potential Risks Suicide One report of suicidal attempt involving multivitamin overdose in the medical literature. Overdose Accidental multivitamin ingestion is the most frequent inquiry to pediatric poison control centers, mostly pre-school children; 1/3 require treatment, 0.3% life-threatening due to iron overload. Physical Dependence and Withdrawal No known cases of physical dependence or discontinuation syndrome with micronutrients.
    105. 110. Contraindications Strict contraindications Wilson’s disease re copper Hemochromatosis re iron Phenylketonuria re phenylalanine Trimethylaminuria re choline Prostate cancer ? Other cancers
    106. 111. Multiple Daily Doses of Broad-Specrum Micronutrients May Increase the Spread of Prostate Cancer Prospective study of 295,000 men. Lawson et al. 2007 Examined 3 commonly used commercial multivitamin brands. Increase in prostate cancer: 32% increase in metastatic prostate cancer. 98% increase fatal prostate cancer. No increase in new-onset or localized (non-metastatic) cancer. So no evidence of causing new cancer, but may increase the spread of metastases and death, especially if family history of prostate cancer. Observed when multivitamins were used more than once daily, not when taken once daily.
    107. 112. Contraindications Prostate cancer Consider broad-spectrum micronutrient treatment as • contraindicated in men with prostate cancer. • probably in men with elevated PSA’s. • possibly in all older men with a family history of prostate cancer. Other cancers, too ??
    108. 113. Contraindications Relative contraindications Recreational drug dependence. Recent use of medical drugs with withdrawal syndromes. Necessary medical treatment with CNS-active agents. Treatment-resistant Candida. Infections requiring chronic or repeated antibiotic (or antifungal) treatment. Autoimmune thyroid disease or nodular goiter (iodine). Liver or renal disease. High alcohol intake, hyperlipidemia, or severe protein malnutrition (which are associated with increased susceptibility to vitamin A toxicity).
    109. 114. Contraindications: Pregnancy? Broad-spectrum micronutrients are healthy for the fetus, and are routinely recommended to pregnant mothers. Vitamin A toxicity to the fetus In pregnancy, Upper Limit (UL) for Vitamin A is 3,000 µg/d (or 2,800 µg/d if mother < 18 yo). MCN36 contains 1,920 µg in a daily dose of 15 pills. No large-scale systematic studies of MCN36 in pregnancy. Contraindication? Or Potential Indication?
    110. 115. Course of Treatment
    111. 116. Careful Documentation Careful documentation of informed consent: No randomized controlled trials to evaluate safety or efficacy. Potential lack of effectiveness. Conventional and established psychiatric treatments are available. Discontinuing previous psychiatric medications is planned and expected to cause a worsening of psychiatric symptoms. Adverse effects: Diarrhea, nausea, agitation, worsening of Candida. Some scientific data suggest possible aggravation of certain cancers. Drug interactions, incl. antibiotics, OTCs, botanicals, and abusables. Agree to call MD if starting on antibiotics or any other drug. Likely need to reduce or stop use of caffeine, alcohol, and smoking. Careful documentation of reason for using non-established treatment. Careful documentation of reason for lowering drug doses based on clinical observations in this patient; state risks and precautions.
    112. 117. Medical Monitoring Baseline medical evaluation Baseline physical examination, esp. re vitamin or mineral toxicity. Baseline laboratory tests are not required : CBC with differential Fasting blood glucose AST, ALT, Bili-T Creatinine and BUN Thyroid stimulating hormone Iron, ferritin Potassium, Sodium, Calcium, Magnesium, Copper Vitamins A and D Albumin Uric acid PT, PTT, INR Lipid panel Urinalysis EKG Periodic follow-up is optional : PE and lab tests every 6-12 months.
    113. 118. Medical Monitoring Antibiotics (and antifungals) Adding oral antibiotics to ongoing MCN36 treatment requires a 50% increase in MCN dose for duration of antibiotic treatment + 4 days. Intestinal flora are crucially involved in gastrointestinal absorption of micronutrients, so decimation of flora by antibiotics sharply reduces GI entry. Compensated by increase in MCN36 dose. Dose change is not needed for parenteral administration of antibiotics. Gastrointestinal conditions affecting absorption may interfere with effectiveness of MCN36 (e.g., watery diarrhea, infection, inflammation, irritable bowel). Candida MCN36 can induce or aggravate pre-existing Candida infections.
    114. 119. Course of Treatment : If symptoms return during treatment… First, examine for presence of Interfering Factors : Start/change CNS-active medications (psychiatric, medical, OTC). Use of caffeine, smoking, alcohol, marijuana, abusable drugs. Oral antibiotics. Systematic infection, such as Candida. Gastrointestinal symptoms affecting nutrient absorption, and use of laxatives, antacids, and proton pump inhibitors. Recurrent or chronic medical conditions. Treatment noncompliance. Consider possibility of delayed drug withdrawal. Re-optimize micronutrient intake by trying both higher and lower doses (A return of previously stable psychiatric symptoms might require an increase OR decrease in micronutrient dose).
    115. 121. Treating Residual Psychiatric Symptoms
    116. 122. Treating Residual Psychiatric Symptoms in Combination with MCN36 If symptoms of mania, depression, or anxiety remain despite MCN36 treatment, residual symptoms are best treated by adding non-pharmaceutical agents. Unlike conventional psychiatric medications, certain endogenous (i.e., naturalistic) agents can be combined with MCN36 without nutrient-drug interactions or untoward complications. Note: The dose ranges for these agents are somewhat lower than usual when used with broad-spectrum micronutrients.
    117. 123. Treating Residual Mania in Combination with MCN36 Lithium in micro-doses In combination with MCN36, typical dose range is 1 mg to 5 mg four times daily [4-20 mg daily]. Requires routine lithium monitoring, except no need to monitor plasma lithium levels. Choline bitartrate In combination with MCN36, typical dose range is 50-100 mg four times daily. Excessive dosing can induce depression.
    118. 124. Treating Residual Depression: SAMe in Combination with MCN36 SAMe (S-adenosyl methionine) In combination with MCN36, typical SAMe dose range is 200-400 mg each morning. Without MCN36, usual SAMe dose is 400-800 mg. Watch for antidepressant/psychostimulant side effects.
    119. 125. Treating Residual Depression: 5HTP in Combination with MCN36 5HTP (5-Hydroxytryptophan) In combination with MCN36 and decarboxylase inhibitor carbidopa 25 -50 mg each morning, the typical 5HTP dose range is 0.01 to 1 mg each morning. Without MCN36, usual 5HTP dose is 50-100 mg. Monitor kynurenine, prolactin, and TSH.
    120. 126. Treating Residual Anxiety in Combination with MCN36 Inositol Typical dose range with MCN36 is 1,000-5,000 mg four times daily. L-theanine Typical dose range with MCN36 is 200-600 mg four times daily. Amino acids Balanced mixtures as tolerated.
    121. 127. Terminating MCN36 Treatment Typical reasons Cannot tolerate the transition process, usually due to drug withdrawal problems. Lack of benefit. Cannot manage the number of pills involved. Cannot manage the uninsured cost ($150 monthly). Dose management If MCN36 treatment was brief, discontinue MCN36 without tapering and restore medication doses as tolerated. If stopped after longer use (> 2 weeks), medication doses may need to be gradually increased over days or weeks, as the micronutrient effects gradually subside.
    122. 128. Further Reflections on Mechanisms of Action
    123. 129. How could micronutrients treat bipolar disorder? No proven therapeutic effect of broad-spectrum micronutrients in bipolar disorder, so talk about mechanism of action is purely speculative. Mechanism of Action
    124. 130. Do we think of lithium as a “drug” or a “mineral”? Medical Pharmacology: “ We don’t yet know the mechanism of lithium’s action, but we have a lot of theories.” Nutritional Pharmacology: “ We expect that many mechanisms are involved in lithium’s effects on bipolar disorder.” A search for one mechanism or many? How does Lithium Treat Bipolar Disorder?
    125. 131. Cobalt Pondering Mechanism of Lithium Action
    126. 132. <ul><li>Multiple Mechanisms of Lithium Action </li></ul><ul><ul><li>Receptors and transporters </li></ul></ul><ul><ul><li>Enhancement of folate and B12 transport into cells (Vanyo 1991). </li></ul></ul><ul><ul><li>Neurotransmission </li></ul></ul><ul><ul><li>Increase in serotonin, decrease in dopamine and glutamate. </li></ul></ul><ul><ul><li>Neurosignaling </li></ul></ul><ul><ul><li>Inositol monophosphatase </li></ul></ul><ul><ul><li>Glycogen synthase kinase-3beta </li></ul></ul><ul><ul><li>Cyclic AMP dependent kinase </li></ul></ul><ul><ul><li>Protein kinase C </li></ul></ul><ul><ul><li>Etc. </li></ul></ul><ul><ul><li>Gene expression </li></ul></ul><ul><ul><li>Transcription factors </li></ul></ul><ul><ul><li>Neuroplasticity </li></ul></ul><ul><ul><li>Neuroprotection </li></ul></ul><ul><ul><li>Is just one mechanism responsible for lithium’s mechanism of action? </li></ul></ul>
    127. 133. Drug or Mineral: Does Lithium have Endogenous Biological Functions? <ul><li>Animals </li></ul><ul><li>Low lithium intake is associated with behavioral changes, low litter size, low litter weight, and increased spontaneous abortion. </li></ul><ul><li>May be involved in transforming pluripotential stem cells to more specialized progenitor cells. </li></ul><ul><li>Humans </li></ul><ul><li>Endogenous lithium levels peak during first trimester, then decline. </li></ul><ul><li>No known deficiency syndrome, but low lithium intake is associated with increased bipolar disorder, suicide, and murder. </li></ul><ul><li>Average human dietary intake is 0.6 to 3 mg daily. </li></ul><ul><li>Proposed RDA of 1 mg daily (Schrauzer, J Am Coll Nutr 2002). </li></ul>
    128. 134. <ul><li>Bipolar Disorder: </li></ul><ul><li>A Micronutrient Deficiency Disorder? </li></ul><ul><ul><li>If micronutrient efficacy in bipolar disorder were proven, would that imply that a deficiency was corrected? </li></ul></ul><ul><ul><ul><ul><ul><li>If olanzapine improves mania, we </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>do not infer an olanzapine deficiency. </li></ul></ul></ul></ul></ul>
    129. 135. <ul><li>Bipolar Disorder: </li></ul><ul><li>A Micronutrient Deficiency Disorder? </li></ul><ul><ul><li>When lithium improves mania, should we </li></ul></ul><ul><ul><ul><ul><ul><li>infer a lithium deficiency? </li></ul></ul></ul></ul></ul><ul><ul><li>May depend on whether we believe that lithium has endogenous functions. </li></ul></ul><ul><li> </li></ul><ul><li>Nutritional model: Relative lithium deficiency </li></ul><ul><li>Medical model: Pharmacological effect </li></ul><ul><ul><li>Which is it? We don’t know. </li></ul></ul>
    130. 136. Mechanism of Action If efficacy in bipolar disorder were proven, it would generate other questions: Which are the active ingredients? Are the same micronutrients active in all patients? Are the same mechanisms relevant in all patients? Would a smaller number of ingredients have the same clinical effects? Or is a broad-spectrum of micronutrients necessary?
    131. 137. Broad Biological Advantages to Optimizing Micronutrient Intake Genetic polymorphisms may cause reduced binding affinity (Km) of an enzyme for its cofactor (micronutrient), leading to genetic disease, which can be countered by higher micronutrient dosing (e.g., B vitamins). Micronutrient deficiencies can lead to DNA damage (B12, folic acid, B6, C, E, iron, zinc). Micronutrient deficiencies (iron, biotin) aggravate mitochondrial oxidative decay, leading to accelerated aging and neuronal deterioration. Micronutrient deficiencies can restrict less essential biological functions in order to favor functions related to short-term survival (triage theory), leading to increased disease and aging. Ames BN, Arch Biochem Biophys 2004 McCann and Ames, Am J Clin Nutr 2009
    132. 138. <ul><li>Mechanism of Action: </li></ul><ul><li>A Metabolic Tune-Up </li></ul><ul><li>Where do micronutrients work? </li></ul><ul><li>Everywhere – </li></ul><ul><li>How do they work? </li></ul><ul><li>Revving up enzymes. </li></ul><ul><li>Potentiating mineral actions. </li></ul><ul><li>“ Feeding” certain infections and cancers. </li></ul><ul><li>Potentiating the CNS effects of medications. </li></ul><ul><ul><ul><li>Repairing DNA. </li></ul></ul></ul><ul><ul><ul><li>Reducing oxidative stress. </li></ul></ul></ul><ul><ul><ul><li>Promoting neuronal repair and slowing neuronal deterioration. </li></ul></ul></ul>
    133. 139. Mechanism of Action: A Metabolic Tune-Up Ames BN: A role for supplements in optimizing health: The metabolic tune-up. Arch Biochem Biophys 423:227-234, 2004
    134. 140. Clinical Summary: Opinion
    135. 141. Clinical Opinion: Summary Unproven but probable mood-stabilizing and antidepressant effects.
    136. 142. Clinical Opinion: Summary Compared to standard psychopharmacological treatment: Fewer adverse effects -- especially cognitive. Fewer residual symptoms. No or lower doses of concurrent psychiatric drugs. Fewer dose adjustments. Fewer doctor’s visits. Fewer relapses. Fewer hospitalizations. Increasing benefits over time. More stable and even course over the years. But…
    137. 143. Clinical Opinion: Summary But: Lack of controlled safety data. Lack of controlled efficacy data. Worsening of certain infections and possibly certain cancers. Difficulty of transitioning from conventional medications. Weaker response to MCN36 if recent prior use of psychiatric medications or CNS-active drugs: Slower response and fewer responders. Not suitable for certain patients, such as drug abusers. No insurance reimbursement. More out-of-pocket expense: $150 monthly.
    138. 144. Clinical Recommendations: Opinion With safety and efficacy are not established, this treatment is not ready for general use by the public. Established conventional psychiatric drug treatments remain the standard of care.
    139. 145. First-line Use? Not recommended for general use: Lack of controlled trials regarding safety or efficacy. In selected cases, some clinicians may want to offer MCN36 as a first treatment: Defensible if presentation is mild and non-acute. “ Low clinical risk to delaying established treatment” must be clearly supported in chart documentation. Documentation of reasons for use prior to established treatment, reasons to lower conventional drugs, and informed consent.
    140. 146. First-line Use? Careful informed consent (lack of controlled safety and efficacy data, risk of relapse, drug interactions, adverse effects, Candida, cancer question, availability of established treatments). Start with an unmedicated patient with bipolar or major depressive disorder in a mild, non-acute, low-risk presentation. Training and consultation are advisable for management of adverse effects and intercurrent medical complications. Clinicians without specialized training and supervisory consultation should not attempt to transition patients from conventional to micronutrient treatment.
    141. 147. First-line Use? Clinician’s responsibility to manage a patient’s potentially excessive enthusiasm for a treatment. Be prepared to deal with overly enthusiastic patients (and colleagues) whose excitement about a “ na tural ” treatment might cloud their thinking or disrupt their balance in assessing risks. And Be prepared to deal with excessive skeptics, especially colleagues (and some patients), whose doubts about “natural” treatment might lead them to disregard evidence of effectiveness because micronutrients do not fit the prevailing models of how drugs works.
    142. 148. Opinion: MCN36 Appears to have Fewer Cognitive and Emotional Adverse Effects Compared to Conventional Psychopharmacological Treatment Virtually every adult who successfully transitions from conventional to MCN36 treatment reports a striking improvement in mental clarity. Almost to a person, patients describe less “brain fog” and mental slowness on MCN36 compared to traditional medications. Many say that they had not been aware of their long-term drug-induced cognitive slowness and emotional “sludge” until after transitioning to micronutrients.
    143. 149. Catastrophic Psychological Reactions On completing the transition from conventional to micronutrient treatment, about 5-10% of patients experience the “shock” of realizing that they had spent many years in mental disease or drug-induced dysfunction, which they can now examine from a psychological distance. This perspective can be harshly distressing for some individuals, who may need considerable support in mourning the past and in accepting the increased expectations by self and others. This is clinically very distinct from a depressive reaction. Clinical opinion: I have never observed this with a psychopharmacological treatment.
    144. 150. “ Superbabies” Some mothers who used MCN36 during pregnancy have given birth to children who reportedly appear unusually healthy. Anecdotes of babies who, compared to siblings, appear calmer, more attentive, less fussy, less crying, fewer health problems, and show more rapid developmental attainments. Unpublished: 107 women on MCN36 during pregnancy Miscarriage rate < 5% (vs 8-25% in general population) Virtually no birth defects (vs 3% in general population) Large-scale systematic data are lacking.
    145. 151. Nutrients with Mood-Stabilizing Properties Lithium Omega-3 fatty acids MCN36 [ MCN36 contains no lithium or omega-3]
    146. 152. Clinical Indications for Broad-Spectrum Micronutrients Opinion Established indications None Probable indications Bipolar disorder Major depressive disorder
    147. 153. Potential Applications for Broad-Spectrum Micronutrients Speculative Uses Dysthymic disorder Postpartum depression Depressive anxiety Aggressive and antisocial behavior in incarcerated criminals (perhaps youths with conduct disorder). Other psychiatric disorders, such as anxiety disorders, OCD, ADHD, eating disorders, autism. In investigating non-mood psychiatric indications, note that observed symptom improvements may be due to indirect effects mediated by MCN36 effects on comorbid mood disorders and associated functional gains. For such psychiatric conditions, it is preferable to conduct research on subjects without concurrent mood disorders.
    148. 154. Imaginable Applications for Broad-Spectrum Micronutrients Cognition and mood in normal subjects. Neurological conditions; e.g., seizures, migraine. General medical disorders; e.g., vascular, immunological. Neurorecovery; e.g., nerve injury. Neuroprotection; e.g., Alzheimer’s, neurodegenerative disorders Neurodevelopmental disorders; e.g., learning disorders, autism. Pregnancy Prevention Enhancement of general health Anti-aging Sleep architectural improvement “ Normal” development: Stronger bodies, better brains, “superbabies” “ Everyone above average”
    149. 155. Super-Pooch Development aided by Broad-Spectrum Micronutrients
    150. 156. <ul><li>The Future of Nutritional Psychopharmacology: </li></ul><ul><li>Over-the-Counter Self-Treatment of Bipolar Disorder? </li></ul><ul><ul><ul><li>Even if nutritional treatments become trivially easy, </li></ul></ul></ul><ul><ul><ul><li>psychiatric patients will still need help with: </li></ul></ul></ul><ul><ul><ul><li>Awareness of symptoms or severity. </li></ul></ul></ul><ul><ul><ul><li>Identification of medical causes and mimics of psychiatric symptoms. </li></ul></ul></ul><ul><ul><ul><li>Diagnosis and management of comorbidity. </li></ul></ul></ul><ul><ul><ul><li>Education about illness. </li></ul></ul></ul><ul><ul><ul><li>Psychological support. </li></ul></ul></ul><ul><ul><ul><li>Psychodevelopmental treatment. </li></ul></ul></ul><ul><ul><ul><li>Diagnosis and treatment of psychiatric disorders in family members (children’s parents, parents’ children, siblings). </li></ul></ul></ul><ul><ul><ul><li>Education, support, and management counseling for family. </li></ul></ul></ul>
    151. 157. <ul><li>Beyond Fixed “On e Size Fits All” Formulations </li></ul><ul><li>“ One size fits all” is good for public health needs of treating populations of patients with bipolar disorder. </li></ul><ul><li>Scientifically na ï v e for individual treatment, but it’s a place to start. </li></ul><ul><li>Not too far off, micronutrient treatments may be custom- made to respect the genetic, physiological, and biochemical individuality of patients. </li></ul><ul><li>Or the inexpensive “off-the-shelf” “one size fits all” approach to health maintenance and optimization might endure. </li></ul>
    152. 158. Micronutrients in Medicine
    153. 159. Micronutrients are the biologically primary treatment. Micronutrients are not supplements.
    154. 160. There is nothing complementary or alternative about micronutrients. It’s the drugs that are the “supplement.” Bonnie Kaplan, Ph.D.
    155. 161. Treating with a patented synthetic pharmaceutical is introducing a foreign body to make a correction. Something like surgery.
    156. 162. Not “Supplements” but “ Micronutrient Formulations” Not “Complementary/Alternative Medicine” but Micronutrient Medicine
    157. 163. <ul><li>Micronutrient Medicine: Commercial Implications </li></ul><ul><li>Minerals are not patentable (chelates might be). </li></ul><ul><li>Vitamins are not patentable (analogs are). </li></ul><ul><li>Multinutrient formulas are patentable, but patent protection is weak. </li></ul><ul><li>Brand names are patentable, with added value if attached to scientific research. </li></ul><ul><li>Micronutrients are potential low-cost alternatives </li></ul><ul><li>to expensive pharmaceuticals. </li></ul>
    158. 164. Micronutrient Medicine: Research Needs <ul><li>Need clinical studies on safety and efficacy of micronutrient combinations in psychiatric, neurological (seizures, migraine, nerve injury, etc.), and medical disorders as well as other applications, such as pregnancy, prevention, developmental enhancement, and anti-aging. </li></ul><ul><li>Individualization of micronutrient formulations. </li></ul><ul><li>Investigations into basic mechanisms: </li></ul><ul><li>Nutrient interaction with enzymes, genes, receptors, channels, membranes, etc. </li></ul><ul><li>Nutrient-nutrient interactions at these sites. </li></ul><ul><li>Drug-nutrient interactions at these sites. </li></ul><ul><li>Alterations in physiology and systems characteristics in different micronutrient environments. </li></ul>
    159. 165. Micronutrient Medicine: Policy Needs <ul><li>Legal and regulatory changes to foster research (INDs for multi-ingredient products), commercial development of micronutrient products, FDA marketing approval (nutraceuticals for specific disease indications, not just general health claims), product quality control, and (once controlled studies of safety and efficacy are available) insurance coverage for specific nutritional treatments. </li></ul><ul><li>Governmental, university, and private programs to promote improved nutrition in institutions (schools, corporations, prisons) and for the general public. </li></ul><ul><li>Policies aimed at improving agricultural methods (e.g., soil management, nutrient repletion). </li></ul>
    160. 166. Micronutrient Medicine: Policy Needs <ul><li>National Food Policy </li></ul><ul><li>Minimum nutritional adequacy standards for processed foods </li></ul><ul><li>Sugar </li></ul><ul><li>Corn </li></ul><ul><li>Junk </li></ul><ul><li>Pesticides, hormones, preservatives. </li></ul><ul><li>Storage and delivery delays. </li></ul>
    161. 167. Li Yooki before Micronutrients
    162. 168. Li Yooki on Micronutrients
    163. 169. EMPowerPlus ® , and consultation on its use, can be obtained from: Truehope Nutritional Support Box 888 Raymond, Alberta Canada T0K 2S0 1-888-Truehope 1-888-878-3467
    164. 170. Charles Popper, M.D. <ul><li>No financial conflicts of interest : </li></ul><ul><li> No stock, financial interest, or leadership roles in any </li></ul><ul><li>pharmaceutical, nutraceutical, or nutritional company. </li></ul><ul><li> No grants or research funding. </li></ul><ul><li> No speaker bureau fees. </li></ul><ul><li> No intellectual property except publications. </li></ul><ul><li> No travel or honoraria except from academic departments and professional societies. </li></ul>

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