1. Nutritional Supplement Research: Beyond the Status Quo

2. Background What is the Status Quo? Common Problems and Solutions –Quality control –Dosing Overview

3. Background Dietary Supplement Health and Education Act of 1994 (DSHEA) DSHEA deregulation No GMP’s No quality control standards No requirement to show safety or efficacy The Office of Dietary Supplements (ODS) was established through DSHEA (by NIH in 1995) and collaborates with the National Center for CAM (NCCAM) ODS and NCCAM promote and award funding for scientific research on dietary supplements Nesheim, Pub Health Nutr, 1999 www.ods.od.nih.gov

4. Table 1. Total number of projects and funding for the NIH and USDA top 10 dietary supplement ingredients in the CARDS database, FY 1999-2007 NIHUSDA Ingredient Projects, n Funding, USD millions Projects, n Funding, USD millions Vitamins and minerals319710931443294 Botanicals158343959287 Phytochemicals1470415697123 Fatty acids and lipids1051304685130 Proteins and amino acids59715622945 Antioxidants52814229082 Dietary Fiber and carbohydrates 1967916524 Hormones/precursors18557101 Other19663649 Background Regan et al., J Nutr, 2010 $1.9 billion $347 million NCCAM $370 million

5.  Mitochondria  Mitochondrial enzymes IA Task Area I Year 1 12 months > 20% change To Task II Task Area III Year 2 18-24 months IIIAIIIBIIICIIIDIIIE Endurance Performance Soldier Task Performance Muscle Injury  Inflammation Cognitive Performance Environmental Extremes Performance To Task IV Each > 20% change: IIIA or IIIB or IIIC or IIIDor IIIE Human Performance Testing Task Area IV Field Testing Performance Final FormulationIncorporation into Ration Transition to Ration Task Area II Year 1 12 months IIA IIBIICIID Bioavailability Dosing Human Pharmacokinetics Acceptable Formulation Acceptable To Task III AchievedCompletedHedonics > 6 Analysis FRS Components  Mitochondria  Mitochondrial enzymes IA Task Area I > 20% change To Task II  Mitochondria  Mitochondrial enzymes IA  Mitochondria  Mitochondrial enzymes IA Task Area I 12 > 20% change To Task II Task Area III Year 2 18-24 months IIIAIIIBIIICIIIDIIIE Endurance Performance Soldier Task Performance Muscle Injury  Inflammation Cognitive Performance Environmental Extremes Performance To Task IV Each > 20% change: IIIA or IIIB or IIIC or IIIDor IIIE Human Performance Testing Task Area III Year 2 18-24 months IIIAIIIBIIICIIIDIIIE Endurance Performance Soldier Task Performance Muscle Injury  Inflammation Cognitive Performance Environmental Extremes Performance To Task IV Each > 20% change: IIIA or IIIB or IIIC or IIIDor IIIE Task Area III Year 2 18-24 months IIIAIIIBIIICIIIDIIIE Endurance Performance Soldier Task Performance Muscle Injury  Inflammation Cognitive Performance Environmental Extremes Performance To Task IV Each > 20% change: IIIA or IIIB or IIIC or IIIDor IIIE Human Testing Task Area IV Field Testing Performance Final FormulationIncorporation into Ration Transition to Ration Task Area IV Field Testing Performance Final FormulationIncorporation into Ration Transition to Ration Task Area II Year 1 12 months IIA IIBIICIID Bioavailability Dosing Human Pharmacokinetics Acceptable Formulation Acceptable To Task III AchievedCompletedHedonics > 6 Analysis FRS Components Task Area II Year 1 12 months IIA IIBIICIID Bioavailability Dosing Human Pharmacokinetics Acceptable Formulation Acceptable To Task III AchievedCompletedHedonics > 6 Task Area II Year 1 12 months IIA IIBIICIID Bioavailability Dosing Human Pharmacokinetics Acceptable Formulation Acceptable To Task III AchievedCompletedHedonics > 6 Analysis FRS Components What is the Status Quo? Slide provided courtesy of Dr. Ed Zambraski, USARIEM Ideal?

6. What is the ‘Status Quo?’ Source of Supplement?:Usually off-the-shelf Verification of quality?:Usually not Dose?:Usually what others have used Kinetics/bioavailability?:Usually not Study design?:Usually good! Data analysis?:Conventional and sound Data display & interpretation?:Usually marginal or poor Reality?

7. Quality Control (Problem - Dissolution) > 50% of calcium supplements and many single and multivitamin-mineral preparations fail to meet USP disintegration and dissolution standards. > 40% of melatonin supplements fail to meet USP disintegration standards. Carr and Shangraw, Am Pharm, 1987 (adapted from Table 3) Carr and Shangraw, Am Pharm, 1987; Shangraw, Pub Health Rep Suppl, 1990; Hahm et al., J Am Pharm Assoc, 1999

8. Quality Control (Problem - Content) Gurley et al., Am J Health Syst Pharm, 2000 Harkey et al., Am J Clin Nutr, 2001 Parasrampuria et al., JAMA 1998 Green et al., Clin J Sports Med, 2001 Andrews et al., Anal Bioanal Chem, 2007 Pharmaceutical Standard (USP)

9. Good Manufacturing Practices (GMP) provide a system of processes, procedures, and documentation to assure a product has the identity, strength, composition, quality, and purity that it claims. Three independent non- governmental programs provide GMP guidelines for dietary supplements. Adoption is VOLUNTARY Natural Products Association (NPA GMP) NSF GMP USP Dietary Supplement Verification Program Quality Control (Solution)

10. Quality Control A word about mixtures (cocktails) or “Product Testing” Effects (or lack of effects) observed using multiple ingredients violates basic scientific philosophy. There is no way to know if the ingredients (or which ingredients) are acting synergistically, antagonistically, or if they are biologically active at all. > 100 interactions possible between ingredient pairs; > than 1,000,000 interactions possible among random groupings SuperStuff 5000 5x stronger than our 1000 formula! Ingredient List: Chinese Ginseng, Siberian Ginseng, Vitamin B-12, Guarana, Yohimbine, L-Carnitine, Bee Pollen, Caffeine, Ginkgo Biloba (leaf), Coenzyme Q10, DHEA, SAMe, Fish Oil, Quercetin, Glucosamine Chondroitin, FD&C Green #2. Product Claims: Boost Immunity Reverse Male-Pattern Baldness Burn Fat Improve Memory Increase Energy Enhance Labido ≠