The majority of commercially available multivitamin and mineral formulas are designed to meet 100% of the RDA or AI, or some percentage thereof. These levels represent the minimum intake required to reduce risk for overt debility, manifested by deficiency diseases such as scurvy or pellagra; they were not derived for the purpose of optimizing health and physiological function, nor reducing risk for age- or lifestyle-related degenerative diseases.(1) 

The optimal intake of vitamins and minerals for the general population remains open for debate and is a topic of ongoing research. For example, since 2001, research by Fenech et al. has investigated the potential to redefine the Australian RDAs for folate, B12, and other micronutrients to levels proven to support healthy DNA replication (also referred to as genomic stability), an important determinant of cellular health.(12-15) Interestingly, the newly proposed Australian RDAs are higher than US RDAs for B12 (7 mcg versus 2.6 mcg) and folate (700 mcg versus 400 mcg), as are the estimated Paleolithic era intakes (see Table 1). This is likely not a coincidence since folate and B12 are necessary for adequate DNA replication, which is in turn critical to successful human evolution.(16)

Other multivitamin and mineral formulas contain ingredients at levels 10-100 times higher than the RDA/AI, based on potential to alleviate genetic polymorphisms affecting nutrient status(2) or to compensate for nutrient depletions resulting from commonly used pharmaceutical drugs. However, with the availability of clinical markers of nutritional deficiencies and genetics-based tests and recommendations, it is no longer necessary to provide such high levels of B vitamins in foundational formulas. Rather, additional nutrients can be supplemented based on relevant tests such as GenomicInsightTM Genomic Health Profile (offered by Diagnostic Solutions). Unlike other DNA tests, GenomicInsightTM enables clinicians to customize reports using the most advanced artificial intelligence, which integrates findings from peer-reviewed research. For example, the levels of vitamins B2, B6, B12 and folate found in TDM are adequate in maintaining healthy homocysteine (Hcy) levels for some individuals but not for those with single nucleotide polymorphisms on particular Hcy metabolic pathways and/or folate receptor activity.(20-22) The GenomicInsight™ report identifies which of these nutrients are required in higher doses in order to normalize Hcy levels. Other nutritionally relevant tests include NutrEval® (offered by Genova Diagnostics) and ALCAT Functional Cellular Assays (By Cell Science Systems).

2/A Day Multi is a two-a-day multivitamin designed to provide nutrients that are difficult to obtain in the typical daily diet. Its formulation has been guided by principles of evolutionary biology and human physiological adaptation to a whole food, nutrient-dense diet that supplies adequate energy, guided additionally by common nutrient insufficiencies in the US and by criteria beyond the established Recommended Dietary Allowances (RDAs) and Adequate Intakes (AIs). TDM includes a tocopherol-free form of vitamin E Isomers, a blend of gamma and delta-tocotrienols, which have unique health and healthy aging benefits, and a unique blend of vitamin K1 with various forms of vitamin K2. It also includes a natural form of folate that addresses common genetic polymorphisms, and an effective dose of vitamin B12 to help overcome various malabsorption syndromes.

Comparison of 2/A Day Multi, estimated Paleolithic diets, average US intakes and US RDA/AI 

Table 1 (see link on back) compares the ingredients in 2/A Day Multi to estimated dietary intakes of the corresponding nutrients during the Paleolithic era, the current US RDA/AI, and average US intakes (based on data from NHANES 2001-2002).(40) The estimated Paleo era nutrient intakes are based on values reported by Cordain,(6) a recalculation of Cordain’s data with more advanced nutrition analysis software, and the evaluation of another sample Paleo diet.(17-19) The data in Table 1 show that average Paleo nutrient intakes are significantly higher than current US RDA/AI, except for molybdenum. A twocapsule serving of 2/A Day Multi offers comparable amounts of essential micronutrients to those found in a 2000 kcal “Paleo-like” diet, with some adjustments based on average US intakes, nutrient bioavailability, and upper tolerable levels. Magnesium, calcium, iron and copper are not included in TDM because this formula is designed to allow for more flexible and individualized supplementation of these nutrients. They may be derived from the diet or from condition-specific formulas or various mineral formulas. Healthcare practitioners may recommend additional supplements based on patients’ diets, lifestyle factors and clinical evaluations.

References 

1. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes. National Academy Press, Washington, DC, 2001. 

2. Ames BN. Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake. J Nucleic Acids. 2010 Sep 22;2010. pii: 725071. doi: 10.4061/2010/725071. PubMed PMID: 20936173; PubMed Central PMCID: PMC294568. 

3. Lucock MD, Martin CE, Yates ZR, Veysey M. Diet and our genetic legacy in the recent anthropocene: a Darwinian perspective to nutritional health. J Evid Based Complementary Altern Med. 2014 Jan;19(1):68-83. doi: 10.1177/2156587213503345. Epub 2013 Sep 12. Review. PubMed PMID: 24647381. 

4. Kuipers RS, Joordens JC, Muskiet FA. A multidisciplinary reconstruction of Palaeolithic nutrition that holds promise for the prevention and treatment of diseases of civilisation. Nutr Res Rev. 2012 Jun;25(1):96-129. doi: 10.1017/S0954422412000017. Review. PubMed PMID: 22894943. 

5. Jew S, AbuMweis SS, Jones PJ. Evolution of the human diet: linking our ancestral diet to modern functional foods as a means of chronic disease prevention. J Med Food. 2009 Oct;12(5):925-34. doi: 10.1089/ jmf.2008.0268. Review. PubMed PMID: 19857053. 

6. Cordain L., The Nutritional Characteristics of a Contemporary Diet Based Upon Paleolithic Food Groups., JANA Vol. 5, No. 3, 2002., 14-24. 

7. Frassetto LA, Schloetter M, Mietus-Synder M, Morris RC Jr, Sebastian A. Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr. 2009 Aug;63(8):947-55. doi: 10.1038/ejcn.2009.4. Epub 2009 Feb 11. Erratum in: Eur J Clin Nutr. 2015 Dec;69(12):1376. PubMed PMID: 19209185. 

8. Eaton SB, Strassman BI, Nesse RM, Neel JV, Ewald PW, Williams GC, Weder AB, Eaton SB 3rd, Lindeberg S, Konner MJ, Mysterud I, Cordain L. Evolutionary health promotion. Prev Med. 2002 Feb;34(2):109-18. Review. PubMed PMID: 11817903. 

9. Eaton SB, Cordain L, Eaton SB. An evolutionary foundation for health promotion. World Rev Nutr Diet. 2001;90:5-12. Review. PubMed PMID: 11545045. 

10. Cordain L, Miller JB, Eaton SB, Mann N. Macronutrient estimations in hunter-gatherer diets. Am J Clin Nutr. 2000 Dec;72(6):1589-92. PubMed PMID: 11101497. 

11. Cordain L, Miller JB, Eaton SB, Mann N, Holt SH, Speth JD. Plant-animal subsistence ratios and macronutrient energy estimations in worldwide hunter-gatherer diets. Am J Clin Nutr. 2000 Mar;71(3):682- 92. PubMed PMID: 10702160. 

12. Fenech M. Micronutrients and genomic stability: a new paradigm for recommended dietary allowances (RDAs). Food Chem Toxicol. 2002 Aug;40(8):1113-7. Review. PubMed PMID: 12067572. 

13. Fenech M, Ferguson LR. Vitamins/minerals and genomic stability in humans. Mutat Res. 2001 Apr 18;475(1- 2):1-6. PubMed PMID: 11295148. 

14. Fenech M. Nutritional treatment of genome instability: a paradigm shift in disease prevention and in the setting of recommended dietary allowances. Nutr Res Rev. 2003 Jun;16(1):109-22. doi: 10.1079/NRR200359. PubMed PMID: 19079941. 

15. Fenech M. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res. 2012 May 1;733(1-2):21-33. doi: 10.1016/j.mrfmmm.2011.11.003. Epub 2011 Nov 7. Review. PubMed PMID: 22093367. 

16. Fenech M. The role of folic acid and Vitamin B12 in genomic stability of human cells. Mutat Res. 2001 Apr 18;475(1-2):57-67. Review. PubMed PMID: 11295154. 

17. Nutrition software analysis “Food Processor’ by ESHA Professional Nutrition & Fitness Software https:// www.esha.com/products/food-processor/ Twice Daily Multi™ 

18. Nutrition software analysis NutriBase Professional Nutrition & Fitness Software www.esha.com/products/food-processor/

19. C. Paul. Vitamin K-Chapter 136. Textbook of Natural Medicine (4th edition), editors Michal Murray, Joseph Pizzorno ISBN-13: 9781437723335 Publisher: Elsevier Health Sciences: 9/28/2012 

20. 5-methyltetrahydrofolate. Monograph. Altern Med Rev. 2006 Dec;11(4):330-7.

21. Mazza A, Cicero AF, Ramazzina E, Lenti S, Schiavon L, Casiglia E, Gussoni G. Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial. J Biol Regul Homeost Agents. 2016 Jul-Sep;30(3):921-927. PubMed PMID: 27655522. 

22. Deshmukh US, Joglekar CV, Lubree HG, Ramdas LV, Bhat DS, Naik SS, Hardikar PS, Raut DA, Konde TB, Wills AK, Jackson AA, Refsum H, Nanivadekar AS, Fall CH, Yajnik CS. Effect of physiological doses of oral vitamin B12 on plasma homocysteine: a randomized, placebo-controlled, double-blind trial in India. Eur J Clin Nutr. 2010 May;64(5):495-502. doi: 10.1038/ejcn.2010.15. Epub 2010 Mar 10.PubMed PMID: 20216560; PubMed Central PMCID: PMC2865445. 

23. Abdullah M, Jamil RT, Attia FN. Vitamin C (Ascorbic Acid). 2019 Jun 3. StatPearls Publishing; 2019 Jan-. Available from www.esha.com/products/food-processor/ PMID: 29763052.

24. White paper on 5-MTHF (Quatrefolic), by Gnosis. www.esha.com/products/food-processor/

25. Tam C, O’Connor D, Koren G. Circulating unmetabolized folic Acid: relationship to folate status and effect of supplementation. Obstet Gynecol Int. 2012;2012:485179. doi: 10.1155/2012/485179. Epub 2012 Feb 19. PubMed PMID:22529856. 

26. Sauer J, Mason JB, Choi SW. Too much folate: a risk factor for cancer and cardiovascular disease? Curr Opin Clin Nutr Metab Care. 2009 Jan;12(1):30-6. doi: 10.1097/MCO.0b013e32831cec62. Review. PubMed PMID: 19057184; PubMed Central PMCID: PMC2790187. 

27. Prinz-Langenohl R, Brämswig S, Tobolski O, Smulders YM, Smith DE, Finglas PM, Pietrzik K. [6S]- 5- methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->Tpolymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009 Dec;158(8):2014-21. doi: 10.1111/j.1476-5381.2009.00492.x. Epub . PubMed PMID:19917061; PubMed Central PMCID: PMC2807663.

28. Ashmead, H.D., Graff, D.J., Ashmead, H.H. (1985): Intestinal Absorption of Metal Ions and Chelates. Charles C. Thomas, Springfield, Illinois

29. Roohani N, Hurrell R, Kelishadi R, Schulin R. Zinc and its importance for human health: An integrative review. J Res Med Sci. 2013 Feb;18(2):144-57. PubMed PMID: 23914218; PubMed Central PMCID: PMC3724376. 

30. Anderson RA. Chromium as an essential nutrient for humans. Regul Toxicol Pharmacol 1997; 26:S35-41. 

31. Lamson DW, Plaza SM. The safety and efficacy of high-dose chromium. Altern Med Rev. 2002 Jun;7(3):218- 35. Review. PubMed PMID: 12126463. 

32. Hotz CS, Fitzpatrick DW, Trick KD, L'Abbe MR. Dietary Iodine and selenium interact to affect thyroid hormone metabolism of rats. J Nutr 1997; 127:1214-8. 

33. Arthur JR, Nicol F, Beckett GJ. The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism. Biol Trace Elem Res 1992; 33:37-42. 

34. Nielsen FH. Is boron nutritionally relevant? Nutr Rev. 2008 Apr;66(4):183-91. doi: 10.1111/j.1753- 4887.2008.00023.x. Review. PubMed PMID: 18366532. 

35. Penland JG. The importance of boron nutrition for brain and psychological function. Biol Trace Elem Res 1998; 66:299-317. 

36. Biotin. Altern Med Rev. 2007 Mar;12(1):73-8. PubMed PMID: 17397270. 

37. B. Tan. The Truth about Vitamin E: The Secret to Thriving with Annatto Tocotrienols Kindle Edition. 2019. ISBN 1733887423, 9781733887427.

38. Pennington JA, Young BE. Total diet study nutritional elements, 1982-1989. J Am Diet Assoc 1991;91:179-83. 

39. NHANES (National Health and Nutrition Examination Survey) 2001-2002. www.esha.com/products/food-processor/

40. Murray CW, Egan SK, Kim H, Beru N, Bolger PM. US Food and Drug Administration’s Total Diet Study: dietary intake of perchlorate and iodine. J Expo Sci Environ Epidemiol. 2008 Nov;18(6):571-580. 

41. Iyenga GV, Wolfe WR, Tanner JT, et al. Content of minor and trace elements, and organic nutrients in representative mixed total diet composites from the USA. Sci Total Environ 2000;256:215-26. 

42. Zempleni J, Wijeratne SSK, Kuroishi T. Biotin. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Washington, DC: Wiley-Blackwell; 2012:359-74