The Evidence

We did our best to provide you with some of the most current and clinically useful evidence from all over the globe. For additional references and more on Functional Medicine, go to ifm.org or my.clevelandclinic.org.

We hope you find this helpful. ​

For Information on the Functional Medicine approach to COVID-19, go to ifm.org.

Immune Health
  • Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013;8(6):e65835. doi:10.1371/journal.pone.0065835

  • Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2011;463(1):121-137. doi:10.1007/s00424-011-1044-0

  • Yeah, YK, Zuo T, Lui GC, et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.BMJ. Gut 2021;70:698-706. Accessed February 23, 2021. https://gut.bmj.com/content/70/4/698

  • Iddir M, Brito A, Dingeo G, et al. Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: considerations during the COVID-19 crisis. Nutrients. 2020;12(6):1562. doi:10.3390/nu12061562

  • Olson EJ. Lack of sleep: can it make you sick? Mayo Clinic. Published November 28, 2018. Accessed February 23, 2021. https://www.mayoclinic.org/diseases-conditions/insomnia/expert-answers/lack-of-sleep/faq-20057757

  • Exercise and immunity. MedlinePlus. Updated February 8, 2021. Accessed February 23, 2021. https://medlineplus.gov/ency/article/007165.htm

  • Phytonutrients. NutritionFacts. Accessed February 23, 2021. https://nutritionfacts.org/topics/phytonutrients/

  • Percival SS. Aged garlic extract modifies human immunity. J Nutr. 2016;146(2):433S-436S. doi:10.3945/jn.115.210427

  • Hojsak I, Abdovi S, Szajewska H, Milosevi M, Krznari Z, Kolacek S. Lactobacillus GG in the prevention of nosocomial gastrointestinal and respiratory tract infections. Pediatrics. 2010;125(5):e1171-e1177. doi:10.1542/peds.2009-2568

  • Prasad AS. Zinc is an antioxidant and anti-inflammatory agent: its role in human health. Front Nutr. 2014;1:14. doi:10.3389/fnut.2014.00014

  • What happens when your immune system gets stressed out? Cleveland Clinic. Published March 1, 2017. Accessed February 23, 2021. https://health.clevelandclinic.org/what-happens-when-your-immune-system-gets-stressed-out/

  • Yaribeygi H, Panahi Y, Sahraei H, Johnston TP, Sahebkar A. The impact of stress on body function: a review. EXCLI J. 2017;16:1057-1072. doi:10.17179/excli2017-480

  • Hato T, Dagher PC. How the innate immune system senses trouble and causes trouble. Clin J Am Soc Nephrol. 2015;10(8):1459-1469. doi:10.2215/CJN.04680514

  • Elliott DE, Siddique SS, Weinstock JV. Innate immunity in disease. Clin Gastroenterol Hepatol. 2014;12(5):749-755. doi:10.1016/j.cgh.2014.03.007

  • Jiao Y, Wu L, Huntington ND, Zhang X. Crosstalk between gut microbiota and innate immunity and its implication in autoimmune diseases. Front Immunol. 2020;11:282. doi:10.3389/fimmu.2020.00282

  • Kamada N, Rogler G. The innate immune system: a trigger for many chronic inflammatory intestinal diseases. Inflamm Intest Dis. 2016;1(2):70-77. doi:10.1159/000445261

  • Ding S, Jiang H, Fang J. Regulation of immune function by polyphenols. J Immunol Res. 2018;2018:1264074. doi:10.1155/2018/1264074

  • Panaro MA, Corrado A, Benameur T, Paolo CF, Cici D, Porro C. The emerging role of curcumin in the modulation of TLR-4 signaling pathway: focus on neuroprotective and anti-rheumatic properties. Int J Mol Sci. 2020;21(7):2299. doi:10.3390/ijms21072299

Brain Health
  • Bredesen, DE, Sharlin K., Jenkins,D. et al. Reversal of Cognitive Decline: 100 patients. J Alzheimers Dis Parkinsonism 2018, Vol 8(5): 450. DOI: 10.4172/2161-0460.1000450

  • Labzin LI, Heneka MT, Latz E. Innate immunity and neurodegeneration. Annu Rev Med. 2018;69:437-449. doi:10.1146/annurev-med-050715-104343​

  • Pistollato F, Cano SS, Elio I, Vergara MM, Giampieri F, Battino M. Associations between sleep, cortisol regulation, and diet: possible implications for the risk of Alzheimer disease. Adv Nutr. 2016;7(4):679-689. doi:10.3945/an.115.011775

  • Bredesen DE. Reversal of cognitive decline: A novel therapeutic program. Aging. 2014;6(9):707–717. https://pubmed.ncbi.nlm.nih.gov/25324467/

  • Spilman, P., B. Jagodzinska, D. E. Bredesen, and John Varghese. Enhancement of sAPPα as a therapeutic strategy for Alzheimer's and other neurodegenerative diseases. HSOA Journal of Alzheimer's & Neurodegenerative Diseases 1: 1-10 (2015). doi: 10.24966/AND-9608/100001

  • Theendakara V, Peters-Libeu CA, Bredesen DE, Rao RV. Transcriptional Effects of ApoE4: Relevance to Alzheimer's Disease. Mol Neurobiol. 2018 Jun;55(6):5243-5254. doi: 10.1007/s12035-017-0757-2

  • Famenini S, Rigali EA, Olivera-Perez HM, Dang J, Chang MT, Halder R, Rao RV, Pellegrini M, Porter V, Bredesen D, Fiala M. Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on ω-3 supplementation. FASEB J. 2017 Jan;31(1):148-160. doi: 10.1096/fj.201600677RR.

  • Kurakin A, Bredesen DE. Alzheimer's disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics. Aging (Albany NY). 2020 Sep 21;12(18):17815-17844. doi: 10.18632/aging.103883

  • See 200+ more publications : https://www.apollohealthco.com/dr-bredesen/#publications

Gut Health
  • US Department of Health and Human Services and US Department of Agriculture. 2015-2020 Dietary Guidelines for Americans.8th ed. Office of Disease Prevention and Health Promotion; 2015. http://health.gov/dietaryguidelines/2015/guidelines

  • Nutrition: micronutrient facts. Centers for Disease Control and Prevention. Reviewed December 3, 2020. Accessed March 9, 2021. https://www.cdc.gov/nutrition/micronutrient-malnutrition/micronutrients/index.html

  • Drake VJ. Subpopulations at risk for micronutrient inadequacy or deficiency. Linus Pauling Institute, Oregon State University. Published January 2018. Accessed March 9, 2021. https://lpi.oregonstate.edu/mic/micronutrient-inadequacies/subpopulations-at-risk

  • Only 1 in 10 adults get enough fruits or vegetables. Centers for Disease Control and Prevention. Published November 16, 2017. Accessed March 9, 2021. https://www.cdc.gov/media/releases/2017/p1116-fruit-vegetable-consumption.html

  • Cammarota G, Ianiro G. Gut microbiota and cancer patients: a broad-ranging relationship. Mayo Clin Proc. 2017;92(11):1605-1607. doi:1016/j.mayocp.2017.09.009​

  • Lach G, Schellekens H, Dinan TG, Cryan JF. Anxiety, depression, and the microbiome: a role for gut peptides. Neurotherapeutics. 2018;15(1):36-59. doi:10.1007/s13311-017-0585-0

  • Cryan JF, O’Riordan KJ, Cowan CSM, et al. The microbiota-gut-brain axis. Physiol Rev. 2019;99(4):1877?2013. doi:10.1152/physrev.00018.2018

  • Hodges RE, Minich DM. Modulation of metabolic detoxification pathways using foods and food-derived components: a scientific review with clinical application. J Nutr Metab. 2015;2015:760689. doi:10.1155/2015/760689

  • The Sonnenburg Lab: The gut microbiota. Accessed February 25, 2021. https://sonnenburglab.stanford.edu/research.html

  • Mu Q, et al. Leaky gut as a danger signal for autoimmune diseases. Front Immunol. 2017; 8: 598. doi: 10.3389/fimmu.2017.00598

  • Wilkins LJ, Monga M, Miller AW. Defining dysbiosis for a cluster of chronic diseases. Sci Rep. 2019; Sep 9;9(1):12918. doi: 10.1038/s41598-019-49452-y

  • Cleveland Clinic Lerner Research Institute. Researchers Identify Protector of Intestinal Barrier. Reviewed January 18, 2021. Accessed March 1, 2021. https://pubmed.ncbi.nlm.nih.gov/33195251/

Preventative Health
  • Beidelschies M, Alejandro-Rodriguez, M, Xinge Ji, et al. Association of the functional medicine model of care with patient-reported health-related quality-of-life outcomes. JAMA. 2019; 2(10): e1914017. doi: 10.1001/jamanetworkopen.2019.14017

  • Liu YZ, Wang YX, Jiang CL. Inflammation: the common pathway of stress-related diseases. Front Hum Neurosci. 2017;11:316. doi:10.3389/fnhum.2017.00316

  • Jiang X, Liu Y, Ma L, et al. Chemopreventive activity of sulforaphane. Drug Des Devel Ther. 2018;12:2905-2913. doi:10.2147/DDDT.S100534​

  • Minich DM, Brown BI. A review of dietary (phyto)nutrients for glutathione support. Nutrients. 2019;11(9):2073. doi: 10.3390/nu11092073

  • Babu NC, Gomes AJ. Systemic manifestations of oral diseases. J Oral Maxillofac Pathol. 2011;15(2):144-147. doi:4103/0973-029X.84477

  • Evans CA, Kleinman DV, Maas WR, et al. Oral Health in America: A Report of the Surgeon General (Executive Summary). US Department of Health and Human Services, National Institute of Dental and Craniofacial Research, National Institutes of Health; 2000. Accessed February 24,2021. https://www.nidcr.nih.gov/research/data-statistics/surgeon-general#download-full-report

  • Cleven L, Krell-Roesch J, Nigg CR, Woll A. The association between physical activity with incident obesity, coronary heart disease, diabetes and hypertension in adults: a systematic review of longitudinal studies published after 2012. BMC Public Health. 2020;20(1):726. doi:10.1186/s12889-020-08715-4

  • Hall KS, Hyde ET, Bassett DR, et al. Systematic review of the prospective association of daily step counts with risk of mortality, cardiovascular disease, and dysglycemia. Int J Behav Nutr Phys Act. 2020;17(1):78. doi:10.1186/s12966-020-00978-9

  • Lewis P, Korf HW, Kuffer L, Groß JV, Erren TC. Exercise time cues (zeitgebers) for human circadian systems can foster health and improve performance: a systematic review. BMJ Open Sport Exerc Med. 2018;4(1):e000443. doi:10.1136/bmjsem-2018-000443

  • About chronic diseases. The Centers for Disease Control and Prevention. Reviewed January 12, 2021. Accessed February 25, 2021. https://www.cdc.gov/chronicdisease/about/index.htm.

  • UCSF Osher Center for Integrative Medicine. Current Research Studies. Accessed March 1, 2021. https://osher.ucsf.edu/research/current-research-studies

  • Cleveland Clinic: ConsultQD. Microbiome Reveals Clues into Idiopathic Male Infertility. Accessed March 1, 2021. https://consultqd.clevelandclinic.org/microbiome-reveals-clues-to-idiopathic-male-infertility/

Cardiovascular Health
  • Heart Disease Facts. Reviewed: September 8, 2020. The Centers for Disease Control and Prevention. Accessed February 25, 2021. https://www.cdc.gov/heartdisease/facts.htm

  • Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med. 2018;387(25):e34. doi:1056/NEJMoa1800389

  • Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350. doi:1016/j.jacc.2018.11.003

  • Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):1376-1414. doi:1016/j.jacc.2019.03.009

  • University of Cambridge. Inflammation links heart disease and depression, study finds. Published March 19, 2019. Accessed March 9, 2021. https://www.cam.ac.uk/research/news/inflammation-links-heart-disease-and-depression-study-finds

  • Delange N, Lindsay S, Lemus H, Finlayson TL, Kelley ST, Gottlieb RA. Periodontal disease and its connection to systemic biomarkers of cardiovascular disease in young American Indian/Alaskan natives. J Periodontol. 2018;89(2):219-227. doi:1002/JPER.17-0319

  • Patrakka O, Pienimäki JP, Tuomisto S, et al. Oral bacteria signatures in cerebral thrombi of patients with acute ischemic stroke treated with thrombectomy. J Am Heart Assoc. 2019;8(11):e012330. doi:1161/JAHA.119.012330

  • American Heart Association recommendations for physical activity in adults and kids. American Heart Association. Reviewed April 18, 2018. Accessed February 24, 2021. https://www.heart.org/en/healthy-living/fitness/fitness-basics/aha-recs-for-physical-activity-in-adults

  • Pires NF, Coelho-Júnior HJ, Gambassi BB, et al. Combined aerobic and resistance exercises evokes longer reductions on ambulatory blood pressure in resistant hypertension: a randomized crossover trial. Cardiovasc Ther. Published online July 20, 2020. doi:10.1155/2020/8157858

  • Hannan AL, Hing W, Simas V, et al. High-intensity interval training versus moderate-intensity continuous training within cardiac rehabilitation: a systematic review and meta-analysis. Open Access J Sports Med. 2018;9:1-17. doi:10.2147/OAJSM.S150596

  • Rodrigues-Krause J, Farinha JB, Ramis TR, et al. Effects of dancing compared to walking on cardiovascular risk and functional capacity of older women: a randomized controlled trial. Exp Gerontol. 2018;114:67-77. doi:10.1016/j.exger.2018.10.015

  • Chu P, Gotink RA, Yeh GY, Goldie SJ, Hunink MG. The effectiveness of yoga in modifying risk factors for cardiovascular disease and metabolic syndrome: a systematic review and meta-analysis of randomized controlled trials. Eur J Prev Cardiol. 2016;23(3):291-307. doi:10.1177/2047487314562741

  • Best Practices For Cardiovascular Disease Programs. The Centers for Disease Control and Prevention. Reviewed March 2, 2018. Accessed February 25, 2021 https://www.cdc.gov/dhdsp/pubs/guides/best-practices/

Hormone Health
  • Silvestris E, Lovero D, Palmirotta R. Nutrition and female fertility: an interdependent correlation. Front Endocrinol. 2019;10:346. doi:10.3389/fendo.2019.00346

  • Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev. 2014;94(2):355-382. doi:10.1152/physrev.00030.2013

  • Winnicki M, Somers VK, Accurso V, et al. Fish-rich diet, leptin, and body mass. Circulation. 2002;106(3):289-291. doi:10.1161/01.cir.0000025241.01418.4d

  • Del Río JP, Alliende MI, Molina N, Serrano FG, Molina S, Vigil P. Steroid hormones and their action in women’s brains: the importance of hormonal balance. Front Public Health. 2018;6:141. doi:3389/fpubh.2018.00141

  • McCabe D, Lisy K, Lockwood C, Colbeck M. The impact of essential fatty acid, B vitamins, vitamin C, magnesium, and zinc supplementation on stress levels in women: a systematic review. JBI Database System Rev Implement Rep. 2017;15(2):402-453. doi:11124/JBISRIR-2016-002965

  • Ranabir S, Reetu K. Stress and hormones. Indian J Endocrinol Metab. 2011;15(1):18-22. doi:4103/2230-8210.77573

  • Sato K, Iemitsu M, Matsutani K, Kurihara T, Hamaoka T, Fujita S. Resistance training restores muscle sex steroid hormone steroidogenesis in older men. FASEB J. 2014;28(4):1891-1897. doi:1096/fj.13-245480

  • Dada T, Mittal D, Mohanty K, et al. Mindfulness meditation reduces intraocular pressure, lowers stress biomarkers and modulates gene expression in glaucoma: a randomized controlled trial. J Glaucoma. 2018;27(12):1061-1067. doi:1097/IJG.0000000000001088

  • American Psychological Association. Stress in America: the impact of discrimination. Stress in America Survey. Published March 10, 2016. Accessed March 9, 2021. https://www.apa.org/news/press/releases/stress/2015/impact-of-discrimination.pdf