Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.

To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.

The following protocols were developed using only A through C-quality evidence.

Class
Qualifying studies
Minimum requirements
A
Systematic review or meta-analysis of human trials
 
B
RDBPC human trials
2+ studies and/or 1 study with 50 + subjects
C
RDBPC human trials
1 study

In designing a protocol for general wellness in adults, several aspects were considered. First, what are the top causes of morbidity and mortality in North America? Second, what are some ingredients with sufficient evidence to support a wide variety of conditions or health concerns that may be broadly applicable to this population?

The most common conditions affecting North American adults include cardiovascular disease (e.g. heart attack, stroke), cancer, respiratory conditions, cognitive decline, musculoskeletal disorders, and mental health concerns. (CDC 2021; Vos 2020) Dietary and nutrient risk factors for these conditions may include low omega-3 intake (Abdelhamid 2020) and low vitamin D intake (Rejnmark 2017). Nutrients such as magnesium (Mah 2021) and B complex vitamins (Young 2019) may also reduce morbidity associated with these conditions. Lastly, the herbal adaptogen ashwagandha was chosen for its potential role in improving stress, sleep, and overall quality of life. (Langade 2021; Lopresti 2019)

While there are many ingredients that may be considered part of a general wellness protocol, Fullscript’s Medical Advisory Team has selected these based on general safety, effectiveness, and broad applicability and availability to the adult population.

Omega-3

2-4 g EPA+DHA daily for a minimum of 3 months (Abdelhamid, 2020; Elagizi, 2021; Madison, 2021; Wolters 2021)

  • Cardiovascular disease and all-cause mortality: 2020 Cochrane review of 86 RCTs (n=162,796) concluded EPA+DHA reduced coronary heart disease mortality (10%), but not overall risk of CVD (primary or secondary), or all-cause mortality, noting that high intake of EPA+DHA vs low decreased triglycerides by 15%. (Abdelhamid 2020) 
  • Longevity and aging: 1.25-2.5 g/day of omega-3 (n-3) supplements were given to 138 individuals for 4 months and were found to be associated with improved markers of aging, including reduced levels of telomerase (24%), cortisol (33%), IL-6 (33%), and IL-10 (26%), with a note that 2.5 g/day produced superior results to 1.25 g/day. (Madison, 2021)
  • Cognitive decline: In two separate systematic reviews, n-3 supplementation was associated with improvements in episodic memory (immediate recall) (Yurko-Mauro, 2015), as well as improvements in global cognition, visual memory, and executive functioning. (Masana 2017)
  • Mood: A 2021 meta-analysis found n-3 supplementation to benefit depressive symptoms regardless of severity; subgroup analyses identified possible additional benefits with lower severity (no, or mild-moderate depression), and with longer treatment duration (>12 weeks). (Wolters 2021)
Omega-3 in the Fullscript catalog

Vitamin D

800-3000 IU per day for ~6 months (Gao 2017; Jolliffe 2021; NIH 2021)

Upper limit (UL) of vitamin D is 4,000 IU per day (NIH 2021)

  • All-cause mortality: A 2017 systematic review of meta-analyses (MAs) on vitamin D found that 8 of 12 MAs showed a significant correlation between vitamin D and reduced all-cause mortality; (Rejnmark 2017) the most recent MA on D3 found a risk reduction of 11%. (Chowdhury 2014)
  • Immune health: A 2021 MA of 46 randomized controlled trials (n=75,541) found that 400-1,000 IU/day of vitamin D safely reduced acute respiratory infection (ARI) risk by 8% (Jolliffe 2021); vitamin D may also play a role in autoimmune health. (Antico 2012)
  • Musculoskeletal health: With regards to aging and arthritis, a 2017 MA found doses of vitamin D over 2000 IU to improve pain and function scores in knee osteoarthritis. (Gao 2017)
  • Mood: A 2019 meta-analysis found an association between vitamin D and moderate effect size improvements in symptoms of major depression. (Vellekkatt 2019)
Vitamin D in the Fullscript catalog

Magnesium

400 mg per day (NIH 2021a; Zhao 2019) for > 8 weeks (Mah 2021)

  • Hypertension: A meta-analysis found that both serum and dietary levels of magnesium were significantly inversely associated with both coronary heart disease and cardiovascular disease overall, with effects seen between 173-457 mg per day in their model (Zhao 2019). Magnesium appears to reduce blood pressure in uncontrolled hypertensive patients at >240 mg per day. (Rosanoff 2021)
  • Headaches: Magnesium has strong evidence for the prevention of migraine headaches as it was found to reduce risk by 62% in a 2020 meta-analysis. (Veronese 2020)
  • Sleep: Sleep latency was found to be significantly reduced by magnesium supplementation in a 2021 meta-analysis where < 1000 mg of elemental magnesium three times per day was recommended. (Mah 2021)
  • Cognitive health: A 2019 meta-analysis of observational studies showed a significant relationship between ADHD and lower serum magnesium. (Effatpanah 2019)
Magnesium in the Fullscript catalog

B complex

Variable based on each B vitamin and form

  • Stress and mood: B complex supplementation was found to benefit feelings of stress in healthy populations and populations “at-risk” for low mood and anxiety. (Young 2019)
  • Cognitive health: B Vitamins have been shown to reduce homocysteine, and in those with elevated homocysteine, B vitamins improved global cognition, episodic memory, and semantic memory. (de Jager 2012)
  • Pain: Acute low back pain may be improved through B complex supplementation as it reduced treatment duration by 50% in a 2020 meta-analysis when added to diclofenac (an NSAID). (Calderon-Ospina 2020)
  • Hormonal health: B6, in particular, may improve premenstrual symptoms as a meta-analysis found an overall 2.3 fold improvement vs. placebo. (Wyatt 1999)
B complex in the Fullscript catalog

Ashwagandha (Withania somnifera)

600 mg per day for 8 weeks (Lopresti 2019)

  • Sexual health: A 2018 systematic review noted ashwagandha was associated with enhanced sexual behavior in females, as measured by the female sexual function index (FSFI) and female sexual distress index (FSDI), and improved spermatogenesis in males. (Azgomi 2018)
  • Strength training: Ashwagandha supplementation has been associated with increased muscle mass, strength, and testosterone, and reduced muscle damage and fat mass compared to placebo. (Wankhede 2015)
  • Stress and mood: Increased testosterone and reduced cortisol, anxiety, and borderline depression scores were associated with ashwagandha versus placebo. (Lopresti 2019)
  • Sleep: Ashwagandha was found to benefit sleep onset latency, mental alertness, sleep quality, and anxiety versus placebo. (Langade 2021)
Ashwagandha in the Fullscript catalog

Disclaimer

The Fullscript Medical Advisory Team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

View protocol on Fullscript
References
  1. Abdelhamid, A. S., Brown, T. J., Brainard, J. S., Biswas, P., Thorpe, G. C., Moore, H. J., Deane, K. H. O., Summerbell, C. D., Worthington, H. V., Song, F., Hooper, L., & Cochrane Heart Group. (2020). Omega‐3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews , 2020(2). https://doi.org/10.1002/14651858.CD003177.pub5 
  2. Antico, A., Tampoia, M., Tozzoli, R., & Bizzaro, N. (2012). Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? A systematic review of the literature. Autoimmunity Reviews, 12(2), 127–136. https://doi.org/10.1016/j.autrev.2012.07.007 
  3. Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle, R. T., Jr, Juliano, R. A., Jiao, L., Granowitz, C., Tardif, J.-C., Ballantyne, C. M., & REDUCE-IT Investigators. (2019). Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. The New England Journal of Medicine, 380(1), 11–22. https://doi.org/10.1056/NEJMoa1812792 
  4. Calderon-Ospina, C.-A., Nava-Mesa, M. O., & Arbeláez Ariza, C. E. (2020). Effect of Combined Diclofenac and B Vitamins (Thiamine, Pyridoxine, and Cyanocobalamin) for Low Back Pain Management: Systematic Review and Meta-analysis. Pain Medicine , 21(4), 766–781. https://doi.org/10.1093/pm/pnz216 
  5. CDC. (2021, March 1). Leading Causes of Death. https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm 
  6. Chowdhury, R., Kunutsor, S., Vitezova, A., Oliver-Williams, C., Chowdhury, S., Kiefte-de-Jong, J. C., Khan, H., Baena, C. P., Prabhakaran, D., Hoshen, M. B., Feldman, B. S., Pan, A., Johnson, L., Crowe, F., Hu, F. B., & Franco, O. H. (2014). Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ , 348, g1903. https://doi.org/10.1136/bmj.g1903 
  7. de Jager, C. A., Oulhaj, A., Jacoby, R., Refsum, H., & Smith, A. D. (2012). Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. International Journal of Geriatric Psychiatry, 27(6), 592–600. https://doi.org/10.1002/gps.2758 
  8. Effatpanah, M., Rezaei, M., Effatpanah, H., Effatpanah, Z., Varkaneh, H. K., Mousavi, S. M., Fatahi, S., Rinaldi, G., & Hashemi, R. (2019). Magnesium status and attention deficit hyperactivity disorder (ADHD): A meta-analysis. Psychiatry Research, 274, 228–234. https://doi.org/10.1016/j.psychres.2019.02.043 
  9. Elagizi, A., Lavie, C. J., O’Keefe, E., Marshall, K., O’Keefe, J. H., & Milani, R. V. (2021). An update on omega-3 polyunsaturated fatty acids and cardiovascular health. Nutrients, 13(1), 204. https://doi.org/10.3390/nu13010204 
  10. Gao, X.-R., Chen, Y.-S., & Deng, W. (2017). The effect of vitamin D supplementation on knee osteoarthritis: A meta-analysis of randomized controlled trials. International Journal of Surgery , 46, 14–20. https://doi.org/10.1016/j.ijsu.2017.08.010 
  11. Harris, W. S., Tintle, N. L., Imamura, F., Qian, F., Korat, A. V. A., Marklund, M., Djoussé, L., Bassett, J. K., Carmichael, P.-H., Chen, Y.-Y., Hirakawa, Y., Küpers, L. K., Laguzzi, F., Lankinen, M., Murphy, R. A., Samieri, C., Senn, M. K., Shi, P., Virtanen, J. K., … Fatty Acids and Outcomes Research Consortium (FORCE). (2021). Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nature Communications, 12(1), 2329. https://doi.org/10.1038/s41467-021-22370-2 
  12. Jolliffe, D. A., Camargo, C. A., Jr, Sluyter, J. D., Aglipay, M., Aloia, J. F., Ganmaa, D., Bergman, P., Bischoff-Ferrari, H. A., Borzutzky, A., Damsgaard, C. T., Dubnov-Raz, G., Esposito, S., Gilham, C., Ginde, A. A., Golan-Tripto, I., Goodall, E. C., Grant, C. C., Griffiths, C. J., Hibbs, A. M., … Martineau, A. R. (2021). Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials. The Lancet. Diabetes & Endocrinology, 9(5), 276–292. https://doi.org/10.1016/S2213-8587(21)00051-6 
  13. Langade, D., Thakare, V., Kanchi, S., & Kelgane, S. (2021). Clinical evaluation of the pharmacological impact of ashwagandha root extract on sleep in healthy volunteers and insomnia patients: A double-blind, randomized, parallel-group, placebo-controlled study. Journal of Ethnopharmacology, 264, 113276. https://doi.org/10.1016/j.jep.2020.113276 
  14. Lopresti, A. L., Drummond, P. D., & Smith, S. J. (2019). A Randomized, Double-Blind, Placebo-Controlled, Crossover Study Examining the Hormonal and Vitality Effects of Ashwagandha ( Withania somnifera) in Aging, Overweight Males. American Journal of Men’s Health, 13(2), 1557988319835985. https://doi.org/10.1177/1557988319835985 
  15. Lopresti, A. L., Smith, S. J., Malvi, H., & Kodgule, R. (2019). An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: A randomized, double-blind, placebo-controlled study. Medicine, 98(37), e17186. https://doi.org/10.1097/MD.0000000000017186 
  16. Madison, A. A., Belury, M. A., Andridge, R., Renna, M. E., Rosie Shrout, M., Malarkey, W. B., Lin, J., Epel, E. S., & Kiecolt-Glaser, J. K. (2021). Omega-3 supplementation and stress reactivity of cellular aging biomarkers: an ancillary substudy of a randomized, controlled trial in midlife adults. Molecular Psychiatry. https://doi.org/10.1038/s41380-021-01077-2 
  17. Mah, J., & Pitre, T. (2021). Oral magnesium supplementation for insomnia in older adults: a Systematic Review & Meta-Analysis. BMC Complementary Medicine and Therapies, 21(1), 125. https://doi.org/10.1186/s12906-021-03297-z 
  18. Masana, M. F., Koyanagi, A., Haro, J. M., & Tyrovolas, S. (2017). n-3 Fatty acids, Mediterranean diet and cognitive function in normal aging: A systematic review. Experimental Gerontology, 91, 39–50. https://doi.org/10.1016/j.exger.2017.02.008 
  19. Nasimi Doost Azgomi, R., Zomorrodi, A., Nazemyieh, H., Fazljou, S. M. B., Sadeghi Bazargani, H., Nejatbakhsh, F., Moini Jazani, A., & Ahmadi AsrBadr, Y. (2018). Effects of Withania somnifera on Reproductive System: A Systematic Review of the Available Evidence. BioMed Research International, 2018, 4076430. https://doi.org/10.1155/2018/4076430 
  20. NIH. (2021a). Magnesium. https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/ 
  21. NIH. (2021b). Vitamin D. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ 
  22. Pérez-Gómez, J., Villafaina, S., Adsuar, J. C., Merellano-Navarro, E., & Collado-Mateo, D. (2020). Effects of Ashwagandha (Withania somnifera) on VO2max: A Systematic Review and Meta-Analysis. Nutrients, 12(4). https://doi.org/10.3390/nu12041119 
  23. Rejnmark, L., Bislev, L. S., Cashman, K. D., Eiríksdottir, G., Gaksch, M., Grübler, M., Grimnes, G., Gudnason, V., Lips, P., Pilz, S., van Schoor, N. M., Kiely, M., & Jorde, R. (2017). Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data. PloS One, 12(7), e0180512. https://doi.org/10.1371/journal.pone.0180512 
  24. Rosanoff, A., Costello, R. B., & Johnson, G. H. (2021). Effectively Prescribing Oral Magnesium Therapy for Hypertension: A Categorized Systematic Review of 49 Clinical Trials. Nutrients, 13(1). https://doi.org/10.3390/nu13010195 
  25. Spedding, S. (2014). Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients, 6(4), 1501–1518. https://doi.org/10.3390/nu6041501 
  26. Vellekkatt, F., & Menon, V. (2019). Efficacy of vitamin D supplementation in major depression: A meta-analysis of randomized controlled trials. Journal of Postgraduate Medicine, 65(2), 74–80. https://doi.org/10.4103/jpgm.JPGM_571_17 
  27. Veronese, N., Demurtas, J., Pesolillo, G., Celotto, S., Barnini, T., Calusi, G., Caruso, M. G., Notarnicola, M., Reddavide, R., Stubbs, B., Solmi, M., Maggi, S., Vaona, A., Firth, J., Smith, L., Koyanagi, A., Dominguez, L., & Barbagallo, M. (2020). Magnesium and health outcomes: an umbrella review of systematic reviews and meta-analyses of observational and intervention studies. European Journal of Nutrition, 59(1), 263–272. https://doi.org/10.1007/s00394-019-01905-w 
  28. Vos, T., Lim, S. S., Abbafati, C., Abbas, K. M., Abbasi, M., Abbasifard, M., Abbasi-Kangevari, M., Abbastabar, H., Abd-Allah, F., Abdelalim, A., Abdollahi, M., Abdollahpour, I., Abolhassani, H., Aboyans, V., Abrams, E. M., Abreu, L. G., Abrigo, M. R. M., Abu-Raddad, L. J., Abushouk, A. I., … Murray, C. J. L. (2020). Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet, 396(10258), 1204–1222. https://doi.org/10.1016/S0140-6736(20)30925-9
  29. Wankhede, S., Langade, D., Joshi, K., Sinha, S. R., & Bhattacharyya, S. (2015). Examining the effect of Withania somnifera supplementation on muscle strength and recovery: a randomized controlled trial. Journal of the International Society of Sports Nutrition, 12, 43. https://doi.org/10.1186/s12970-015-0104-9 
  30. Wolters, M., von der Haar, A., Baalmann, A.-K., Wellbrock, M., Heise, T. L., & Rach, S. (2021). Effects of n-3 Polyunsaturated Fatty Acid Supplementation in the Prevention and Treatment of Depressive Disorders-A Systematic Review and Meta-Analysis. Nutrients, 13(4). https://doi.org/10.3390/nu13041070 
  31. Wu, Z., Yang, J., Liu, J., & Lian, K. (2019). The relationship between magnesium and osteoarthritis of knee: A MOOSE guided systematic review and meta-analysis. Medicine, 98(45), e17774. https://doi.org/10.1097/MD.0000000000017774 
  32. Wyatt, K. M., Dimmock, P. W., Jones, P. W., & Shaughn O’Brien, P. M. (1999). Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ , 318(7195), 1375–1381. https://doi.org/10.1136/bmj.318.7195.1375 
  33. Young, L. M., Pipingas, A., White, D. J., Gauci, S., & Scholey, A. (2019). A Systematic Review and Meta-Analysis of B Vitamin Supplementation on Depressive Symptoms, Anxiety, and Stress: Effects on Healthy and “At-Risk” Individuals. Nutrients, 11(9). https://doi.org/10.3390/nu11092232 
  34. Yurko-Mauro, K., Alexander, D. D., & Van Elswyk, M. E. (2015). Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PloS One, 10(3), e0120391. https://doi.org/10.1371/journal.pone.0120391 
  35. Zhao, L., Hu, M., Yang, L., Xu, H., Song, W., Qian, Y., & Zhao, M. (2019). Quantitative Association Between Serum/Dietary Magnesium and Cardiovascular Disease/Coronary Heart Disease Risk: A Dose-Response Meta-analysis of Prospective Cohort Studies. Journal of Cardiovascular Pharmacology, 74(6), 516–527. https://doi.org/10.1097/FJC.0000000000000739