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

Homocysteine is a non-essential amino acid and metabolite of methionine, an essential amino acid obtained in the diet. (20) Homocysteine is involved in vitamin B-dependent methylation cycles that generate and breakdown the universal methyl-group donor, S-adenosyl-methionine (SAMe). Disruptions in this cycle, whether caused by reduced enzymatic expression or activity of various methylation cycle proteins including methylenetetrahydrofolate reductase (MTHFR), pyridoxal-5’-phosphate (P5P), or cystathionine B-synthase (CBS), may theoretically lead to elevated levels of homocysteine. (28)

Normal homocysteine levels can range from 5-15 μmol/L, while hyperhomocysteinemia occurs when homocysteine levels are elevated beyond 15 μmol/L. (35) Hyperhomocysteinemia can be further classified as mild (16-30 μmol/L), intermediate (31-100 μmol/L), or severe (>100 μmol/L). (20)

Hyperhomocysteinemia has been linked to numerous diseases, including: 

  • Age-related conditions, such as Alzheimer’s disease, Parkinson’s disease, and stroke 
  • Endocrine-related conditions, such as diabetes, hypothyroidism, insulin resistance, and osteoporosis
  • Endothelial-related conditions, including cerebrovascular and vascular diseases
  • Other conditions, such as end-stage renal disease, various cancers, schizophrenia, and complications in pregnancy (1)(20)(28)

A number of factors may contribute to hyperhomocysteinemia, including:

  • Genetic polymorphisms of methylation enzymes, such as MTHFR, CBS, methionine synthase, and methionine synthase reductase
  • Nutrient deficiencies, such as folate, vitamin B6, vitamin B12, or betaine deficiencies
  • Diet and lifestyle considerations, such as excess methionine intake, smoking, excess alcohol or caffeine intake, and sedentarism (1)(33)

Please see the following articles for more information on the impact of nutrition on the methylation process and on supporting patients with MTHFR polymorphisms.

Folic acid and vitamin B12

0.2-0.8 mg as folic acid or 5-methylfolate (5-MTHF) per day, minimum 12 weeks for greatest benefit and maintenance for up to ~5 years, with optional 0.4-1.0 mg vitamin B12 for improved efficacy in patients with elevated homocysteine (3)(5)(6)(7)(10)(12)(15)(16)(21)(23)(34)(37)(38)

  • Folic acid provided primary effect on homocysteine reductions ranging between ~13-30% (3)(4)(5)(6)(7)(10)(12)(15)(16)(21)(22)(23)(26)(32)(34)(40)
  • Proportions of reductions in homocysteine were highly dependent on greater baseline homocysteine and lower baseline folate levels (5)(15)(16)(29)(37)
  • Higher folic acid doses ranging between 5-60 mg per day were safely used, but did not reduce homocysteine further than ingestion of 0.8 mg (16)(22)(29)(32)(40)
  • Most human evidence did not support greater folate bioavailability or efficacy in reducing homocysteine by 5-MTHF over folic acid, but it may provide extended retention of benefit upon discontinuation in patients with poor methylation capacity (2)
  • Vitamin B12 produced additional ~7% reduction in homocysteine (4)(5)(15)(16)(21) 
  • Individual trials showed benefit of adding vitamin B6 for further reductions in homocysteine, however this was not supported in meta-analyses (3)(5)(15)(16)(23)(34)
  • Males may have required higher folic acid dose ranges than women (6)
Folic acid and vitamin B12 in the Fullscript catalog

Omega-3 fatty acids

200-6,000 mg (~98-2,000 mg EPA/490-1,000 mg DHA) per day, for 1-12 months in patients with hyperhomocysteinemia or elevated homocysteine within normal ranges (8)(11)(13)(17)(18)(19)(25)(30)(42)(43)

  • Reduced homocysteine by 1.18-1.58 μmol/L on average using wide dose ranges, as shown in meta-analyses (8)(18)
  • Reduced homocysteine by ~2.5-4.0 μmol/L in patients with type II diabetes, patients on hemodialysis, or healthy adults using mid-range doses of 2,000-3,600 mg per day for 1-3 months and up to one year (11)(17)(25)(30)(42)(43)
  • Reduced homocysteine by ~1.6 μmol/L over 12 months in patients younger than 65 years, previously suffering from myocardial infarction (13)
  • Adjunct therapy with folic acid, vitamin B6, and vitamin B12 improved efficacy (8)(17)
  • Adjunct aerobic exercise and cognitive stimulation may be required for benefit in some populations, including older adults with mild cognitive impairment (19)
Omega-3 fatty acids in the Fullscript catalog

N-acetylcysteine (NAC)

600 mg, 2-3 times per day, for 2-8 weeks (14)(24)(36)(41)

  • Reduced total homocysteine by 12-45% in healthy patients or patients at increased risk for CVD (9)(14)(24)(36)(39)
  • Oral formulations reduced total homocysteine in patients with end-stage renal disease by 21-25%, while intravenous formulations further reduce homocysteine during hemodialysis by ~90% (24)(27)(31)
  • Reduced SBP (~7.1 mmHg) and DBP (~3.3 mmHg) in hyperlipidemic men and SBP (~3.2 mmHg) in normolipidemic men; each 10% reduction in homocysteine is associated with 1.45-2.55 reduction in pulse pressure mmHg in patients undergoing hemodialysis (14)(27)(31)
  • Increased urinary excretion of homocysteine in its sulfonated form (36)
NAC 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. Azzini, E., Ruggeri, S., & Polito, A. (2020). Homocysteine: Its possible emerging role in at-risk population groups. International Journal of Molecular Sciences, 21(4). https://www.ncbi.nlm.nih.gov/pubmed/32093165 (F)
  2. Bayes, J., Agrawal, N., & Schloss, J. (2019). The bioavailability of various oral forms of folate supplementation in healthy populations and animal models: A systematic review. Journal of Alternative and Complementary Medicine, 25(2), 169–180. https://pubmed.ncbi.nlm.nih.gov/30010385/ (A)
  3. Bostom, A. G., Gohh, R. Y., Beaulieu, A. J., Nadeau, M. R., Hume, A. L., Jacques, P. F., Selhub, J., & Rosenberg, I. H. (1997). Treatment of hyperhomocysteinemia in renal transplant recipients. A randomized, placebo-controlled trial. Annals of Internal Medicine, 127(12), 1089–1092. https://www.ncbi.nlm.nih.gov/pubmed/9412311 (C)
  4. Brönstrup, A., Hages, M., Prinz-Langenohl, R., & Pietrzik, K. (1998). Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma homocysteine concentrations in healthy, young women. The American Journal of Clinical Nutrition, 68(5), 1104–1110. https://www.ncbi.nlm.nih.gov/pubmed/9808229 (B)
  5. Clarke, R. (2000). Lowering blood homocysteine with folic acid-based supplements: meta-analysis of randomised trials. Indian Heart Journal, 52(7), S59–S64. https://www.ncbi.nlm.nih.gov/pubmed/11339443 (A)
  6. Coppen, A., & Bailey, J. (2000). Enhancement of the antidepressant action of fluoxetine by folic acid: A randomised, placebo controlled trial. Journal of Affective Disorders, 60(2), 121–130. https://www.ncbi.nlm.nih.gov/pubmed/10967371 (C)
  7. Crowe, F. L., Skeaff, C. M., McMahon, J. A., Williams, S. M., & Green, T. J. (2008). Lowering plasma homocysteine concentrations of older men and women with folate, vitamin B-12, and vitamin B-6 does not affect the proportion of (n-3) long chain polyunsaturated fatty acids in plasma phosphatidylcholine. The Journal of Nutrition, 138(3), 551–555. https://www.ncbi.nlm.nih.gov/pubmed/18287365 (B)
  8. Dawson, S. L., Bowe, S. J., & Crowe, T. C. (2016). A combination of omega-3 fatty acids, folic acid and B-group vitamins is superior at lowering homocysteine than omega-3 alone: A meta-analysis. Nutrition Research, 36(6), 499–508. https://www.ncbi.nlm.nih.gov/pubmed/27188895 (A)
  9. Doshi, S., McDowell, I., Goodfellow, J., Stabler, S., Boger, R., Allen, R., Newcombe, R., Lewis, M., & Moat, S. (2005). Relationship between S-adenosylmethionine, S-adenosylhomocysteine, asymmetric dimethylarginine, and endothelial function in healthy human subjects during experimental hyper- and hypohomocysteinemia. Metabolism: Clinical and Experimental, 54(3), 351–360. https://www.ncbi.nlm.nih.gov/pubmed/15736113 (C)
  10. Durga, J., van Boxtel, M. P. J., Schouten, E. G., Kok, F. J., Jolles, J., Katan, M. B., & Verhoef, P. (2007). Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomised, double blind, controlled trial. The Lancet, 369(9557), 208–216. https://www.ncbi.nlm.nih.gov/pubmed/17240287 (B)
  11. Fontani, G., Corradeschi, F., Felici, A., Alfatti, F., Bugarini, R., Fiaschi, A. I., Cerretani, D., Montorfano, G., Rizzo, A. M., & Berra, B. (2005). Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with Omega-3 polyunsaturated fatty acids. European Journal of Clinical Investigation, 35(8), 499–507. https://www.ncbi.nlm.nih.gov/pubmed/16101670 (C)
  12. Galan, P., Kesse-Guyot, E., Czernichow, S., Briancon, S., Blacher, J., Hercberg, S., & SU.FOL.OM3 Collaborative Group. (2010). Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: A randomised placebo controlled trial. BMJ, 341, c6273. https://www.ncbi.nlm.nih.gov/pubmed/21115589 (B)
  13. Grundt, H., Nilsen, D. W. T., Mansoor, M. A., Hetland, Ø., & Nordøy, A. (2003). Reduction in homocysteine by n-3 polyunsaturated fatty acids after 1 year in a randomised double-blind study following an acute myocardial infarction: No effect on endothelial adhesion properties. Pathophysiology of Haemostasis and Thrombosis, 33(2), 88–95. https://www.ncbi.nlm.nih.gov/pubmed/14624050 (B)
  14. Hildebrandt, W., Sauer, R., Bonaterra, G., Dugi, K. A., Edler, L., & Kinscherf, R. (2015). Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status. The American Journal of Clinical Nutrition, 102(5), 1014–1024. https://www.ncbi.nlm.nih.gov/pubmed/26447155 (B)
  15. Homocysteine Lowering Trialists’ Collaboration. (1998). Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ, 316(7135), 894–898. https://www.ncbi.nlm.nih.gov/pubmed/9569395 (A)
  16. Homocysteine Lowering Trialists’ Collaboration. (2005). Dose-dependent effects of folic acid on blood concentrations of homocysteine: A meta-analysis of the randomized trials. The American Journal of Clinical Nutrition, 82(4), 806–812. https://www.ncbi.nlm.nih.gov/pubmed/16210710 (A)
  17. Huang, T., Li, K., Asimi, S., Chen, Q., & Li, D. (2015). Effect of vitamin B-12 and n-3 polyunsaturated fatty acids on plasma homocysteine, ferritin, C-reaction protein, and other cardiovascular risk factors: A randomized controlled trial. Asia Pacific Journal of Clinical Nutrition, 24(3), 403–411. https://www.ncbi.nlm.nih.gov/pubmed/26420180 (C)
  18. Huang, T., Zheng, J., Chen, Y., Yang, B., Wahlqvist, M. L., & Li, D. (2011). High consumption of Ω-3 polyunsaturated fatty acids decrease plasma homocysteine: A meta-analysis of randomized, placebo-controlled trials. Nutrition, 27(9), 863–867. https://www.ncbi.nlm.nih.gov/pubmed/21501950 (A)
  19. Köbe, T., Witte, A. V., Schnelle, A., Lesemann, A., Fabian, S., Tesky, V. A., Pantel, J., & Flöel, A. (2016). Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment. NeuroImage, 131, 226–238. https://www.ncbi.nlm.nih.gov/pubmed/26433119 (C)
  20. Kumar, A., Palfrey, H. A., Pathak, R., Kadowitz, P. J., Gettys, T. W., & Murthy, S. N. (2017). The metabolism and significance of homocysteine in nutrition and health. Nutrition & Metabolism, 14, 78. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741875/ (F)
  21. Manns, B., Hyndman, E., Burgess, E., Parsons, H., Schaefer, J., Snyder, F., & Scott-Douglas, N. (2001). Oral vitamin B(12) and high-dose folic acid in hemodialysis patients with hyper-homocyst(e)inemia. Kidney International, 59(3), 1103–1109. https://www.ncbi.nlm.nih.gov/pubmed/11231366 (B)
  22. Mayer, O., Jr, Simon, J., Rosolová, H., Hromádka, M., Subrt, I., & Vobrubová, I. (2002). The effects of folate supplementation on some coagulation parameters and oxidative status surrogates. European Journal of Clinical Pharmacology, 58(1), 1–5. https://www.ncbi.nlm.nih.gov/pubmed/11956665 (C)
  23. McKinley, M. C., McNulty, H., McPartlin, J., Strain, J. J., Pentieva, K., Ward, M., Weir, D. G., & Scott, J. M. (2001). Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete. The American Journal of Clinical Nutrition, 73(4), 759–764. https://www.ncbi.nlm.nih.gov/pubmed/11273851 (C)
  24. Nolin, T. D., Ouseph, R., Himmelfarb, J., McMenamin, M. E., & Ward, R. A. (2010). Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease. Clinical Journal of the American Society of Nephrology, 5(9), 1588–1594. https://www.ncbi.nlm.nih.gov/pubmed/20538838 (C)
  25. Pooya, S., Jalali, M. D., Jazayery, A. D., Saedisomeolia, A., Eshraghian, M. R., & Toorang, F. (2010). The efficacy of omega-3 fatty acid supplementation on plasma homocysteine and malondialdehyde levels of type 2 diabetic patients. Nutrition, Metabolism, and Cardiovascular Diseases, 20(5), 326–331. https://www.ncbi.nlm.nih.gov/pubmed/19540739 (B)
  26. Qin, X., Xu, M., Zhang, Y., Li, J., Xu, X., Wang, X., Xu, X., & Huo, Y. (2012). Effect of folic acid supplementation on the progression of carotid intima-media thickness: A meta-analysis of randomized controlled trials. Atherosclerosis, 222(2), 307–313. https://www.ncbi.nlm.nih.gov/pubmed/22209480 (A)
  27. Scholze, A., Rinder, C., Beige, J., Riezler, R., Zidek, W., & Tepel, M. (2004). Acetylcysteine reduces plasma homocysteine concentration and improves pulse pressure and endothelial function in patients with end-stage renal failure. Circulation, 109(3), 369–374. https://www.ncbi.nlm.nih.gov/pubmed/14732754 (C)
  28. Son, P., & Lewis, L. (2020). Hyperhomocysteinemia. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK554408/ (F)
  29. Sunder-Plassmann, G., Födinger, M., Buchmayer, H., Papagiannopoulos, M., Wojcik, J., Kletzmayr, J., Enzenberger, B., Janata, O., Winkelmayer, W. C., Paul, G., Auinger, M., Barnas, U., & Hörl, W. H. (2000). Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: Results of the Vienna multicenter study. Journal of the American Society of Nephrology, 11(6), 1106–1116. https://www.ncbi.nlm.nih.gov/pubmed/10820175 (B)
  30. Tayebi-Khosroshahi, H., Dehgan, R., Habibi Asl, B., Safaian, A., Panahi, F., Estakhri, R., & Purasgar, B. (2013). Effect of omega-3 supplementation on serum level of homocysteine in hemodialysis patients. Iranian Journal of Kidney Diseases, 7(6), 479–484. https://www.ncbi.nlm.nih.gov/pubmed/24241095 (C)
  31. Thaha, M., Yogiantoro, M., & Tomino, Y. (2006). Intravenous N-acetylcysteine during haemodialysis reduces the plasma concentration of homocysteine in patients with end-stage renal disease. Clinical Drug Investigation, 26(4), 195–202. https://www.ncbi.nlm.nih.gov/pubmed/17163251 (C)
  32. Thambyrajah, J., Landray, M. J., McGlynn, F. J., Jones, H. J., Wheeler, D. C., & Townend, J. N. (2000). Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure? Circulation, 102(8), 871–875. https://www.ncbi.nlm.nih.gov/pubmed/10952955 (B)
  33. Tinelli, C., Di Pino, A., Ficulle, E., Marcelli, S., & Feligioni, M. (2019). Hyperhomocysteinemia as a risk factor and potential nutraceutical target for certain pathologies. Frontiers in Nutrition, 6, 49. https://pubmed.ncbi.nlm.nih.gov/31069230/ (F)
  34. van der Griend, R., Biesma, D. H., Haas, F. J., Faber, J. A., Duran, M., Meuwissen, O. J., & Banga, J. D. (2000). The effect of different treatment regimens in reducing fasting and postmethionine-load homocysteine concentrations. Journal of Internal Medicine, 248(3), 223–229. https://www.ncbi.nlm.nih.gov/pubmed/10971789 (B)
  35. Veeranki, S., Gandhapudi, S. K., & Tyagi, S. C. (2017). Interactions of hyperhomocysteinemia and T cell immunity in causation of hypertension. Canadian Journal of Physiology and Pharmacology, 95(3), 239–246. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519337/ (F)
  36. Ventura, P., Panini, R., Abbati, G., Marchetti, G., & Salvioli, G. (2003). Urinary and plasma homocysteine and cysteine levels during prolonged oral N-acetylcysteine therapy. Pharmacology, 68(2), 105–114. https://www.ncbi.nlm.nih.gov/pubmed/12711838 (C)
  37. Wald, D. S., Bishop, L., Wald, N. J., Law, M., Hennessy, E., Weir, D., McPartlin, J., & Scott, J. (2001). Randomized trial of folic acid supplementation and serum homocysteine levels. Archives of Internal Medicine, 161(5), 695–700. https://www.ncbi.nlm.nih.gov/pubmed/11231701 (B)
  38. Wang, W.-W., Wang, X.-S., Zhang, Z.-R., He, J.-C., & Xie, C.-L. (2017). A meta-analysis of folic acid in combination with anti-hypertension drugs in patients with hypertension and hyperhomocysteinemia. Frontiers in Pharmacology, 8, 585. https://www.ncbi.nlm.nih.gov/pubmed/28912716 (A)
  39. Wiklund, O., Fager, G., Andersson, A., Lundstam, U., Masson, P., & Hultberg, B. (1996). N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels. Atherosclerosis, 119(1), 99–106. https://www.ncbi.nlm.nih.gov/pubmed/8929261 (C)
  40. Woo, K. S., Chook, P., Chan, L. L. T., Cheung, A. S. P., Fung, W. H., Qiao, M. u., Lolin, Y. I., Thomas, G. N., Sanderson, J. E., Metreweli, C., & Celermajer, D. S. (2002). Long-term improvement in homocysteine levels and arterial endothelial function after 1-year folic acid supplementation. The American Journal of Medicine, 112(7), 535–539. https://www.ncbi.nlm.nih.gov/pubmed/12015244 (C)
  41. Yilmaz, H., Sahin, S., Sayar, N., Tangurek, B., Yilmaz, M., Nurkalem, Z., Onturk, E., Cakmak, N., & Bolca, O. (2007). Effects of folic acid and N-acetylcysteine on plasma homocysteine levels and endothelial function in patients with coronary artery disease. Acta Cardiologica, 62(6), 579–585. https://www.ncbi.nlm.nih.gov/pubmed/18214123 (C)
  42. Zeman, M., Zák, A., Vecka, M., Tvrzická, E., Písaríková, A., & Stanková, B. (2005). [Effect of n-3 polyunsaturated fatty acids on plasma lipid, LDL lipoperoxidation, homocysteine and inflammation indicators in diabetic dyslipidemia treated with statin + fibrate combination]. Casopis lekaru ceskych, 144(11), 737–741. https://www.ncbi.nlm.nih.gov/pubmed/16335699 (C)
  43. Zeman, M., Zák, A., Vecka, M., Tvrzická, E., Písaríková, A., & Stanková, B. (2006). N-3 fatty acid supplementation decreases plasma homocysteine in diabetic dyslipidemia treated with statin-fibrate combination. The Journal of Nutritional Biochemistry, 17(6), 379–384. https://www.ncbi.nlm.nih.gov/pubmed/16214329 (C)

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