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 D-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
D
Non-RDBPC human or In-vivo animal trials
 

Introduction

While some degree of cognitive change is a natural part of aging, non-normative decline can progress to more serious cognitive impairment, increasing the risk of disability, loss of independence, and increased healthcare costs. (Murman 2015)(Robinson 2020) Projections suggest that at least 13 million adults will experience significant cognitive decline by 2050, highlighting the urgent need for preventive intervention strategies. (Cummings 2017) 

As evidence continues to accumulate on modifiable risk factors for cognitive decline, there is increasing recognition that nutritional interventions may play a supportive role in maintaining cognitive health and helping slow disease progression. (Lavretsky 2009)(Colita 2024) This protocol aims to provide healthcare providers with evidence-based guidance on select nutrients identified by the Council for Responsible Nutrition’s (CRN’s) Supplement to Savings report as having clinically supported roles in cognitive support.

Ingredients

B Vitamins

Dosing: Variable based on ingredients and formulation; dosage regimens in clinical trials typically range from vitamin B6 20 mg, folic acid 0.8–1.2 mg, and vitamin B12 50–500 mcg daily for 6–24 months (Wang 2022)

  • Note: Although many clinical studies utilize folic acid and non-methylated forms of vitamin B12, they require enzymatic conversion in the body before they can be utilized effectively. In individuals with common genetic variants in the methylenetetrahydrofolate reductase (MTHFR) gene, the conversion of B vitamins to their metabolically active forms can be significantly reduced. (Hustad 2007)(Lyon 2020) Supplementing with L-5-methyltetrahydrofolate (L-5-MTHF) and methylcobalamin bypasses this metabolic step, ensuring that the bioactive form is directly available to support methylation pathways and homocysteine regulation, both of which are linked to cognitive health. (Hooshmand 2019)(Pokushalov 2024)

Supporting evidence:

  • A cross-sectional observational study of 321 elderly Koreans (100 with MCI, 100 with AD, and 121 healthy controls) found that higher intake of B vitamins (B2, B6, B12, and folate) was associated with better cognitive test scores (e.g., Mini-Mental Status Examination, Boston Naming, Word Fluency) in those with MCI and AD. No such associations were observed in subjects with no cognitive impairment. Plasma levels of folate and B12 were positively correlated with B vitamin intake, and higher intake was associated with lower homocysteine (Hcy) levels. This association was strongest in patients with AD. (Kim 2014)
  • This cross-sectional study, which included 4,605 older Chinese adults (age >55 years), found that higher serum Hcy (an indicator of folate, B6, and B12 deficiency) was associated with an increased risk of AD. (Mohan 2023) Conversely, higher serum concentrations of vitamin B12 and folate and higher educational level were protective factors against AD. (Meng 2019)
  • Short-term (35-day) supplementation with folate (750 mcg), vitamin B12 (15 mcg), or vitamin B6 (75 mg) in 211 healthy women aged 20–92 years resulted in slight improvements in immediate and delayed recall. Additionally, higher dietary intake of these vitamins was associated with better performance in processing speed, recall, recognition, and verbal ability. (Bryan 2002)
  • This randomized, single-blind, placebo-controlled trial (n=101 patients) evaluated the impact of daily folic acid (1.2 mg per day) and vitamin B12 (50 mcg per day) supplementation over six months in patients with clinically diagnosed AD who were not on a folic acid-fortified diet. The intervention group demonstrated significant improvements in cognitive performance—specifically in Montreal Cognitive Assessment (MoCA) total scores, naming, orientation, and attention domains—compared to controls (taking a placebo). B vitamin supplementation also increased plasma S-adenosylmethionine (SAM) and the SAM/S-adenosylhomocysteine (SAH) ratio, and decreased serum Hcy, plasma SAH, and serum tumor necrosis factor-alpha (TNF-α) levels. These changes indicated a reduction in peripheral inflammation and improved methylation status. (Chen 2021)
  • The Beyond Ageing Project was a randomized controlled trial (RCT) including 900 community-dwelling adults (aged 60–74 years) with elevated psychological stress. Participants were administered oral folic acid (400 mcg) and vitamin B12 (100 mcg) or a placebo for two years, and cognitive function was assessed using validated telephone-based measures. Compared to placebo, folic acid and B12 supplementation led to modest but significant improvements in global cognitive scores, specifically in immediate and delayed memory recall. However, there were no significant changes in other cognitive domains, such as orientation, attention, semantic memory, processing speed, or informant-reported cognitive decline. (Walker 2012)
B Vitamins in the Fullscript catalog

Disclaimer

The Fullscript Integrative 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. Bryan, J., Calvaresi, E., & Hughes, D. (2002). Short-Term Folate, Vitamin B-12 or Vitamin B-6 Supplementation Slightly Affects Memory Performance But Not Mood in Women of Various Ages. The Journal of Nutrition, 132(6), 1345–1356. https://doi.org/10.1093/jn/132.6.1345
  2. Colita, E., Mateescu, V. O., Olaru, D.-G., et al. (2024). Cognitive Decline in Ageing and Disease: Risk factors, Genetics and Treatments. PubMed, 50(2), 170–180. https://doi.org/10.12865/chsj.50.02.02
  3. Cummings, J., Lee, G., Mortsdorf, T., et al. (2017). Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement (N Y), 3(3), 367–384. https://doi.org/10.1016/j.trci.2017.05.002
  4. Hooshmand, B., Refsum, H., Smith, A. D., et al. (2019). Association of Methionine to Homocysteine Status With Brain Magnetic Resonance Imaging Measures and Risk of Dementia. JAMA Psychiatry, 76(11), 1198. https://doi.org/10.1001/jamapsychiatry.2019.1694
  5. Hustad, S., Midttun, Ø., Schneede, J., et al. (2007). The Methylenetetrahydrofolate Reductase 677C→T Polymorphism as a Modulator of a B Vitamin Network with Major Effects on Homocysteine Metabolism. The American Journal of Human Genetics, 80(5), 846–855. https://doi.org/10.1086/513520
  6. Kim, H., Kim, G., Jang, W., et al. (2014). Association between intake of B vitamins and cognitive function in elderly Koreans with cognitive impairment. Nutrition Journal, 13, 118. https://doi.org/10.1186/1475-2891-13-118
  7. Lavretsky, H. (2009). Complementary and alternative medicine use for treatment and prevention of late-life mood and cognitive disorders. Aging Health, 5(1), 61–78. https://doi.org/10.2217/1745509x.5.1.61
  8. Lyon, P., Strippoli, V., Fang, B., et al. (2020). B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease. Nutrients, 12(9), 2867. https://doi.org/10.3390/nu12092867
  9. Meng, H., Li, Y., Zhang, W., et al. (2019). The relationship between cognitive impairment and homocysteine in a B12 and folate deficient population in China. Medicine, 98(47), e17970. https://doi.org/10.1097/md.0000000000017970
  10. Mohan, A., Kumar, R., Kumar, V., et al. (2023). Homocysteine, Vitamin B12 and Folate Level: Possible Risk Factors in the Progression of Chronic Heart and Kidney Disorders. Current Cardiology Reviews, 19(4), e090223213539. https://doi.org/10.2174/1573403×19666230209111854
  11. Murman, D. L. (2015). The Impact of Age on Cognition. Seminars in Hearing, 36(3), 111–121. https://doi.org/10.1055/s-0035-1555115
  12. Pokushalov, E., Ponomarenko, A., Bayramova, S., et al. (2024). Effect of Methylfolate, Pyridoxal-5′-Phosphate, and Methylcobalamin (SolowaysTM) Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled Trial. Nutrients, 16(11), 1550. https://doi.org/10.3390/nu16111550
  13. Robinson, R. L., Rentz, D. M., Andrews, J. S., et al. (2020). Costs of Early Stage Alzheimer’s Disease in the United States: Cross-Sectional Analysis of a Prospective Cohort Study (GERAS-US)1. Journal of Alzheimer’s Disease, 75(2), 437–450. https://doi.org/10.3233/jad-191212
  14. Walker, J. G., Batterham, P. J., Mackinnon, A. J., et al. (2012). Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms—the Beyond Ageing Project: a randomized controlled trial. The American Journal of Clinical Nutrition, 95(1), 194–203. https://doi.org/10.3945/ajcn.110.007799
  15. Wang, Z., Zhu, W., Xing, Y., et al. (2022). B vitamins and prevention of cognitive decline and incident dementia: a systematic review and meta-analysis. Nutrition Reviews, 80(4), 931–949. https://doi.org/10.1093/nutrit/nuab057