What is the evidence for B vitamins and metabolic syndrome? Are any dose or duration found to be harmful?

Comment by InpharmD Researcher

While concrete clinical evidence is limited, some literature has discussed metabolic implications of vitamin B deficiencies. However, most available data assessing impact on metabolic syndrome are limited to studies of dietary intake of B vitamins, generally concluding that vitamin B may be associated with decreased risk of parameters such as lower BMI, systolic BP, waist circumference, triglycerides, and others. Data related to adverse effects due to dosing regimens of B vitamins is further limited, but older case reports document occurrence of muscle weakness, fasciculations, paresthesia, and neuropathy due to excessive doses of pyridoxine. Of available data, toxicity with vitamin B6 (pyridoxine), at doses greater than 200 mg, appears more likely to result in worsening neurological symptoms. However, doses and durations found to be harmful in patients with metabolic disorder are uncertain.

Background

A 2021 review discussed the relationship between metabolic syndrome and supplementation with vitamin B complex, particularly folic acid (B9) and vitamin B12. Existing literature reports a positive association with folic acid and B12 for reduction of cardiovascular disease and insulin resistance. The involvement of these two B vitamins on metabolic processes is based on their role in mitochondrial pathways, and deficiencies in their levels may have downstream metabolic implications. While some studies have supported folate supplementation for reduction in insulin resistance, results may be inconsistent, and definitive dosing related information has not been established. Most relevant studies used to support the role of either of these B vitamins in metabolic syndrome are based on studies assessing dietary intake or baseline low serum levels. In addition to reduction of insulin resistance, such studies have observed low levels of folate and/or B12 are associated with an increased risk of ischemic stroke, myocardial infarction, and atherosclerosis. Still, further clinical studies must be conducted to explore dosing recommendations for these vitamins, as well as risk of adverse effects associated with their use. [1]

A 2023 prospective cohort study assessed the association between the incidence of metabolic syndrome and folate, vitamin B6, and vitamin B12 serum levels. Black and White young adults (n= 1240) across the United States were enrolled from 1985-1986 and followed up until 2015-2016. Follow-up exams were conducted at years 2, 5, 7, 10, 15, 20, 25 and 30 years. Incidence of metabolic syndrome was evaluated by collecting waist circumference, blood pressure (BP) and serum concentrations of folate, vitamin B6, vitamin B12, homocysteine (Hyc), triglyceride, high-density lipoprotein cholesterol (HDL-C), and fasting plasma glucose. Additionally, physical activity and vitamin B dietary and supplemental intake was assessed. Multiple sensitivity analyses were carried out to reduce potential confounding factors. Of 1240 participants, individuals with characteristics that predisposed to higher consumption of vitamin B include females, caucasians, the higher educated, never-smokers, and those with reduced alcohol intake. These individuals were associated with lower BMI, systolic BP, waist circumference, triglycerides (folate and vitamin B12), serum Hyc, and higher HDL-C at baseline. Compared to the lowest quintile of each energy-adjusted vitamin B intake, incidence of metabolic syndrome in the highest quintile was lower by 61% in those with folate intake (hazards ratio [HR] 0.39; 95% confidence interval [CI] 0.31-0.49; p< 0.001), 39% with vitamin B6 intake (HR 0.61; 95% CI 0.46-0.81; p< 0.002), and 26% for vitamin B12 (HR 0.74; 95% CI 0.58-0.95; p< 0.008). Metabolic syndrome was inversely associated with serum concentrations of all vitamins, including folate (HR 0.23; 95% CI 0.17-0.33; p<0.001), B6 (HR, 0.48; 95% CI, 0.34-0.67; p<0.001) and B12 (HR 0.70; 95% CI 0.51-0.96; p= 0.01). For vitamin B12, the inverse association with metabolic syndrome was only observed in those who were taking supplements. Strengths of this study included longitudinal follow-up, balanced baseline characteristics, and comprehensive analysis of dietary and supplemental vitamin intake along with physical activity. Limitations included the observational nature of this study (unable to conclude causal inference) and exclusion of evaluating for genetic risk factors that could influence vitamin B metabolism and incidence of metabolic syndrome. This study concluded that intake of vitamin B may be recommended for the prevention of metabolic syndrome, however further larger, randomized controlled trials are needed to confirm these findings and establish causal inference. [2]

A 2020 database analysis investigated the relationship between dietary vitamin B1, B2, niacin, B6, B12, and dietary folate equivalents and incidence of metabolic syndrome. The study compiled data using the National Health and Nutrition Examination Survey (NHANES), encompassing a total of 8,077 patients. The NHANES collected measurements for weight, height, and waist circumference based on National Institute of Health guidelines; the diagnosis of metabolic syndrome was based on patients meeting one of three following thresholds: (1) elevated blood pressure; (2) high triglyceride; (3) reduced HDL cholesterol; (4) elevated fasting glucose and (5) abdominal obesity. Assessment of dietary B vitamin intake was based on 24-hour recall reviews, one conducted in person and the second via telephone over the following days; results of these two assessments were averaged. Patients were then identified based on those with metabolic syndrome and those without. Overall, approximately 39% of included patients were documented to have metabolic syndrome; when comparing baseline characteristics, significant differences were observed between patients with and without metabolic syndrome based on age, race, education level, annual household income, smoking status, drinking status, dietary energy intake, and level of physical activity. Based on multivariate analysis, higher intake of vitamin B1, B2, niacin, B6, and folate were all associated with reduced risk of metabolic syndrome. For vitamin B1, significantly reduced risk was associated with dosing ≥ 2.79 mg/day; B2, ≥ 2.26 mg/day; niacin ≥ 40.25 mg/day; B6 ≥ 4.09 mg/day; and folate ≥ 1,057 mg/day. Overall, moderate intake levels of B1, B12, and higher intake levels of B2 and B3 were inversely associated with triglyceride levels. Similarly, higher intakes of B1, B2, and B6 were related with high HDL cholesterol levels, and moderate niacin was inversely associated with elevated fasting glucose. Higher intakes of vitamin B1, B2, niacin, B6, and folate were also all inversely associated with abdominal obesity. While the current study demonstrates decreased risk of many aspects of metabolic syndrome associated with several B vitamins, the derived association may not be considered casual due to the study design. Furthermore, the data were limited to dietary intake of B vitamins, with no consideration of supplements or proposed dosages for supplementation, whether in regard to beneficial effects or undesired side effects. [3]

Hypervitaminosis with B vitamins has not been attributed to worsening tremors or muscle weakness. However, hypervitaminosis with vitamin B9 (folic acid) has been associated with tonic convulsions in the gastric muscles. Prolonged use of vitamin B6 (pyridoxine) supplements at a dose of 300 to 500 mg/day has been reported to cause severe and progressive sensory neuropathy with ataxia based on case reports, as well as painful skin rashes, photosensitivity, nausea, and heartburn. The severity of symptoms is thought to be dose-dependent. Excessive doses are suggested to cause damage to sensory neurons resulting in paresthesia in the hands and feet, difficulty in walking, tiredness, and reduced sensation to touch. Additional morbidity includes dermatoses, photosensitivity, dizziness, and nausea with long-term intake of dosages above 250 mg/day, as well as ataxia and dysesthesias. [4], [5]

A 2019 review notes that sustained very high doses of pyridoxine can cause a severe toxic sensory ataxic neuropathy (ganglionopathy). Limited data have observed doses exceeding 200 mg daily, and probably much higher in most cases, seem to be required for toxicity. There is little evidence to suggest, however, that pyridoxine intoxication causes predominantly sensory or sensorimotor axonal polyneuropathy. [6]

The effects of Metanx, a prescription medical food containing active folate, vitamin B6, and B12, were assessed in a 2016 pre-post survey study (N= 544). Adult patients with diabetic peripheral neuropathy naive to Metanx were enrolled in the study, with surveys conducted prior to initiation and 12 weeks after Metanx use. Patients' neuropathic symptoms were assessed using a modified 6-item Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire; pain rating and quality of life were assessed using a 0 to 10 scale, with 0 indicating no pain or no life disruption and 10 indicating the worst possible pain or complete life disruption. Metanx use was associated with significant reduction in NTSS-6 score (reduced deep aching pain, burning pain, prickling feeling, numbness, lancinating pain, and allodynia), pain severity, and quality of life disruption (p<0.05). There were no reports of increasing neurologic symptoms such as tremors or muscle weakness. The study is inherently limited by its design and patients were allowed to use other medications concomitantly for their neuropathy, which could also be a confounding factor. [7]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What is the evidence for B vitamins and metabolic disorder? Are any dose or duration found to be harmful?

Please see Tables 1-4 for your response.

Micronutrient Intake and the Presence of the Metabolic Syndrome
Design	Cross-sectional study N= 3,800
Objective	To compare the micronutrient intake between individuals with and without metabolic syndrome (MS)
Study Groups	Men MS (n= 521) Without MS (n= 714) Women MS (n= 1,178) Without MS (n= 1,222)
Inclusion Criteria	Age 35 to 65 years, recruited from an urban population
Exclusion Criteria	Pregnancy/lactation, established cardiovascular disease or diabetes, taking dietary supplements, extreme outliers for one or more variable, taking a total daily energy intake between 800-4200 kcal
Methods	Patients were enrolled from an urban population and underwent physical and biochemical assessment. Diagnosis of MS was based on the International Diabetes Federation: the presence of three or more of the following components defined MS: fasting plasma glucose ≥110 mg/dl (6.1 mmol/l); systolic or diastolic blood pressure ≥130 or ≥85 mmHg; High-density lipoprotein (HDL) cholesterol <50mg/dl (1.29 mmol/l) for women or <40mg/dl (1.04 mmol/l) for men; triglyceride ≥150 mg/dl (1.79 mmol/l); and waist circumference ≥80 cm for women or ≥94 cm for men. Micronutrient intake was collected based on the patient's diet over a 24-hour period, and the odds of MS was calculated based on each micronutrient. Result groups are represented as five quintile (Q) of intake. The lowest quintile represents the reference category.
Duration	24 hours
Outcome Measures	Odds ratio (OR) of MS based on vitamin B6, vitamin B12, riboflavin (vitamin B2), niacin (vitamin B3), and thiamine (vitamin B1)
Baseline Characteristics		Men		Women
		MS (n= 521)	Without MS (n= 714)	MS (n= 1,178)	Without MS (n= 1,222)
	Age, years	49.1	48.95	48.7	46.9
	Current cigarette smoking Yes No	28% 71%	24% 75%	21% 78%	14% 85%
	Physical activity level Sedimentary Low activity Active Very active	80% 14% 4.1% 1.9%	58.2% 23.2% 12.4% 6.2%	76% 18% 3% 0.8%	58% 33% 9% 1.2%
	Body mass index, kg/m²	28.8	25.5	30.1	29.9
	Education level < 1 year 1-8 years > 8 years	7% 41.8% 50.4%	6.8% 40.3% 52.9%	21.9% 51.4% 26.7%	19.9% 49.9% 30.2%
Results	Endpoint	Q1	Q2	Q3	Q4	Q5	p-Value
	Vitamin B6 Median intake, g/d OR	1.32 1	1.61 1.02 (0.8 to 1.2)	1.81 0.98 (0.7 to 1.2)	2.03 1.10 (0.8 to 1.3)	2.41 1.20 (0.9 to 1.5)	0.41
	Vitamins B12 Median intake, g/d OR	1.03 1	1.95 1.11 (0.8 to 1.3)	2.67 1.007 (0.8 to 1.2)	3.54 0.94 (0.7 to 1.1)	5.24 1.14 (0.9 to 1.4)	0.66
	Riboflavin Median intake, g/d OR	1.23 1	1.50 0.95 (0.7 to 1.1)	1.73 1.005 (0.8 to 1.2)	2.001 1.09 (0.8 to 1.3)	2.47 1.001 (0.8 to 1.2)	0.57
	Niacin Median intake, g/d OR	7.88 1	10.83 1.13 (0.9 to 1.4)	10.83 to 12.97 1.02 (0.8 to 1.2)	15.07 1.22 (0.9 to 1.5)	19.2 1.21 (0.9 to 1.5)	0.59
	Thiamine Median intake, g/d OR	1.03 1	1.32 0.84 (0.6 to 1)	1.52 0.99 (0.7 to 1.2)	1.75 1.08 (0.8 to 1.3)	2.17 0.95 (0.7 to 1.2)	0.24
Adverse Events	N/A
Study Author Conclusions	We found no significant association between micronutrient intake and MS.
InpharmD Researcher Critique	This study used a cross-sectional design, which means it only captures data at one point in time rather than longitudinally. This limits the ability to draw conclusions about causation. Furthermore, the study relied on self-reported recall, which can be unreliable due to recall bias.

References:

Motamed S, Ebrahimi M, Safarian M, et al. Micronutrient intake and the presence of the metabolic syndrome. N Am J Med Sci. 2013;5(6):377-385. doi:10.4103/1947-2714.114171

Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia
Design	Double-blind, parallel, placebo-controlled, randomized study N= 50
Objective	To study whether a folate and vitamin B12 treatment, aimed at decreasing homocysteine levels, might ameliorate insulin resistance and endothelial dysfunction in patients with metabolic syndrome according to the National Cholesterol Education Program–Adult Treatment Panel-III criteria and to evaluate whether, under these metabolic conditions, there is a relationship between hyperhomocysteinemia and insulin resistance
Study Groups	Diet plus placebo (Group 1; n= 25) Diet plus folic acid plus vitamin B12 (Group 2; n= 25)
Inclusion Criteria	Patients with metabolic syndrome, hyperinsulinemia
Exclusion Criteria	Not specified
Methods	Patients were randomized to one of two groups; in group 1 patients were treated with diet plus placebo for 2 months and in group 2 patients were treated for 1 month with diet plus placebo and then for 1 month with diet plus 5 mg/day oral folic acid and 500 mcg/day vitamin B12. Patients underwent review with dietician every 14 days to maintain a constant body weight throughout the study and to equalize diet between groups.
Duration	Intervention: 2 months
Outcome Measures	Difference in metabolic and endothelial values at 2 months
Baseline Characteristics		All patients (N= 50)
	Age, years	67.3
	Female	0.18
	Weight, kg	79.5
	Body mass index (BMI), kg/m²	28.7
	Waist circumference, cm	125.3

Results	Endpoint	Group 1 (n= 25)	Group 2 (n= 25)
	Body weight, kg	-0.32 ± 0.43	-1.1 ± 1.23
	BMI, kg/m²	-0.1 ± 0.1	-0.7 ± 0.3
	Blood pressure, mmHg Systolic Diastolic	0 ± 2 1 ± 1	-10 ± 3 -4 ± 2
	Fasting glucose, mmol/L	-0.08 ± 0.10	-0.23 ± 0.12
	Fasting insulin, µU/mL	-0.4 ± 1.0	-5.72 ± 1.10
	Fasting triglycerides, mmol/L	-0.18 ± 0.21	-0.61 ± 0.18
	Folate, ng/mL	0.3 ± 0.7	16.9 ± 2.5
	Vitamin B12, pg/mL	0 ± 14	186 ± 18
	Homocysteine, µmol/mL	-0.2 ± 0.6	-3.4 ± 0.8
	All endpoints depicted as difference between baseline and 2 months of therapy within each group.
Adverse Events	Not evaluated
Study Author Conclusions	In conclusion, in patients with metabolic syndrome, folate treatment improved insulin resistance and endothelial dysfunction, along with decreasing homocysteine and ADMA levels, suggesting that folic acid may have several beneficial effects on cardiovascular disease risk factors.
InpharmD Researcher Critique	Although the included patient sample size was limited, this study is unique due to the use of supplemental B vitamins rather than simply dietary intake. Dosing related to incidence of potential adverse effects was not evaluated.

References:

Setola E, Monti LD, Galluccio E, et al. Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia. Eur J Endocrinol. 2004;151(4):483-489. doi:10.1530/eje.0.1510483-

Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome
Design	Case report
Case presentation	A 27-year-old female presented with increased difficulty walking. Two years prior, she had started taking vitamin B6 500 mg daily for premenstrual edema; in the previous year, she increased her dose to 5 grams daily. During this period, the patient began noticing tingling sensations in her neck, legs, and soles of her feet (Lhermitte's sign). Prior to presenting for her examination, the patient reported increased unsteadiness in her gait and difficulty with fine motor skills, as well as altered sensation in her lips and tongue. The patient reported no muscle weakness, but an examination revealed a lack of limb reflexes and severely impaired sensations in upper and lower limbs. The patient was withdrawn from pyridoxine and two months later, an improvement in gait and sensation was noticed. Seven months after withdrawal, the patient was able to walk steadily without assistance from a cane, could stand, and was able to return to work. While there was notable recovery of central conduction, no improvement was noted for peripheral sensory conduction at the time. Additional patients (N= 7) were discussed in the case report with similar clinical profiles. Presentation was typically defined by unstable gait and foot numbness, but with muscle strength retained. Each patient was thoroughly evaluated to rule out other possible explanations, including toxic, metabolic, and immunologic factors. Each patient consumed pyridoxine at maximum doses ranging from 2 to 6 grams daily. Doses were typically initiated at 50 to 100 mg daily, and increased in an attempt to achieve a therapeutic level. No symptoms were reported in any patient at doses less than 2 grams daily. Substantial improvement in symptoms was reported in all patients in the months after withdrawal of pyridoxine, but sometimes with lasting diminished sensory perception, especially vibratory sense. After 2 to 3 years, some patients were observed to have almost completely recovered.
Study Author Conclusions	Since pyridoxine is used to treat peripheral neuropathy associated with isoniazid or hydralazine therapy, the idea that it can cause neuropathy seems at first improbable or paradoxical. This medical use of pyridoxine - an essential vitamin - as an antineurotoxic agent, combined with widely help, scientifically unsupported belief that it has anti-edema properties, has contributed to its acceptance as a generally safe substance. It is clear that long term megavitamin pyridoxine therapy is not safe. Limits should be put on its use, and safe levels established through further experiments in animals or in vitro. Megavitamin B6 for behavioral disorders should be strongly discouraged, as has recently been done with vitamin A use, until the value of such treatment has been clearly determined through controlled studies and safe guidelines for pyridoxine therapy have been established.

References:

Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med. 1983;309(8):445-448. doi:10.1056/NEJM198308253090801

Characteristics of pyridoxine overdose neuropathy syndrome
Design	Case series N= 172
Objective	To evaluate characteristics of pyridoxine overdose in women
Study Groups	Neurotoxic group (n= 103) Control group (n= 69)
Inclusion Criteria	Women attending a private practice specializing in premenstrual syndrome, currently taking vitamin B6 with vitamin B6 level > 18 ng/mL
Exclusion Criteria	Not explicitly stated
Methods	Patients were advised to have their serum vitamin B6 levels estimated. They were also asked if they experienced any altered sensations in their limbs or skin, or if they had noticed muscle weakness or pains. Positive replies were recorded with the patient's description and site of symptoms, and a neurological examination followed. The normal assay range for vitamin B6 was 3.16 to 18 ng/mL with an upper limit of sensitivity of 34 ng/mL. All women with raised levels were advised to stop taking vitamin preparations.
Duration	N/A
Outcome Measures	Neurological symptoms in neurotoxic group
Baseline Characteristics		All patients (N= 172)	Neurotoxic group (n= 103)	Control group (n= 69)
	Age, years	N/A	41.5 ± 8.8	41.9 ± 9.8
	Neurological symptoms	103 (60%)	N/A	N/A
	No neurological symptoms	69 (40%)	N/A	N/A
	Serum B6 levels > 34 ng/mL	N/A	70%	55%
	Daily dose of B6, mg	N/A	117 ± 92	116 ± 66
	Duration of vitamin B6 intake, years	N/A	2.9 ± 1.9	1.6 ± 2.1
	The neurotoxic group had a significantly longer duration of vitamin B6 intake (p< 0.01).
Results	Endpoint	Neurotoxic group (n= 103)
	Neurological symptoms in all limbs, n Paresthesia Bone pains Hyperesthesia Muscle weakness Numbness Fasciculation	59 45 33 33 21 18
	Symptoms were bilateral in 85%, with unilateral symptoms tending only to occur if the limb had previously suffered trauma. Three months after stopping B6, 55% reported partial or complete recovery of neurological symptoms and at 6 months all reported complete recovery. Additionally, the areas of hyperesthesia and numbness noted at the initial examination had disappeared. Muscle weakness was reported to be manifested by difficulty in running, lifting, climbing stairs, and loss of manual dexterity causing problems with typing, playing the piano, kneading pastry, and maintaining a grip on the steering wheel. Movement was hampered by stiffness, clumsiness, or a staggering gait. There was no mention of dropping objects. Examination revealed bilateral loss of power and diminished, but not absent reflexes, especially of the ankles. L‘hermitte’s test was positive in 10 women. Fasciculation was variously described as twitching, jangling, restlessness, fidgeting and ‘movements within’.
Adverse Events	See 'Results'
Study Author Conclusions	The duration of drug exposure was greater in this series than in previous reports and appears to have been a significant factor in the development of neurological symptoms, however, there may have been inaccuracy in the patient’s recall of the exact dose and duration of B6 intake when the period of ingestion exceeded five years. If duration is an important factor in the development of neurological symptoms it would explain the absence of side effects in reports of double-blind controlled trials lasting only a few months.
InpharmD Researcher Critique	This report is likely outdated with various confounders unaccounted for, potentially reducing the validity of the observations.

References:

Dalton K, Dalton MJ. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand. 1987;76(1):8-11. doi:10.1111/j.1600-0404.1987.tb03536.x