High-dose B Vitamins in Parkinson’s disease: promising findings
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INTRODUCTION
Thiamine is not the only vitamin of the B-group which has been tried in Parkinson’s Disease (PD) with promising results at pharmacological doses or doses much higher than RDA (recommended dietary allowance). In addition to thiamine, other examples include riboflavin (vitamin B2), niacin and nicotinamide riboside (vitamin B3) and cobalamin (vitamin B12).
The relevant studies on vitamins other than B1 are presented here to show the role that vitamins B at high doses potentially play. These vitamins are being used as disease therapy interventions (therapeutics) and no longer just as supplements to replenish nutritional deficiencies. This has been defined as a “medical revolution in the medical field” (Lonsdale, 2021).
Adequate levels of all vitamins of the group-B vitamins are essential for optimal neurological functioning and cellular metabolism (Kennedy, 2016). However, most studies in PD have until recently focused on few vitamins B (namely, vitamins B6, B9 and B12) because of their role in homocysteine metabolism. An increasing number of observational studies have recently looked at the safety of some vitamins B taken alone or in combination (e.g. vitamins, B6, folic acid, B12).
Once the impact of these individual vitamins on PwP’s quality of life and on PD progression has been ascertained and the safety of high doses given long-term has been determined, it is auspicable that research will address the safety and efficacy of these vitamins when they are administered in combination.
Selected references
Derrick Lonsdale, High Dose Thiamine and Parkinson’s Disease, 17 January 2021, accessed 10.01.2023.
D. O. Kennedy, B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review, Nutrients 2016, 8, 68
Thiamine is not the only vitamin of the B-group which has been tried in Parkinson’s Disease (PD) with promising results at pharmacological doses or doses much higher than RDA (recommended dietary allowance). In addition to thiamine, other examples include riboflavin (vitamin B2), niacin and nicotinamide riboside (vitamin B3) and cobalamin (vitamin B12).
The relevant studies on vitamins other than B1 are presented here to show the role that vitamins B at high doses potentially play. These vitamins are being used as disease therapy interventions (therapeutics) and no longer just as supplements to replenish nutritional deficiencies. This has been defined as a “medical revolution in the medical field” (Lonsdale, 2021).
Adequate levels of all vitamins of the group-B vitamins are essential for optimal neurological functioning and cellular metabolism (Kennedy, 2016). However, most studies in PD have until recently focused on few vitamins B (namely, vitamins B6, B9 and B12) because of their role in homocysteine metabolism. An increasing number of observational studies have recently looked at the safety of some vitamins B taken alone or in combination (e.g. vitamins, B6, folic acid, B12).
Once the impact of these individual vitamins on PwP’s quality of life and on PD progression has been ascertained and the safety of high doses given long-term has been determined, it is auspicable that research will address the safety and efficacy of these vitamins when they are administered in combination.
Selected references
Derrick Lonsdale, High Dose Thiamine and Parkinson’s Disease, 17 January 2021, accessed 10.01.2023.
D. O. Kennedy, B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review, Nutrients 2016, 8, 68
Riboflavin (vitamin B2)
The results of a study on riboflavin in PD were published in 2003 (Coimbra, 2003). Of thirty-one (31) consecutive outpatients with PD who presented abnormal riboflavin status without dietary deficiency, nineteen (19) - 8 of whom males and 11 females - were given riboflavin orally (30 mg every 8 h) in addition to their current treatment.
Within a month, the riboflavin status of the patients was normalized. All the 19 patients who completed 6 months of treatment showed an improvement in motor capacity, ranging from 44 to 71%, based on Hoehn and Yahr’s scoring system.
The authors suggested that oral riboflavin, at those doses, caused clinical improvement. The study had some limitations, including the fact that the 12 patients who did not complete the 6-months therapy period were excluded from the analysis. Although the reasons are not given in the paper, it is possible that at least some of them dropped out because they could not tolerate the doses of riboflavin given.
Nonetheless, it was an interesting study, which used a B vitamin at high doses in PD. The vitamin B used, vitamin B2, has important functions. Riboflavin is an essential component of two major coenzymes, which play major roles in energy production and which are involved in niacin (Vitamin B3) and pyridoxine (Vitamin B6) metabolic pathways, including the activation of vitamin B6 (E.T. Marashly, 2017). Also, inadequate intake of riboflavin and pyridoxine may lead to niacin deficiency, as these vitamins are needed for the generation of niacin from tryptophan.
Riboflavin deficiency may reduce the metabolism of other B vitamins, namely folate and vitamin B6 (Powers, 2003).
Riboflavin is also involved in homocysteine metabolism, in which it plays an essential role interacting with other vitamins, namely vitamin B6, folate and vitamin B12 (Powers, 2003; Marashly, 2017). This is important, as homocysteine is toxic to brain cells.
It has been proposed that B2 might have neuroprotective mechanisms, due to its effects on oxidative stress, mitochondrial dysfunction, neuro-inflammation, and glutamate excitotoxicity (E.T. Marashly, 2017). These factors are currently believed to play a role in the pathogenesis of PD. This would make riboflavin a suitable, potential target for further research in PD.
Selected references
C.G. Coimbra and V.B.C. Junqueira - High doses of riboflavin and the elimination of dietary red meat promote the recovery of some motor functions in Parkinson’s disease patients, Brazilian Journal of Medical and Biological Research. 2003, 36: 1409-1417 Riboflavin and Parkinson’s disease ISSN 0100-879X.
Eyad T Marashly, Saeed A Bohlega, Riboflavin Has Neuroprotective Potential: Focus on Parkinson's Disease and Migraine Front Neurol. 2017 Jul 20;8:333
Hilary J Powers, Riboflavin (vitamin B-2) and health, The American Journal of Clinical Nutrition. 2003 Jun 77(6):1352–1360
Nicotinamide riboside (vitamin B3)
Other researchers have looked at Nicotinamide riboside (NR), a form of vitamin B3, for its effects on increasing NAD (Nicotinamide adenine dinucleotide). NAD is essential for the production of energy by the mitochondria in cells. For their role in energy production, mitochondria have been defined the “power station” of the cell (Stott, 2018). They transform food nutrients into Adenosine Triphosphate (ATP). ATP represents “the fuel which cells run on.” (Stott, 2018). PwP have lower NAD levels than people who have no PD (C. Wakade, 2021) and this deficiency is expected to impact negatively on mitochondrial functions. In fact, Schöndorf and collaborators showed that increasing NAD levels by NR in patient-derived induced pluripotent stem cells - differentiated into dopaminergic neurons - remarkably improved mitochondrial function (Schöndorf, 2018). The rationale of using NR in PD in a clinical trial is then that, if NR is able to increase intracellular NAD levels, it would correct the mitochondrial dysfunction linked to NAD-deficiency and thus improve cerebral metabolism (Schöndorf, 2018). A clinical trial had showed that in healthy adults chronic supplementation with NR was well tolerated and able to stimulate NAD metabolism (Martens, 2018).
The NADPARK study - a Phase 1, double-blinded clinical trial - was carried out to test the safety and efficacy of nicotinamide riboside in replenishing NAD in the brain in PwP (Brakedal, 2022).
Thirty (30) newly diagnosed PwP, who had not been started on any other medicine for PD, were given 1,000 mg nicotinamide riboside (NR) or placebo for 30 days. NR led to a significant - although variable - increase in cerebral NAD, decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid, and was associated with mild clinical improvement.
NR was well tolerated during the duration of the study. The investigators concluded that this form of vitamin B3 may be neuroprotective in PD.
The same researchers have also started a larger study, the Phase 2 NOPARK randomized, double-blind, placebo controlled clinical trial in 400 PwP at an early stage of the disease to assess the benefits of NR administered at the total dose of 1,000 mg for one year (A Randomized Controlled Trial of Nicotinamide Supplementation in Early Parkinson's Disease (NOPARK). The study is due to be completed in March 2024.
To test the safety of a higher dose of NR (3,000 mg given for four weeks) in PwP, the investigators also conducted a double-blinded randomized safety study (NR-SAFE) in 20 PwP over 4 weeks, which showed “no moderate or severe adverse events, and no signs of acute toxicity”(*). In a previous RCT on the safety of nicotinamide riboside, overweight but otherwise healthy adults received doses of 100, 300 and 1000 mg of NR once a day for eight weeks. There was a significant increase in whole blood NAD within 2 weeks. The effect was dependent on the dose and was maintained for the rest of the study. The authors reported “no significant differences in adverse events between the nicotinamide riboside and placebo groups or between groups at different NR doses” (Conze, 2019). Another clinical trial on safety in which obese men were given a daily dose of 2 grams of NR for 12 weeks yielded similar results (Dollerup, 2018).
Finally, to establish the optimal dose of NR in PwP, a double-blinded, placebo-controlled randomized trial is currently underway, increasing doses from 1,000 to 3,000 mg in 12 weeks (N-DOSE: A Dose Optimization Trial of Nicotinamide Riboside in Parkinson's Disease).
In a study, researchers reported that high levels of NAD resulted in gliomas, which are brain tumour with a low survival rate in adults. This issue would need further investigation (Lucena-Cacace, 2017).
Selected references
Simon Stott, FASN-ating PINK research, The science of Parkinson’s,13 January 2018
Chandramohan Wakade, Low-Dose Niacin Supplementation Improves Motor Function in US Veterans with Parkinson’s Disease: A Single-Center, Randomized, Placebo-Controlled Trial, Biomedicines2021, 9, 1881
David C. Schöndorf, Dina Ivanyuk, Pascale Baden, ..., Thomas Gasser, Alexander J. Whitworth, Michela Deleidi, The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson’s Disease, Cell Reports. 2018 Jun 5;23:2976–2988
Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR, Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults, Nat Commun. 2018 Mar 29;9(1):1286.
Brage Brakedal, Christian Dölle, Frank Riemer, Yilong Ma, Gonzalo S Nido, Geir Olve Skeie, Alexander R Craven, Thomas Schwarzlmüller, Njål Brekke, Joseph Diab, Lars Sverkeli, Vivian Skjeie, Kristin Varhaug, Ole-Bjørn Tysnes, Shichun Peng, Kristoffer Haugarvoll, Mathias Ziegler, Renate Grüner, David Eidelberg, Charalampos Tzoulis, The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease, Cell Metab. 2022 Mar 1;34(3):396-407.e6
A Randomized Controlled Trial of Nicotinamide Supplementation in Early Parkinson's Disease (NOPARK), ClinicalTrials.gov NCT03568968
NR-SAFE: Safety of High-dose Nicotinamide Riboside (NR) in Parkinson's Disease (NR-SAFE), ClinicalTrials.gov NCT05344404)
(*) Reported in the study description summary of N-DOSE: A Dose Optimization Trial of Nicotinamide Riboside in Parkinson's Disease - Full Text View - ClinicalTrials.gov
Dietrich Conze, Charles Brenner, Claire L. Kruger, Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults, Sci Rep. 2019; 9: 9772
Dollerup OL, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. The American journal of clinical nutrition. 2018;108:343–353.
N-DOSE: A Dose Optimization Trial of Nicotinamide Riboside in Parkinson's Disease, ClinicalTrials.gov NCT05589766.
Lucena-Cacace A, Otero-Albiol D, Jiménez-García MP, Peinado-Serrano J, Carnero A, NAMPT overexpression induces cancer stemness and defines a novel tumor signature for glioma prognosis, Oncotarget. 2017 Aug 28;8(59):99514-99530.
Other researchers have looked at Nicotinamide riboside (NR), a form of vitamin B3, for its effects on increasing NAD (Nicotinamide adenine dinucleotide). NAD is essential for the production of energy by the mitochondria in cells. For their role in energy production, mitochondria have been defined the “power station” of the cell (Stott, 2018). They transform food nutrients into Adenosine Triphosphate (ATP). ATP represents “the fuel which cells run on.” (Stott, 2018). PwP have lower NAD levels than people who have no PD (C. Wakade, 2021) and this deficiency is expected to impact negatively on mitochondrial functions. In fact, Schöndorf and collaborators showed that increasing NAD levels by NR in patient-derived induced pluripotent stem cells - differentiated into dopaminergic neurons - remarkably improved mitochondrial function (Schöndorf, 2018). The rationale of using NR in PD in a clinical trial is then that, if NR is able to increase intracellular NAD levels, it would correct the mitochondrial dysfunction linked to NAD-deficiency and thus improve cerebral metabolism (Schöndorf, 2018). A clinical trial had showed that in healthy adults chronic supplementation with NR was well tolerated and able to stimulate NAD metabolism (Martens, 2018).
The NADPARK study - a Phase 1, double-blinded clinical trial - was carried out to test the safety and efficacy of nicotinamide riboside in replenishing NAD in the brain in PwP (Brakedal, 2022).
Thirty (30) newly diagnosed PwP, who had not been started on any other medicine for PD, were given 1,000 mg nicotinamide riboside (NR) or placebo for 30 days. NR led to a significant - although variable - increase in cerebral NAD, decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid, and was associated with mild clinical improvement.
NR was well tolerated during the duration of the study. The investigators concluded that this form of vitamin B3 may be neuroprotective in PD.
The same researchers have also started a larger study, the Phase 2 NOPARK randomized, double-blind, placebo controlled clinical trial in 400 PwP at an early stage of the disease to assess the benefits of NR administered at the total dose of 1,000 mg for one year (A Randomized Controlled Trial of Nicotinamide Supplementation in Early Parkinson's Disease (NOPARK). The study is due to be completed in March 2024.
To test the safety of a higher dose of NR (3,000 mg given for four weeks) in PwP, the investigators also conducted a double-blinded randomized safety study (NR-SAFE) in 20 PwP over 4 weeks, which showed “no moderate or severe adverse events, and no signs of acute toxicity”(*). In a previous RCT on the safety of nicotinamide riboside, overweight but otherwise healthy adults received doses of 100, 300 and 1000 mg of NR once a day for eight weeks. There was a significant increase in whole blood NAD within 2 weeks. The effect was dependent on the dose and was maintained for the rest of the study. The authors reported “no significant differences in adverse events between the nicotinamide riboside and placebo groups or between groups at different NR doses” (Conze, 2019). Another clinical trial on safety in which obese men were given a daily dose of 2 grams of NR for 12 weeks yielded similar results (Dollerup, 2018).
Finally, to establish the optimal dose of NR in PwP, a double-blinded, placebo-controlled randomized trial is currently underway, increasing doses from 1,000 to 3,000 mg in 12 weeks (N-DOSE: A Dose Optimization Trial of Nicotinamide Riboside in Parkinson's Disease).
In a study, researchers reported that high levels of NAD resulted in gliomas, which are brain tumour with a low survival rate in adults. This issue would need further investigation (Lucena-Cacace, 2017).
Selected references
Simon Stott, FASN-ating PINK research, The science of Parkinson’s,13 January 2018
Chandramohan Wakade, Low-Dose Niacin Supplementation Improves Motor Function in US Veterans with Parkinson’s Disease: A Single-Center, Randomized, Placebo-Controlled Trial, Biomedicines2021, 9, 1881
David C. Schöndorf, Dina Ivanyuk, Pascale Baden, ..., Thomas Gasser, Alexander J. Whitworth, Michela Deleidi, The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson’s Disease, Cell Reports. 2018 Jun 5;23:2976–2988
Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR, Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults, Nat Commun. 2018 Mar 29;9(1):1286.
Brage Brakedal, Christian Dölle, Frank Riemer, Yilong Ma, Gonzalo S Nido, Geir Olve Skeie, Alexander R Craven, Thomas Schwarzlmüller, Njål Brekke, Joseph Diab, Lars Sverkeli, Vivian Skjeie, Kristin Varhaug, Ole-Bjørn Tysnes, Shichun Peng, Kristoffer Haugarvoll, Mathias Ziegler, Renate Grüner, David Eidelberg, Charalampos Tzoulis, The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease, Cell Metab. 2022 Mar 1;34(3):396-407.e6
A Randomized Controlled Trial of Nicotinamide Supplementation in Early Parkinson's Disease (NOPARK), ClinicalTrials.gov NCT03568968
NR-SAFE: Safety of High-dose Nicotinamide Riboside (NR) in Parkinson's Disease (NR-SAFE), ClinicalTrials.gov NCT05344404)
(*) Reported in the study description summary of N-DOSE: A Dose Optimization Trial of Nicotinamide Riboside in Parkinson's Disease - Full Text View - ClinicalTrials.gov
Dietrich Conze, Charles Brenner, Claire L. Kruger, Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults, Sci Rep. 2019; 9: 9772
Dollerup OL, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. The American journal of clinical nutrition. 2018;108:343–353.
N-DOSE: A Dose Optimization Trial of Nicotinamide Riboside in Parkinson's Disease, ClinicalTrials.gov NCT05589766.
Lucena-Cacace A, Otero-Albiol D, Jiménez-García MP, Peinado-Serrano J, Carnero A, NAMPT overexpression induces cancer stemness and defines a novel tumor signature for glioma prognosis, Oncotarget. 2017 Aug 28;8(59):99514-99530.
Niacin (Nicotinic acid)(Vitamin B3)
A recent six-month, Randomized, Double-blind, Placebo-controlled Trial (RCT) was conducted to ascertain whether low-dose daily niacin supplementation (250 mg/day) would improve motor symptoms in PwP (Chong, 2021).
Evidence suggests that neuro-inflammation, mitochondrial dysfunction and activation of microglia in the brain may play an important role in the development and progression of PD.
But why Niacin? Niacin (nicotinic acid and nicotinamide) is converted in the body into its main bioactive forms, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are essential cofactors for cellular reactions to reduce oxidation and are vital for cellular metabolism. NAD is crucial for the production of energy in cells, by enhancing mitochondrial functions, and for normal functioning (Chong, 2021; Kirkland, 2018).
PwP have lower Vitamin B3 and NAD levels than people with no PD (C. Wakade, 2021). Also, levodopa depletes niacin levels in PwP by interfering with tryptophan breakdown.
Thus niacin represents a good candidate to be tested as adjunctive treatment in PD to reduce neuro-inflammation and improve motor functions in PwP.
In the study, 47 PwP (32 men and 15 women) were randomly allocated to one of 3 groups: placebo, 100 mg of niacin or 250 mg of niacin, for 3 months.
Next, all of them received open-label niacin 250 mg. Those who were in the placebo and 100-mg groups changed to the 250-mg dose for 12 months, while those who were in the 250-mg group continued to take the same dose for another 9 months.
The dose of 250 mg is over 15 times as high as the RDA.
Niacin treatment was well-tolerated by forty-five out of 47 subjects, although 80% of the subjects in the 100-mg group experienced flushing.
At one year of niacin supplementation, typical PD motor symptoms (rigidity, bradykinesia) were reduced, postural stability improved, grip strength and handwriting size improved as did mood and fatigue, while serotonin levels and REM sleep percentage stabilized. The researchers concluded that treatment with daily niacin supplementation had the potential to improve quality of life in PD and slow disease progression.
Selected references
Raymond Chong, Chandramohan Wakade, Marissa Seamon, Banabihari Giri, John Morgan and Sharad Purohit, Niacin Enhancement for Parkinson’s Disease: An Effectiveness Trial, Front Aging Neurosci. 2021 Jun 17;13:667032
James B Kirkland, Mirella L Meyer-Ficca, Niacin, Adv Food Nutr Res. 2018;83:83-149
Chandramohan Wakade, Low-Dose Niacin Supplementation Improves Motor Function in US Veterans with Parkinson’s Disease: A Single-Center, Randomized, Placebo-Controlled Trial, Biomedicines2021, 9, 1881
A recent six-month, Randomized, Double-blind, Placebo-controlled Trial (RCT) was conducted to ascertain whether low-dose daily niacin supplementation (250 mg/day) would improve motor symptoms in PwP (Chong, 2021).
Evidence suggests that neuro-inflammation, mitochondrial dysfunction and activation of microglia in the brain may play an important role in the development and progression of PD.
But why Niacin? Niacin (nicotinic acid and nicotinamide) is converted in the body into its main bioactive forms, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are essential cofactors for cellular reactions to reduce oxidation and are vital for cellular metabolism. NAD is crucial for the production of energy in cells, by enhancing mitochondrial functions, and for normal functioning (Chong, 2021; Kirkland, 2018).
PwP have lower Vitamin B3 and NAD levels than people with no PD (C. Wakade, 2021). Also, levodopa depletes niacin levels in PwP by interfering with tryptophan breakdown.
Thus niacin represents a good candidate to be tested as adjunctive treatment in PD to reduce neuro-inflammation and improve motor functions in PwP.
In the study, 47 PwP (32 men and 15 women) were randomly allocated to one of 3 groups: placebo, 100 mg of niacin or 250 mg of niacin, for 3 months.
Next, all of them received open-label niacin 250 mg. Those who were in the placebo and 100-mg groups changed to the 250-mg dose for 12 months, while those who were in the 250-mg group continued to take the same dose for another 9 months.
The dose of 250 mg is over 15 times as high as the RDA.
Niacin treatment was well-tolerated by forty-five out of 47 subjects, although 80% of the subjects in the 100-mg group experienced flushing.
At one year of niacin supplementation, typical PD motor symptoms (rigidity, bradykinesia) were reduced, postural stability improved, grip strength and handwriting size improved as did mood and fatigue, while serotonin levels and REM sleep percentage stabilized. The researchers concluded that treatment with daily niacin supplementation had the potential to improve quality of life in PD and slow disease progression.
Selected references
Raymond Chong, Chandramohan Wakade, Marissa Seamon, Banabihari Giri, John Morgan and Sharad Purohit, Niacin Enhancement for Parkinson’s Disease: An Effectiveness Trial, Front Aging Neurosci. 2021 Jun 17;13:667032
James B Kirkland, Mirella L Meyer-Ficca, Niacin, Adv Food Nutr Res. 2018;83:83-149
Chandramohan Wakade, Low-Dose Niacin Supplementation Improves Motor Function in US Veterans with Parkinson’s Disease: A Single-Center, Randomized, Placebo-Controlled Trial, Biomedicines2021, 9, 1881
Cobalamin (Vitamin B12)
Low levels of vitamin B12 in PD have been associated with a number of important negative outcomes in PwP, namely:
How common is vitamin B12 deficiency in PD? This information is important as vitamin B12 status is lower in PwP compared with controls (Sadasivan, 2012; Christine, 2018) and is common even in early PD (Stuart, 2019). PwP are more susceptible to having a vitamin B12 deficiency than persons without PD (Liang Shen, 2015). It has also been suggested that vitamin B12 needs in PD may be higher (Stuart, 2019).
Furthermore, carbidopa/levodopa can reduce vitamin B12 levels, especially at high dosage (Qureshi, 2008) and can then be responsible for symptoms linked to vitamin B12 deficiency, including neuropathy (Toth, 2010).
Finally, symptoms which are present in persons with vitamin B12 deficiency, such as depression, paranoia, weakness, tiredness, muscular numbness, tingling and walking difficulties are symptoms observed also in PD.
Another important point is vitamin B12 contribution to reducing homocysteine levels. Vitamin B12 deficiency in PD is accompanied by higher serum levels of homocysteine. High levels of homocysteine are toxic to the brain and the cardiovascular system and might accelerate dopaminergic cell death through neurotoxic effects (Qureshi, 2008).
Low vitamin B12 and high homocysteine concentrations have been shown to be independently associated with dementia in PwP compared with non-demented PwP (Xie, 2017). PwP with moderately elevated total homocysteine have been found to have greater annualized declines in the Mini-Mental State Exam (Christine, 2020) – MMSE, a screening tool for Parkinson's disease dementia. Also, PwP treated with levodopa have significantly higher homocysteine levels compared with both controls and PwP not treated with levodopa.
So, carbidopa/levodopa can reduce vitamin B12 levels and increase homocysteine levels.
As low B12 and elevated homocysteine can improve with vitamin supplementation, it would be relevant to see whether, through this, vitamin B12 improves motor and cognitive function in patients with PD (Stuart, 2019) and has an effect on PD progression (Christine, 2018).
A longitudinal study of 1,741 participants with early PD aimed at determining whether PD progression differed between PwP who took vitamin B12 supplementation compared to those who did not. Participants were grouped based on their daily use of supplements, namely no B12, multivitamin (MVI) (B12 < 100 μg) or multivitamin (MVI) + B12 (≥ 100 μg); and B12 only (≥ 100 μg)(Dietiker, 2019). At 3 years, although there was no significant difference in clinical outcomes between the groups, a trend was observed of a lower risk for the development of sensory symptoms (as a surrogate marker of neuropathy) in those taking MVI and MVI+B12 compared to those who took no supplement.
This background on vitamin B12 deficiency in PwP had brought a team of researchers to check B12 levels in samples originally taken from 680 PwP not receiving any other treatment for PD, including 456 follow-up samples (Christine, 2018). Thirteen percent (13%) of PwP tested had borderline low levels of vitamin B12, 7% had elevated homocysteine, while 2% had both. PwP who had lower levels of vitamin B12 at the start progressed faster and showed more walking and balance problems than those with higher levels. There was a significant association between high levels of homocysteine and faster cognitive decline. Low vitamin B12 and high homocysteine levels were therefore predictors of worse outcomes, in terms of mobility and cognitive decline, respectively. (Christine, 2018).
Selected references
Toth C, Breithaupt K, Ge S., Duan Y, Terris JM, Thiessen A, Wiebe S., Zochodne DV, Suchowersky O, Levodopa, methylmalonic acid and neuropathy in idiopathic Parkinson’s disease. Ann. Neurol. 2010;67:28–36
Stuart J. McCarter, MD; Levi M. Teigen, PhD, RD; Allison R. McCarter, BS; Eduardo E. Benarroch, MD; Erik K. St. Louis, MD, MS; and Rodolfo Savica, MD, PhD, Low Vitamin B12 and Parkinson Disease: Potential Link to Reduced Cholinergic Transmission and Severity of Disease, Mayo Clin Proc. May 2019;94(5):757-762
Madenci G, Bilen S, Arli B, Saka M, Ak F. Serum iron, vitamin B12 and folic acid levels in Parkinson’s disease. Neurochem Res. 2012;37(7):1436-1441. 35.
Christine CW, Auinger P, Joslin A, Yelpaala Y, Green R; Parkinson Study Group-DATATOP Investigators. Vitamin B12 and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018;33(5):762-770
Triantafyllou NI, Nikolaou C, Boufidou F, et al. Folate and vitamin B12 levels in levodopa-treated Parkinson’s disease patients: their relationship to clinical manifestations, mood and cognition. Parkinsonism Relat Disord. 2008;14(4):321-325.
Chadwick W Christine, Peggy Auinger, Nasrin Saleh, Miao Tian, Teodoro Bottiglieri, Erland Arning, Nam K Tran, Per Magne Ueland, Ralph Green; Parkinson Study Group-DATATOP Investigators, Relationship of Cerebrospinal Fluid Vitamin B12 Status Markers With Parkinson's Disease Progression, Mov Disord. 2020 Aug;35(8):1466-1471G
Ali Qureshi, Aftab A Qureshi, Bika Ram Devrajani, M A Chippa, S Ali Syed, Is the deficiency of vitamin B12 related to oxidative stress and neurotoxicity in Parkinson's patients?, CNS Neurol Disord Drug Targets. 2008 Feb;7(1):20-7
Suja Sadasivan & Joseph H Friedman - Vitamin B12 (cobalamin) and Parkinson’s disease - Clin. Pract. 2012;9(4):353–356
Liang Shen, Associations between B Vitamins and Parkinson's Disease, Nutrients. 2015 Aug 27;7(9):7197-208
Xie Y, Feng H, Peng S, Xiao J, Zhang J. Association of plasma homocysteine, vitamin B12 and folate levels with cognitive function in Parkinson’s disease: a meta-analysis. Neurosci Lett. 2017;636:190-195.
Cameron Dietiker, Soeun Kim, Yunxi Zhang, Chadwick W Christine, Characterization of Vitamin B12 Supplementation and Correlation with Clinical Outcomes in a Large Longitudinal Study of Early Parkinson’s Disease - J Mov Disord 2019;12(2):91-96
Low levels of vitamin B12 in PD have been associated with a number of important negative outcomes in PwP, namely:
- a significantly higher incidence of peripheral neuropathy, compared with persons without PD (55% vs 9%) (Toth, 2010)
- a more rapid rate of disease progression (Stuart, 2019)
- a higher Hoehn-Yahr stage (Madenci, 2012),
- a more rapidly worsening ambulatory capacity (Christine, 2018) and
- cognitive impairment (Triantafyllou, 2008; Christine, 2018).
How common is vitamin B12 deficiency in PD? This information is important as vitamin B12 status is lower in PwP compared with controls (Sadasivan, 2012; Christine, 2018) and is common even in early PD (Stuart, 2019). PwP are more susceptible to having a vitamin B12 deficiency than persons without PD (Liang Shen, 2015). It has also been suggested that vitamin B12 needs in PD may be higher (Stuart, 2019).
Furthermore, carbidopa/levodopa can reduce vitamin B12 levels, especially at high dosage (Qureshi, 2008) and can then be responsible for symptoms linked to vitamin B12 deficiency, including neuropathy (Toth, 2010).
Finally, symptoms which are present in persons with vitamin B12 deficiency, such as depression, paranoia, weakness, tiredness, muscular numbness, tingling and walking difficulties are symptoms observed also in PD.
Another important point is vitamin B12 contribution to reducing homocysteine levels. Vitamin B12 deficiency in PD is accompanied by higher serum levels of homocysteine. High levels of homocysteine are toxic to the brain and the cardiovascular system and might accelerate dopaminergic cell death through neurotoxic effects (Qureshi, 2008).
Low vitamin B12 and high homocysteine concentrations have been shown to be independently associated with dementia in PwP compared with non-demented PwP (Xie, 2017). PwP with moderately elevated total homocysteine have been found to have greater annualized declines in the Mini-Mental State Exam (Christine, 2020) – MMSE, a screening tool for Parkinson's disease dementia. Also, PwP treated with levodopa have significantly higher homocysteine levels compared with both controls and PwP not treated with levodopa.
So, carbidopa/levodopa can reduce vitamin B12 levels and increase homocysteine levels.
As low B12 and elevated homocysteine can improve with vitamin supplementation, it would be relevant to see whether, through this, vitamin B12 improves motor and cognitive function in patients with PD (Stuart, 2019) and has an effect on PD progression (Christine, 2018).
A longitudinal study of 1,741 participants with early PD aimed at determining whether PD progression differed between PwP who took vitamin B12 supplementation compared to those who did not. Participants were grouped based on their daily use of supplements, namely no B12, multivitamin (MVI) (B12 < 100 μg) or multivitamin (MVI) + B12 (≥ 100 μg); and B12 only (≥ 100 μg)(Dietiker, 2019). At 3 years, although there was no significant difference in clinical outcomes between the groups, a trend was observed of a lower risk for the development of sensory symptoms (as a surrogate marker of neuropathy) in those taking MVI and MVI+B12 compared to those who took no supplement.
This background on vitamin B12 deficiency in PwP had brought a team of researchers to check B12 levels in samples originally taken from 680 PwP not receiving any other treatment for PD, including 456 follow-up samples (Christine, 2018). Thirteen percent (13%) of PwP tested had borderline low levels of vitamin B12, 7% had elevated homocysteine, while 2% had both. PwP who had lower levels of vitamin B12 at the start progressed faster and showed more walking and balance problems than those with higher levels. There was a significant association between high levels of homocysteine and faster cognitive decline. Low vitamin B12 and high homocysteine levels were therefore predictors of worse outcomes, in terms of mobility and cognitive decline, respectively. (Christine, 2018).
Selected references
Toth C, Breithaupt K, Ge S., Duan Y, Terris JM, Thiessen A, Wiebe S., Zochodne DV, Suchowersky O, Levodopa, methylmalonic acid and neuropathy in idiopathic Parkinson’s disease. Ann. Neurol. 2010;67:28–36
Stuart J. McCarter, MD; Levi M. Teigen, PhD, RD; Allison R. McCarter, BS; Eduardo E. Benarroch, MD; Erik K. St. Louis, MD, MS; and Rodolfo Savica, MD, PhD, Low Vitamin B12 and Parkinson Disease: Potential Link to Reduced Cholinergic Transmission and Severity of Disease, Mayo Clin Proc. May 2019;94(5):757-762
Madenci G, Bilen S, Arli B, Saka M, Ak F. Serum iron, vitamin B12 and folic acid levels in Parkinson’s disease. Neurochem Res. 2012;37(7):1436-1441. 35.
Christine CW, Auinger P, Joslin A, Yelpaala Y, Green R; Parkinson Study Group-DATATOP Investigators. Vitamin B12 and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018;33(5):762-770
Triantafyllou NI, Nikolaou C, Boufidou F, et al. Folate and vitamin B12 levels in levodopa-treated Parkinson’s disease patients: their relationship to clinical manifestations, mood and cognition. Parkinsonism Relat Disord. 2008;14(4):321-325.
Chadwick W Christine, Peggy Auinger, Nasrin Saleh, Miao Tian, Teodoro Bottiglieri, Erland Arning, Nam K Tran, Per Magne Ueland, Ralph Green; Parkinson Study Group-DATATOP Investigators, Relationship of Cerebrospinal Fluid Vitamin B12 Status Markers With Parkinson's Disease Progression, Mov Disord. 2020 Aug;35(8):1466-1471G
Ali Qureshi, Aftab A Qureshi, Bika Ram Devrajani, M A Chippa, S Ali Syed, Is the deficiency of vitamin B12 related to oxidative stress and neurotoxicity in Parkinson's patients?, CNS Neurol Disord Drug Targets. 2008 Feb;7(1):20-7
Suja Sadasivan & Joseph H Friedman - Vitamin B12 (cobalamin) and Parkinson’s disease - Clin. Pract. 2012;9(4):353–356
Liang Shen, Associations between B Vitamins and Parkinson's Disease, Nutrients. 2015 Aug 27;7(9):7197-208
Xie Y, Feng H, Peng S, Xiao J, Zhang J. Association of plasma homocysteine, vitamin B12 and folate levels with cognitive function in Parkinson’s disease: a meta-analysis. Neurosci Lett. 2017;636:190-195.
Cameron Dietiker, Soeun Kim, Yunxi Zhang, Chadwick W Christine, Characterization of Vitamin B12 Supplementation and Correlation with Clinical Outcomes in a Large Longitudinal Study of Early Parkinson’s Disease - J Mov Disord 2019;12(2):91-96
Safety Concerns
While the preliminary results of the potential effects of high dose vitamins B in PD are encouraging, their safety in the long-run warrants further investigation. There is some concern that combining vitamins B at high dosages or taking some vitamins B at high dosages may be associated with adverse effects, including cancer.
Combined intakes of vitamins B
We report below some studies about the association of combined intakes of vitamins B (B6 + B12; Folate + B6 + B12) with adverse effects.
Vitamin B12 alone
So far, vitamin B12 has been considered to be very safe, even at high dosage. No UL (Upper Tolerable Intake Limit) has been set as no adverse effects at high dosages have been reported.
However, studies, mostly observational, which have specifically looked at cancer risk associated with the intake of vitamin B12 - whether from food sources or from supplements - have found a positive association of vitamin B12 with lung cancer risk.
Two retrospective cohort studies based on health registries have shown an association between elevated B12 levels and newly-diagnosed solid cancer.
A recent review has concluded that there is insufficient evidence to assume that high plasma vitamin B12, high B12 intake, or treatment with pharmacological doses of vitamin B12, is causally related to cancer (Obeid, 2022)
Folic acid alone
A risk for cancer has also been described for high-dosage folic acid supplementation.
Selected references
Haakon E Meyer, Walter C Willett, Teresa T Fung, Kristin Holvik, Diane Feskanich, Association of High Intakes of Vitamins B6 and B12 From Food and Supplements With Risk of Hip Fracture Among Postmenopausal Women in the Nurses' Health Study, JAMA Netw Open. 2019 May 3;2(5):e193591
Sadaf Oliai Araghi; Jessica C. Kiefte-de Jong; Suzanne C. van Dijk; Karin M.A. Swart; Hanneke W. van Laarhoven; Natasja M. van Schoor; Lisette C.P.G.M. de Groot; Valery Lemmens; Bruno H. Stricker; André G. Uitterlinden; Nathalie van der Velde; Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial; Cancer Epidemiol Biomarkers Prev (2019) 28 (2): 275–282.
Helmut Lange, Harry Suryapranata, Giuseppe De Luca, Caspar Börner, Joep Dille, Klaus Kallmayer, M Noor Pasalary, Eberhard Scherer, Jan-Henk E Dambrink, Folate therapy and in-stent restenosis after coronary stenting, N Engl J Med. 2004 Jun 24;350(26):2673-81
Marta Ebbing, Kaare Harald Bønaa, Ottar Nygård, Egil Arnesen, Per Magne Ueland, Jan Erik Nordrehaug, Knut Rasmussen, Inger Njølstad, Helga Refsum, Dennis W Nilsen, Aage Tverdal, Klaus Meyer, Stein Emil Vollset, Cancer incidence and mortality after treatment with folic acid and vitamin B12, JAMA. 2009 Nov 18;302(19):2119-26.
Theodore M Brasky, Emily White, Chi-Ling Chen, Long-Term, Supplemental, One-Carbon Metabolism-Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort, J Clin Oncol. 2017 Oct 20;35(30):3440-3448
Luu, Hung N., Wang, Renweia, Jin, Aizhenc, Koh Woon-Puayc, Yuan Jian-Mina, The association between dietary vitamin B12 and lung cancer risk: findings from a prospective cohort study, European Journal of Cancer Prevention, 2021, May; 30(3):275-281.
Geoffrey Urbanski, Jean-François Hamel, Benoît Prouveur, Cédric Annweiler, Alaa Ghali, Julien Cassereau, Pierre Lozac’h, Christian Lavigne, and Valentin Lacombe, Strength of the Association of Elevated Vitamin B12 and Solid Cancers: An Adjusted Case-Control Study, J Clin Med. 2020 Feb; 9(2): 474.
Johan Frederik Berg Arendt, Lars Pedersen, Ebba Nexo, Henrik Toft Sørensen, Elevated plasma vitamin B12 levels as a marker for cancer: a population-based cohort study, J Natl Cancer Inst. 2013 Dec 4;105(23):1799-805
Johan F H Arendt, Henrik T Sørensen, Laura J Horsfall, Irene Petersen, Elevated Vitamin B12 Levels and Cancer Risk in UK Primary Care: A THIN Database Cohort Study, Cancer Epidemiol Biomarkers Prev. 2019 Apr;28(4):814-821
Anouar Fanidi et al., Is high vitamin B12 status a cause of lung cancer?, Int J Cancer. 2019 Sep 15; 145(6): 1499–1503.
Lacombe, V., Chabrun, F., Lacout, C. et al., Persistent elevation of plasma vitamin B12 is strongly associated with solid cancer, Sci Rep 11, 13361 (2021)
Obeid, R. High Plasma Vitamin B12 and Cancer in Human Studies: A Scoping Review to Judge Causality and Alternative Explanations. Nutrients. 2022 Oct;14, 4476.
Joseph E Baggott 1, Robert A Oster, Tsunenobu Tamura, Meta-analysis of cancer risk in folic acid supplementation trials, Cancer Epidemiol. 2012 Feb;36(1):78-81
Xianhui Qin 1, Yimin Cui, Lin Shen, Ningling Sun, Yan Zhang, Jianping Li, Xin Xu, Binyan Wang, Xiping Xu, Yong Huo, Xiaobin Wang, Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials, Int J Cancer. 2013 Sep 1;133(5):1033-41
Stein Emil Vollset, Robert Clarke, Sarah Lewington, Marta Ebbing, Jim Halsey, Eva Lonn, Jane Armitage, JoAnn E Manson, Graeme J Hankey, J David Spence, Pilar Galan, Kaare H Bønaa, Rex Jamison, J Michael Gaziano, Peter Guarino, John A Baron, Richard F A Logan, Edward L Giovannucci, Martin den Heijer, Per M Ueland, Derrick Bennett, Rory Collins, Richard Peto; B-Vitamin Treatment Trialists' Collaboration, Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals, Lancet. 2013 Mar 23;381(9871):1029-36
Tale Norbye Wien, Eva Pike, Torbjørn Wisløff, Annetine Staff, Sigbjørn Smeland, Marianne Klemp, Cancer risk with folic acid supplements: a systematic review and meta-analysis, BMJ Open. 2012 Jan 12;2(1):e000653
While the preliminary results of the potential effects of high dose vitamins B in PD are encouraging, their safety in the long-run warrants further investigation. There is some concern that combining vitamins B at high dosages or taking some vitamins B at high dosages may be associated with adverse effects, including cancer.
Combined intakes of vitamins B
We report below some studies about the association of combined intakes of vitamins B (B6 + B12; Folate + B6 + B12) with adverse effects.
- An association was found of combined high intakes of vitamins B6 and Vitamin B12 with risk of hip fracture among postmenopausal women (Meyer, 2019). “Risk was highest in women with a combined high intake of both vitamins (Vitamin B6 ≥35 mg/d and Vitamin B12 ≥20 µg/d).” The risk was about 50% higher than with a lower intake of both vitamins (Vitamin B6 <2 mg/d and Vitamin B12 <10 µg/d) (Meyer, 2019).
- Combined supplementation of folic acid and vitamin B12 was found to be associated with an increased risk of colorectal cancer in a multicentre, double-blind, randomized placebo-controlled trial. The study aimed at assessing the effect of daily supplementation for 2-3 years of folic acid (400 μg) and vitamin B12 (500 μg) versus placebo on fracture incidence. The researchers looked also at the long-term effects of combined supplementation of folic acid and vitamin B12 on the risk of cancer. A total of 2,524 participants were included. Participants receiving folic acid plus vitamin B12 had a higher risk of overall cancer (13.6% vs. 11.3%) and of colorectal cancer (3.4% vs. 2.0%) (Araghi, 2019).
- Another study involved 636 patients who had undergone coronary stenting. They were randomly assigned to receiving folic acid, vitamin B6 and vitamin B12, as follows: 1 mg of folic acid, 5 mg of vitamin B6 and 1 mg of vitamin B12 intravenously, followed by daily oral doses of 1.2 mg of folic acid, 48 mg of vitamin B6, and 60 mcg of vitamin B12 for six months, or placebo. The restenosis rate was higher in the folate group than in the placebo group (34.5% vs. 26.5%). Also the percentage of patients who needed repeated target-vessel revascularization was higher in the folate group (15.8% vs. 10.6%). The researchers concluded that taking folate, vitamin B6 and vitamin B12 after coronary stent may increase the risk of occlusion of the stent with a need for emergency revascularization (Lange, 2004)
- In Norway, 6837 patients with ischemic heart disease were treated with oral B vitamins or placebo, as follows: a) folic acid (0.8 mg/d) plus vitamin B12 (0.4 mg/d) and vitamin B6 (40 mg/d); b) folic acid (0.8 mg/d) plus vitamin B12 (0.4 mg/d); c) vitamin B6 alone (40 mg/d); or d) placebo. Treatment with folic acid plus vitamin B12, but not treatment with vitamin B6, was associated with increased occurrence of (lung) cancer and cancer mortality, and all-cause mortality in patients with ischemic heart disease (Ebbing, 2009).
- The Vitamins and Lifestyle (VITAL) cohort looked at supplement use of vitamins B6, folate, and B12 in 77,118 participants, aged 50 to 76 years, in relation to cancer risk. A significant risk was found in men for B6 and B12, especially smokers, but not in women. More specifically, the use of vitamin B6 and B12 from individual supplement sources, but not from multivitamins, was associated with a 30% to 40% increase in lung cancer risk among men, but not women. When the 10-year average supplement dose was considered, men taking > 20 mg/d of vitamin B6 and those taking > 55 µg/d of B12 had almost a two-fold increase in lung cancer risk compared with non-users. The risk was even higher among smokers (Brasky, 2017).
Vitamin B12 alone
So far, vitamin B12 has been considered to be very safe, even at high dosage. No UL (Upper Tolerable Intake Limit) has been set as no adverse effects at high dosages have been reported.
However, studies, mostly observational, which have specifically looked at cancer risk associated with the intake of vitamin B12 - whether from food sources or from supplements - have found a positive association of vitamin B12 with lung cancer risk.
- In a prospective cohort study (Singapore Chinese Health Study), 63 257 persons were followed up for incidence of lung cancer for up to 25 years. Higher intake of dietary vitamin B12 (i.e. from food sources) and high levels of vitamin B12 were associated with a significant increase risk in lung cancer, more in men than women. The authors concluded that the results of the study “highlights the potential harmful effect of vitamin B12 supplementation for lung cancer.” (Luu, 2021).
Two retrospective cohort studies based on health registries have shown an association between elevated B12 levels and newly-diagnosed solid cancer.
- A cohort study using population-based Danish medical registries of 333,667 subjects referred for plasma vitamin B12, found that high levels of B12, especially > 800 pmol/L (1084 ng/L), were associated with the risk of receiving a diagnosis of cancer, mostly within the first year of follow-up (Arendt, 2013)
- Another population-based study on 757,185 persons in UK Primary Care found an association of high levels of B12 (>1,000 pmol/L) with the occurrence of a cancer within one year after the assay. The association was dose-dependent (Arendt, 2019).
- Another study on blood samples from over 5000 case–control pairs found a dose-dependent association of high levels of B12 with the risk for lung cancer, in both men and women. The authors concluded that their findings “support the hypothesis that high vitamin B12 status increases the risk of lung cancer.” (Fanidi, 2019).
- 785 patients with B12 ≥ 1000 ng/L were compared with 785 controls with B12 < 1000 ng/L in another study. A level of B12 ≥ 1000 ng/L was associated with the presence of solid cancer, particularly pancreas, colon/rectum, lungs, prostate, urothelium, and bone, and liver metastases. The association was stronger with increasing B12 levels, in particular in cases of metastases (Urbanski, 2020).
- Lacombe and colleagues found that an elevated plasma B12 level (≥ 1000 ng/mL) persisting at the second measurement was strongly associated with the occurrence of solid cancer, compared with non-persistent plasma B12 elevation (Lacombe, 2021).
A recent review has concluded that there is insufficient evidence to assume that high plasma vitamin B12, high B12 intake, or treatment with pharmacological doses of vitamin B12, is causally related to cancer (Obeid, 2022)
Folic acid alone
A risk for cancer has also been described for high-dosage folic acid supplementation.
- In a meta-analysis of six large prospective folic acid-supplementation trials, Baggott and colleagues reported that cancer incidences were higher in the folic acid-supplemented groups than the non-folic acid-supplemented groups (Baggott, 2012). Participants received folic acid (mean dosage 1.3 mg) during a period of 3 to 8 years. Most of the studies included individual folic acid supplementation without vitamin B12.
- Qin and colleagues carried out a meta-analysis of randomized trials and found no significant risk of folic acid supplementation (mean dosage 1.64 mg) on cancer (n = 49,406, 13 trials), colorectal cancer (n = 33,824, 7 trials), lung cancer (n = 31,864, five trials), other cancers, and total cancer mortality (n = 31,930, six trials) during a mean follow-up time of 5.3 years (Qin, 2013).
- Vollset and colleagues also carried out a meta-analysis of 13 randomized trials including 49,621 participants, comparing those on folic acid (mean dosage 4.7 mg) with those on placebo. They reported no significant effect on cancer incidence including colon cancer during the first 5 years of treatment (Vollset, 2013).
- Another meta-analysis of 19 studies, including 12 randomized control trials, found no significant risk for cancer incidence for folic acid supplementation (0.4–1 mg) in treated subjects, compared with the control group, except for prostate cancer (Wien, 2013).
Selected references
Haakon E Meyer, Walter C Willett, Teresa T Fung, Kristin Holvik, Diane Feskanich, Association of High Intakes of Vitamins B6 and B12 From Food and Supplements With Risk of Hip Fracture Among Postmenopausal Women in the Nurses' Health Study, JAMA Netw Open. 2019 May 3;2(5):e193591
Sadaf Oliai Araghi; Jessica C. Kiefte-de Jong; Suzanne C. van Dijk; Karin M.A. Swart; Hanneke W. van Laarhoven; Natasja M. van Schoor; Lisette C.P.G.M. de Groot; Valery Lemmens; Bruno H. Stricker; André G. Uitterlinden; Nathalie van der Velde; Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial; Cancer Epidemiol Biomarkers Prev (2019) 28 (2): 275–282.
Helmut Lange, Harry Suryapranata, Giuseppe De Luca, Caspar Börner, Joep Dille, Klaus Kallmayer, M Noor Pasalary, Eberhard Scherer, Jan-Henk E Dambrink, Folate therapy and in-stent restenosis after coronary stenting, N Engl J Med. 2004 Jun 24;350(26):2673-81
Marta Ebbing, Kaare Harald Bønaa, Ottar Nygård, Egil Arnesen, Per Magne Ueland, Jan Erik Nordrehaug, Knut Rasmussen, Inger Njølstad, Helga Refsum, Dennis W Nilsen, Aage Tverdal, Klaus Meyer, Stein Emil Vollset, Cancer incidence and mortality after treatment with folic acid and vitamin B12, JAMA. 2009 Nov 18;302(19):2119-26.
Theodore M Brasky, Emily White, Chi-Ling Chen, Long-Term, Supplemental, One-Carbon Metabolism-Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort, J Clin Oncol. 2017 Oct 20;35(30):3440-3448
Luu, Hung N., Wang, Renweia, Jin, Aizhenc, Koh Woon-Puayc, Yuan Jian-Mina, The association between dietary vitamin B12 and lung cancer risk: findings from a prospective cohort study, European Journal of Cancer Prevention, 2021, May; 30(3):275-281.
Geoffrey Urbanski, Jean-François Hamel, Benoît Prouveur, Cédric Annweiler, Alaa Ghali, Julien Cassereau, Pierre Lozac’h, Christian Lavigne, and Valentin Lacombe, Strength of the Association of Elevated Vitamin B12 and Solid Cancers: An Adjusted Case-Control Study, J Clin Med. 2020 Feb; 9(2): 474.
Johan Frederik Berg Arendt, Lars Pedersen, Ebba Nexo, Henrik Toft Sørensen, Elevated plasma vitamin B12 levels as a marker for cancer: a population-based cohort study, J Natl Cancer Inst. 2013 Dec 4;105(23):1799-805
Johan F H Arendt, Henrik T Sørensen, Laura J Horsfall, Irene Petersen, Elevated Vitamin B12 Levels and Cancer Risk in UK Primary Care: A THIN Database Cohort Study, Cancer Epidemiol Biomarkers Prev. 2019 Apr;28(4):814-821
Anouar Fanidi et al., Is high vitamin B12 status a cause of lung cancer?, Int J Cancer. 2019 Sep 15; 145(6): 1499–1503.
Lacombe, V., Chabrun, F., Lacout, C. et al., Persistent elevation of plasma vitamin B12 is strongly associated with solid cancer, Sci Rep 11, 13361 (2021)
Obeid, R. High Plasma Vitamin B12 and Cancer in Human Studies: A Scoping Review to Judge Causality and Alternative Explanations. Nutrients. 2022 Oct;14, 4476.
Joseph E Baggott 1, Robert A Oster, Tsunenobu Tamura, Meta-analysis of cancer risk in folic acid supplementation trials, Cancer Epidemiol. 2012 Feb;36(1):78-81
Xianhui Qin 1, Yimin Cui, Lin Shen, Ningling Sun, Yan Zhang, Jianping Li, Xin Xu, Binyan Wang, Xiping Xu, Yong Huo, Xiaobin Wang, Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials, Int J Cancer. 2013 Sep 1;133(5):1033-41
Stein Emil Vollset, Robert Clarke, Sarah Lewington, Marta Ebbing, Jim Halsey, Eva Lonn, Jane Armitage, JoAnn E Manson, Graeme J Hankey, J David Spence, Pilar Galan, Kaare H Bønaa, Rex Jamison, J Michael Gaziano, Peter Guarino, John A Baron, Richard F A Logan, Edward L Giovannucci, Martin den Heijer, Per M Ueland, Derrick Bennett, Rory Collins, Richard Peto; B-Vitamin Treatment Trialists' Collaboration, Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals, Lancet. 2013 Mar 23;381(9871):1029-36
Tale Norbye Wien, Eva Pike, Torbjørn Wisløff, Annetine Staff, Sigbjørn Smeland, Marianne Klemp, Cancer risk with folic acid supplements: a systematic review and meta-analysis, BMJ Open. 2012 Jan 12;2(1):e000653
Text author: Sergio Pièche
Page updated - 24/04/23
Page updated - 24/04/23
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