Question from a customer:

"I am wondering why Hardy Nutritionals uses the pyridoxine hydrochloride form of B6 and if it is safe?"

Daily Essential Nutrients (DEN) provides 70 milligrams of pyridoxine at the full dose of 12 capsules per day, which is considered safe for children and adults. We have greatly reduced the pyridoxine in favor of P5P in our newest formulation, Daily Essential Nutrients with Added Vitamers, so if anyone is concerned about vitamin B6 toxicity, they can have peace of mind simply by choosing the DEN+V formula instead of the original DEN formula.

What is Vitamin B6?

Vitamin B6 is the generic name for six compounds with vitamin B6 activity: pyridoxine, an alcohol; pyridoxal, an aldehyde; and pyridoxamine, which contains an amino group; and their respective 5’-phosphate esters. Pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) are the active coenzyme forms of vitamin B6. Substantial proportions of the naturally occurring pyridoxine in fruits, vegetables, and grains exist in glycosylated forms that exhibit reduced bioavailability.

Vitamin B6 Clinical Safety Considerations  

Established Safety Recommendations  

In the Dietary Reference Intakes (DRI)¹ published by the Institute of Medicine (IOM) in  the United States, sensory neuropathy is identified as the most critical of the vitamin B6  adverse toxicity effects and the best documented. The first clinical reports of vitamin B6  toxicity documented peripheral sensory neuropathy at a dose of 1-6 grams/day for 2-40  

months, and the expert review panel concluded that “the risk of developing sensory  neuropathy decreases quite rapidly at doses below 1 g/day.”  

However, the DRI publication acknowledges that the dose at which pyridoxine can  cause toxicity varies greatly. After reviewing a broad swath of data, the expert panel  estimated a No Observed Adverse Event Level (NOAEL) at a pyridoxine intake of 200  mg/day (unlikely to cause adverse events in most individuals). They also estimate a  Lowest Observed Adverse Event Level (LOAEL) of 500 mg/day in spite of reports of  neuropathy at doses lower than 500 mg/day. In fact, there are reports of pyridoxine induced neuropathy at doses even lower than 200 mg/day, but this data was not strong,  as it did not confirm by clinical evaluation the purported toxicity symptoms, did not  confirm with certainty the dose, or did not show causality. They concluded that 100  mg/day is likely safe to consume chronically (i.e. the Tolerable Upper Level, or UL) for  adults who have no special considerations.  

Of note, the Institute of Medicine also states, “It is beyond the scope of this report to  address the possible therapeutic benefits of higher nutrient intakes that may offset the  potential risk of adverse effects. The UL is not meant to apply to individuals who are  treated with the nutrient under medical supervision or to individuals with predisposing  conditions that modify their sensitivity to the nutrient.”² 

Special Cases  

Since “special considerations” do exist (such as genetic limitations in B6 metabolism),³ the IOM recommendations will not be generalizable to everyone. There are many  factors which could either sensitize a person to vitamin B6 toxicity at doses lower than  what is tolerated by the majority of individuals, or increase their vitamin B6  requirements. These factors include genetics, the use of certain medications, certain  disorders, adequacy of other nutrients, and duration of use.⁴  

There are anecdotal self-reports of possible B6 toxicity at doses as low as 50 mg or  lower, but the lowest-dose peer-reviewed clinical report of vitamin B6 toxicity we have  found is 100 mg/day, and it was only after many years of use at this dose that toxicity  symptoms emerged.⁵ The individual did have an illness known to increase the risk for  peripheral neuropathy (lupus), which casts some doubt on the generalizability of this  case. For contrast, there is a case report of peripheral neuropathy induced by doses of 

more than 1000 mg/day of pyridoxine taken for 20 years!⁶ This individual also had a  disorder (homocystinuria) which increased her need for vitamin B6, and the pyridoxine  toxicity symptoms completely resolved when the dose was reduced to 500 mg/day.  These two cases demonstrate the wide range of dose sensitivity to vitamin B6. One  individual experienced pyridoxine toxicity at long-term ingestion of 100 mg/day, and the  other could apparently safely tolerate pyridoxine at a dose of 500 mg/day after many  years of taking twice as much.  

Vitamin B6 Metabolism and Mechanism of Toxicity  

There is emerging evidence that in the rare instances that vitamin B6 toxicity does occur at intakes of less than 100 mg/day, it may not be the high level of total B6 that is  problematic per se. Rather, the vitamer composition may be more predictive of clinical  harm. In recent years, multiple studies have provided evidence for the theory that it is  only the inactive vitamer of B6 (pyridoxine) which causes toxicity symptoms, not the  active coenzyme form (pyridoxal-5-phosphate). Furthermore, large inter-individual  differences exist in the ability to metabolize pyridoxine.  

Pyridoxine is a natural form of vitamin B6 which is widely prevalent in foods (especially  plant-based foods), so pyridoxine is not inherently bad or unnatural. Pyridoxine forms a  significant portion of dietary vitamin B6, along with other B6 vitamers: pyridoxal-5- phosphate (P5P or PLP) and pyridoxamine. However, pyridoxine must be converted to  P5P before the body can use it in most enzymatic reactions, so the developing theory is  that B6 toxicity results when pyridoxine doses are high enough to overwhelm the  individual's ability to convert pyridoxine to the active form (P5P).  

The postulated mechanism of toxicity is that unmetabolized pyridoxine  competitively inhibits the active vitamer at coenzyme binding sites and elsewhere,⁷ thus  blocking the action of the active vitamer (P5P) and mimicking B6 deficiency (which is  symptomatically similar to toxicity). The original paper that put forward the theory that it  was only the pyridoxine vitamer which caused toxicity was published in 2017, and there  was only in-vitro evidence at the time (see The Vitamin B6 paradox).⁸ But more recent  in-vivo data now supports this theory, including evidence that pyridoxine metabolism  varies greatly between individuals.⁹ 

Clinical Considerations  

This information creates some difficulty for clinicians. First of all, if doses well below the  UL can cause vitamin B6 toxicity, even for relatively few individuals, how can those at  risk be identified? Which biomarkers most reliably predict toxicity effects? Can in-born  differences in B6 vitamer metabolism be accurately predicted from genetic tests?  

A limitation of the dietary reference intakes is that they are based on oral intake and not  blood biomarker levels. Since large variability in pyridoxine metabolism has been  demonstrated, presumably vitamer-specific blood tests could inform this issue.  However, relevant clinical cutoffs have not yet been established, and unfortunately the terminology can be confusing since “pyridoxine” is sometimes used as a synonym for  “vitamin B6.” In other words, tests for “total pyridoxine” may report the sum of all B6  vitamers and not just the unmetabolized pyridoxine vitamer. Many lab tests only  measure the active co-enzyme vitamer (P5P/PLP) and not unmetabolized pyridoxine,  which is the proposed causative agent in B6 toxicity. Furthermore, serum P5P in lab  reports is compared only to reference ranges which represent commonly observed  levels in unsupplemented individuals; there is a glaring absence of established  correlation between serum values which exceed the high end of the reference range  and anything of clinical relevance - be it toxicity or treatment effects.¹⁰ 

Specific to vitamin B6 biomarker research, a University of Copenhagen review  concluded that at “intake levels of vitamin B6 (3-10 mg daily), a linear relationship  between vitamin B6 and plasma PLP concentration is suggested to exist.” However, at  intakes above 10 mg/day, blood biomarker research appears to reveal a limit to the  conversion of pyridoxine and other B6 vitamer forms to pyridoxal-5-phosphate. The  review concludes, “At considerably higher vitamin B6 intake levels…plasma PLP  concentrations appear to reach an upper level steady-state threshold.”¹¹ Therefore, if  vitamin B6 toxicity symptoms are the result of unmetabolized pyridoxine inhibiting P5P  activity, as has been theorized, clinical outcomes may actually correlate best with a ratio of vitamers instead of the absolute quantity of any one of them.¹² Perhaps as a result of  these factors, researchers examining a dataset of “261 patients enrolled in the Peripheral Neuropathy Research Registry” found that “elevated plasma vitamin B6  levels were not related to any patient-reported neuropathy sign or symptom”.¹³ 

Experience with Daily Essential Nutrients  

Daily Essential Nutrients (DEN) formulas contain between 60-70 mg/day of vitamin B6  in the recommended therapeutic dose. Given the variability in vitamin B6 metabolism, it  is probable that a few individuals would experience toxicity symptoms at a dose of 70  mg per day - especially over many years of use. So far, however, no evidence  of B6 toxicity in long-term DEN users has been published. Published long-term safety  data specific to Daily Essential Nutrients¹⁴ shows no evidence of vitamin B6 toxicity in  individuals consuming doses of 12-15 capsules per day of the original DEN formula for  up to 5 years. Of course, this does not prove that vitamin B6 toxicity is impossible at  these doses. In fact, these data may contain a tolerability bias – i.e. those who are poor  metabolizers of vitamin B6 may have had negative experiences and discontinued  supplementation before meaningful long-term data was collected.  

So far, none of the academic research published on Daily Essential Nutrients has  reported serum vitamin B6 levels. However, a formula substantially similar to DEN in  most other respects but containing less vitamin B6 (only 28.8 mg/day, all as pyridoxine)  did significantly increase serum PLP in a small cohort of children with bipolar disorder.¹⁵ The PLP levels nearly doubled, but remained within the reference range. Given that the  quantities of vitamin B6 in DEN are essentially double those of the similar formula studied, it is not unreasonable to extrapolate that had serum PLP been measured in  studies of DEN serum PLP would likely have been elevated in some number of study 

participants (although, as noted above change in serum PLP is likely not a meaningful  measure to predict B6 toxicity effects).  

Some customers have reported asymptomatic elevated B6 serum levels while taking  Daily Essential Nutrients formulas, but we were not able to rule out the possibility that  biotin interference introduced inaccuracy to these lab tests. We have also received a  

few clinician reports of patients with suspected B6 toxicity symptoms from a DEN  formula (mild peripheral neuropathy, muscle weakness, ataxia). At least one case had  confirmed elevated serum vitamin B6. In all reported cases, these symptoms resolved  completely upon discontinuation of the supplement.  

Conclusion  

In summary, based on the scientific literature and our experience at Hardy Nutritionals,  it is likely that many individuals will see elevated P5P in blood tests – perhaps especially  from the DEN formula with added vitamers. Very few individuals will experience vitamin B6 toxicity even from 12-15 capsules per day of any formula of Daily Essential Nutrients – even the original formula which contains only pyridoxine. However, in rare cases, individuals with special limitations (known or unknown) to vitamin B6 metabolism may  experience toxicity symptoms at these doses. It is not known if or how serum vitamin B6  levels correlate with clinical symptoms of toxicity, but research seems to show that  elevated P5P/PLP alone is not the sole cause.  

Addendum  

As of 2023, the vitamin B6 levels in Daily Essential Nutrients formulas are as follows: - Daily Essential Nutrients capsules (original):  

o 23.3 mg/serving as pyridoxine  

(70 mg in 12 capsules) 

- Daily Essential Nutrients with Added Vitamers capsules 

& Daily Essential Nutrients Powders both contain the same levels of B6 per serving:  o 8 mg/serving (4 capsules; 1 scoop) as pyridoxine 

(24 mg in 12 capsules)  

(24 mg in 3 scoops of powder)  

o 12 mg/serving as pyridoxal-5-phosphate 

(36 mg in 12 capsules)  

(36 mg in 3 scoops of powder)  

o 20 mg/serving total B6  

(60 mg in 12 capsules)  

(60 mg in 3 scoops of powder)  

- The intention of the vitamin B6 quantities in the DEN with Added Vitamers and  powder formulas is to offer the benefits of Daily Essential Nutrients to those who  may have very low-dose sensitivity to pyridoxine. The majority of the vitamin B6 in  these new versions of DEN is P5P, which is theorized not to cause vitamin B6  toxicity even at much higher doses. 

References 

¹ Institute of Medicine. 7 Vitamin B6. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate,  Vitamin B12, Pantothenic Acid, Biotin, and Choline. 1998. Washington, DC: The National Academies Press. doi:  10.17226/6015. 

² Institute of Medicine. 3 A Model for the Development of Tolerable Upper Intake Levels. Dietary Reference Intakes  for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. 1998.  Washington, DC: The National Academies Press. doi: 10.17226/6015. 

³ Hadtstein F, Vrolijk M. Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity. Adv  Nutr. 2021;12(5):1911-1929. doi:10.1093/advances/nmab033. 

⁴ di Salvo ML, Safo MK, Contestabile R. Biomedical aspects of pyridoxal 5'-phosphate availability. Front  Biosci (Elite Ed). 2012;4(3):897-913. Published 2012 Jan 1. doi:10.2741/E428. 

⁵ Silva CD, D'Cruz DP. Pyridoxine toxicity courtesy of your local health food store. Ann Rheum Dis.  2006;65(12):1666-1667. doi:10.1136/ard.2006.054213. 

⁶ Echaniz-Laguna A, Mourot-Cottet R, Noel E, Chanson JB. Regressive pyridoxine-induced sensory neuronopathy in  a patient with homocystinuria. BMJ Case Rep. 2018;2018:bcr2018225059. Published 2018 Jun 28. doi:10.1136/bcr 2018-225059. 

⁷ Hemminger A, Wills BK. Vitamin B6 Toxicity. In: StatPearls. Treasure Island (FL): StatPearls Publishing;  February 7, 2023. 

⁸ Vrolijk MF, Opperhuizen A, Jansen EHJM, Hageman GJ, Bast A, Haenen GRMM. The vitamin B6 paradox:  Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. Toxicol In  Vitro. 2017;44:206-212. doi:10.1016/j.tiv.2017.07.009. 

⁹ Vrolijk MF, Hageman GJ, van de Koppel S, van Hunsel F, Bast A. Inter-individual differences in  pharmacokinetics of vitamin B6: A possible explanation of different sensitivity to its neuropathic  effects. PharmaNutrition. 2020;12:100188. doi:10.1016/j.phanu.2020.100188. 

¹⁰ Stewart SL, Thomas S, Höke E, Simpson D, Singleton JR, Höke A. Vitamin B6 levels do not correlate with  severity of neuropathy in chronic idiopathic axonal polyneuropathy. J Peripher Nerv Syst. 2022;27(1):31-37.  doi:10.1111/jns.12480. 

¹¹ Tetens I, Petersen CF, Christensen SH, Wilkens T, Mikkelsen LS. Preparatory work for the update of the  tolerable upper intake levels for vitamin B6. EFSA Supporting Publications. 2023;20(1):7814E. doi:10.2903/sp.efsa.2023.EN-7814. 

¹² Ueland PM, Ulvik A, Rios-Avila L, Midttun Ø, Gregory JF. Direct and Functional Biomarkers of Vitamin B6  Status. Annu Rev Nutr. 2015;35:33-70. doi:10.1146/annurev-nutr-071714-034330. ¹³ Stewart SL, Thomas S, Höke E, Simpson D, Singleton JR, Höke A. Vitamin B6 levels do not correlate with  severity of neuropathy in chronic idiopathic axonal polyneuropathy. J Peripher Nerv Syst. 2022;27(1):31-37.  doi:10.1111/jns.12480. 

¹⁴ Rucklidge JJ, Eggleston MJF, Ealam B, Beaglehole B, Mulder RT. An Observational Preliminary Study on  the Safety of Long-Term Consumption of Micronutrients for the Treatment of Psychiatric Symptoms. J  Altern Complement Med. 2019;25(6):613-622. doi:10.1089/acm.2018.0352. 

¹⁵ Frazier EA, Gracious B, Arnold LE, et al. Nutritional and safety outcomes from an open-label  micronutrient intervention for pediatric bipolar spectrum disorders. J Child Adolesc Psychopharmacol.  2013;23(8):558-567. doi:10.1089/cap.2012.0098.

About Hardy Nutritionals®

Hardy Nutritionals® multivitamin-mineral products are powered by our proprietary NutraTek™ mineral delivery technology, which combines each mineral with specialized organic molecules—just like nature—to optimize absorption and distribution to body cells. Our flagship supplement, Daily Essential Nutrients, is widely considered to be the most research-backed micronutrient treatment.