Vitamin B6 As Effective, General Anti-stress Therapy

[Such_Saturation]

70mg pyridoxine hydrochloride rocks... I don't know if it's good though because half of that gives me no boost at all.

 

[docall18]

I have been taking a high quality liquid P5P. Just 5mg with food. Done this twice, my god, I felt awful, whooshing butterflies, depressed and anxious.

P5P B6 really shuts down my adrenaline. Maybe you were running on adrenaline..

 

[Greg says]

P5P B6 really shuts down my adrenaline. Maybe you were running on adrenaline..

yeah, I do agree. I'm not sure if I should keep taking B6. I also don't respond well to thyroid or the slightest bit of caffeine, same kind of anxious symptoms. I do like Haiduts B Complex, that gives me positive feelings.

I've taken NOW P5P before for long periods at 50mg with no negative reaction. This stuff must be pretty high quality. 'Epigenetics Vitamin B6 Pyridoxyl-5-Phosphate (Liquid)'.

 

[Drareg]

I was exploring b6 last week for science.
It doesn't agree with me over 10mg, I get an adrenaline response, it could be high adrenaline made worse ,I don't know, it's like an underlying anxiety,jumpiness.
Under 10mg I didn't notice much difference,it does build up though at this level because after 3 days I had this underlying jumpiness again.
P5p did the same thing to me.
Flight or fight stream of conciousness,mild but there.

 

[raypeatclips]

@Greg says did you manage to get b6 or caffeine working for you?

 

[Greg says]

I've slowly been introducing chocolate milk/ hot chocolate over the last few months and can sleep and feel good on it. The only B's I've taken are in Energin which is generally fine but if its not with some food/sugar I can feel a mood slump (a drop in adrenaline). i use it once or twice a week.

 

[Amazoniac]

Quality and stability of extemporaneous pyridoxal phosphate preparations used in the treatment of paediatric epilepsy

"Pyridoxal 5'-phosphate is used for the treatment of epilepsy caused by a deficiency of PNPO which, if untreated, can be fatal. Currently, there is no pharmaceutical form of PLP for paediatric [sick] use, so liquid forms of PLP are prepared from dietary products using crushed tablets or capsule contents mixed in a specific volume of tap water. There are major concerns about these extemporaneous PLP liquids regarding dose accuracy, stability and safety.

There are several issues with the feasibility of preparation of these extemporaneous liquids. At 25°C analytical grade PLP requires continuous stirring for 40 min to completely dissolve at a concentration of 5 mg/ml, therefore, it is likely that PLP prepared from dietary products by manual shaking within a clinical setting or at home might not completely dissolve to give 5 mg/ml. This was evidenced by our findings; PLP contents in liquids that were prepared from dietary products according to common clinical usage were not accurate. Some of these products contained less than the 50 mg stated on the label (Country Life, Food Science, Biocare and Metabolics) and others more (Vitacost and Thorne)."

Spoiler

"The content of PLP in the marketed products was assessed after dissolving the crushed tablets/contents of the capsules in 10 ml of deionised water as in the clinic or 50 ml to ensure complete dissolution of PLP (solubility of PLP is 5.7 mg/ml in water Pyridoxal Phosphate - DrugBank). The maximum experimentally calculated solubility of PLP in water at room temperature was 8.37 0.94 mg/ml. According to the manufacturers, all the dietary products contained 50 mg PLP. Products from Solgar, Bonusan and Thorne contained the stated amount ~ 50 mg when dissolved in 10 ml water (Table 2) whilst Country Life, Food Science and Biocare products contained less than 50 mg (~2–30 mg) (Table 2). When the volume of water used for dissolution was increased to 50 ml, the same PLP content was obtained for all the products except for Country Life and Thorne (Table 2). The content of PLP in both Vitacost and Thorne was higher than 50 mg. The liquid form of PLP (Metabolics(R)) contained 11.01 +- 5.78 mg/ml PLP as well as significant amounts of degradation products. There is therefore a high risk of inaccurate dosing if the PLP dietary supplements from Biocare, Food Science, Vitacost, Thorne or Metabolics are used for preparation of PLP extemporaneous liquids."

"This variation in PLP content can result in dose inaccuracy leading to either inefficacy or toxicity.[18–20] The low amounts of PLP solubilised in some products are particularly dangerous, given that non-response to these supplements can be taken to be diagnostically indicative of a seizure disorder that does not respond to PLP."

"It has been reported that some patients receiving this aqueous form of PLP develop deranged liver function tests (LFTs) and, with time, hepatic cirrhosis.[11,12] Transient LFT increases were shown to occur in 14/28 patients treated with PLP for infantile spasms, these were resolved on cessation of PLP supplementation.[13] In addition, one reported homocystinuria patient treated with 1000 mg/day of PLP developed hepatitis and deranged LFTs within 4 days of his dose being raised.[14] The cause of this liver toxicity is not clear but is hypothesised that it may occur as a result of either the high doses of PLP itself (30–100 mg/kg/day in 4–6 doses) or ingestion of compounds arising as a result of degradation of PLP when in solution. Importantly, hepatic disease is not seen in PNPO patients supplemented with high dose of pyridoxine or in other B6 responsive disorders treated similarly."

"Several dietary PLP products (Biocare, Bonusan and Food Science) did not comply with the B.P guidelines with regard to weight uniformity. This increases the risk of dose inaccuracy. Furthermore, some of the tablets (Solgar and Vitacost) are enteric coated making them difficult to crush and cause the generation of residues that can impair administration."

"When used clinically as a liquid formulation, carers usually only take the supernatant after solubilising PLP and leave any insoluble excipients behind, not knowing what is left, but in this context pragmatism prevails. This study has replicated the clinical scenario by only measuring PLP in the supernatant of the solutions prepared for analysis and has not measured any PLP that may be sequestered in the insoluble fraction. It is possible (indeed likely given its reactivity) that additional PLP is bound to other insoluble excipients (Appendix 1). If these products are taken as a dietary supplement it is likely the acidic conditions found in the stomach will release all PLP found therein. Moreover, it is also thought that these experiments being performed in the laboratory possibly improved the preparation methods of these PLP liquids and are not strictly what an inexperienced parent would do."
@Blossom

"Pyridoxal 50-phosphate is known to be unstable in aqueous form and undergoes photodegradation." "All of the extemporaneous liquids prepared from the tested marketed PLP products showed degradation when exposed to light even for short periods of time (4 h). This was consistent with the studies of Morrison and Long[15] and Ubbink,[21] which showed that pure PLP solutions were unstable after 4 h incubation in simulated daylight (66.5 +- 4.3% drug remaining). Morrison and Long[15] observed that pure PLP dissolved in air-free water completely photolysed after one hour in bright summer sunlight. Our advice is that PLP should always be made up immediately before administration. However, if this is impossible, it is imperative to protect PLP aqueous liquids from light when prepared in advance to avoid risk of dose inaccuracy and potential toxicity from any degradation products that may form. Unfortunately, this might be difficult to implement in the patient’s home."

"Several photolysis products of PLP were first postulated nearly sixty years ago.[15] This photochemical reaction is irreversible and the degradation compounds formed are oxygen concentration-dependent and PLP concentration-dependent.[16] One of the degradation products has been identified as 4-pyridoxic acid 5'-phosphate (PAP), formed by the oxidation of the aldehyde at the 40 position of PLP (Figure 2). In the presence of O2, PAP is readily formed when PLP is present at low concentrations, however, at high concentrations other yet unidentified species, with a peak absorbance of 288 nm are also formed, these are postulated to be dimers of PLP.[16]"

"Analysis of a PLP solution by HPLC-UV/VIS after exposure to light revealed the presence of degradation products (Figure S2). In particular, a major product was seen to elute at 3.5 min. There were also two more minor photoproducts found to elute after PLP between 6.5 and 10 min HPLCUV/VIS analysis (Figure S2)."

"For light stability studies, the liquids were exposed to light with 2 Philips TL 8W/35 fluorescent lamps[.]"
"The PLP liquids were exposed for 4 h along with a solution of pure PLP as a control."

"Most of the extemporaneous liquids prepared from the tested marketed PLP products and pure PLP were stable at room temperature when protected from light (~90% drug remaining). This was not consistent with the study of Shephard and Labadarios,[22] who have reported that 95% of a solution of pure PLP was degraded (mostly by hydrolysis to PL) after storage at room temperature in the dark for 24 h. The concentration of PLP is known to affect its degradation pattern.[14] This might explain the different findings in Shephard and Labadario’s studies in which PLP was assessed at low concentrations (1 mg/ml), while in our studies a higher concentration relevant to the clinical setting was investigated (5 mg/ml)."

"The photodegradation products of PLP were further characterised using LC-MS/MS and showed that after 24 h exposure to light 27.4% of degraded PLP had been converted to PAP with a further 72.6% degraded to other products including a diketone dimer of PLP. This is crucial as these degradation products could cause toxic side effects. PAP, naturally not present in humans, has been shown to inhibit PLP-dependent enzymes and thus theoretically could be a cause of the hepatotoxicity seen in PNPO patients on high-dose PLP supplementation.[23] However! In vivo it is likely that PAP is hydrolysed and subsequently excreted as pyridoxic acid in urine.[24,25] It is known that the B6 vitamers are mostly absorbed in their non-phosphorylated form and do not cross the gastro-intestinal wall in appreciable amounts before hydrolysis.[26] In addition, upon measurement of the B6 vitamer blood levels of patients on PLP supplementation, PAP is not detected in significant amounts (Unpublished data Laboratory of Mills P, 2016)."

"While it seems unlikely that PAP is a major toxic degradation product, other structural analogues of the B6 vitamers are already known to have toxic effects. Gingko toxin (40-O-methylpyridoxine), a naturally occurring plant extract, causes seizures thought to be because of inhibition of the pyridoxal kinase enzyme, responsible for phosphorylation of the B6 vitamers: pyridoxal, pyridoxamine and pyridoxine.[27,28] If other structural analogues of PLP are also capable of inhibition of B6-metabolising or PLPdependent enzymes, the effects could be wide ranging and could indeed result in hepatic dysfunction."

"Coman et al. postulate that the hepatic cirrhosis seen on high-dose PLP supplementation results because of the aberrant purinoceptor activation of hepatic stellate cells (HSC).[11] P2 receptors of HSC are linked with a fibrogenic response through increased collagen production. PLP itself acts on P2 receptors in an antagonist role but other PLP analogues show both agonistic and antagonist effects. It is possible that degradation products or metabolites of PLP may cause the hepatic fibrosis and deranged LFTs seen in PNPO deficient patients on high doses of PLP by purinoceptor activation."

"Pyridoxal 50-phosphate from Solgar, Thorne, Bonusan and Vitacost are the most stable products at room temperature, protected from light. Bonusan tablets are of non-uniform weight. Throne and Vitacost contain higher than stated amounts of PLP [~ 60 mg] which increases the risk of dose inaccuracy and toxicity. Although Solgar was of the best quality, none of the currently marketed products are truly suitable for long-term use at high doses because of possible liver toxicity. There is a need for a more stable pharmaceutically licensed treatment that is easily prepared and administered to PLP-responsive patients."

@haidut

 

[Blossom]

Moreover, it is also thought that these experiments being performed in the laboratory possibly improved the preparation methods of these PLP liquids and are not strictly what an inexperienced parent would do."

What are we going to do about those inexperienced parents trying to mix vitamins at home?

 

[haidut]

Quality and stability of extemporaneous pyridoxal phosphate preparations used in the treatment of paediatric epilepsy

"Pyridoxal 5'-phosphate is used for the treatment of epilepsy caused by a deficiency of PNPO which, if untreated, can be fatal. Currently, there is no pharmaceutical form of PLP for paediatric [sick] use, so liquid forms of PLP are prepared from dietary products using crushed tablets or capsule contents mixed in a specific volume of tap water. There are major concerns about these extemporaneous PLP liquids regarding dose accuracy, stability and safety.

There are several issues with the feasibility of preparation of these extemporaneous liquids. At 25°C analytical grade PLP requires continuous stirring for 40 min to completely dissolve at a concentration of 5 mg/ml, therefore, it is likely that PLP prepared from dietary products by manual shaking within a clinical setting or at home might not completely dissolve to give 5 mg/ml. This was evidenced by our findings; PLP contents in liquids that were prepared from dietary products according to common clinical usage were not accurate. Some of these products contained less than the 50 mg stated on the label (Country Life, Food Science, Biocare and Metabolics) and others more (Vitacost and Thorne)."

View attachment 10823

Spoiler

"The content of PLP in the marketed products was assessed after dissolving the crushed tablets/contents of the capsules in 10 ml of deionised water as in the clinic or 50 ml to ensure complete dissolution of PLP (solubility of PLP is 5.7 mg/ml in water Pyridoxal Phosphate - DrugBank). The maximum experimentally calculated solubility of PLP in water at room temperature was 8.37 0.94 mg/ml. According to the manufacturers, all the dietary products contained 50 mg PLP. Products from Solgar, Bonusan and Thorne contained the stated amount ~ 50 mg when dissolved in 10 ml water (Table 2) whilst Country Life, Food Science and Biocare products contained less than 50 mg (~2–30 mg) (Table 2). When the volume of water used for dissolution was increased to 50 ml, the same PLP content was obtained for all the products except for Country Life and Thorne (Table 2). The content of PLP in both Vitacost and Thorne was higher than 50 mg. The liquid form of PLP (Metabolics(R)) contained 11.01 +- 5.78 mg/ml PLP as well as significant amounts of degradation products. There is therefore a high risk of inaccurate dosing if the PLP dietary supplements from Biocare, Food Science, Vitacost, Thorne or Metabolics are used for preparation of PLP extemporaneous liquids."

"This variation in PLP content can result in dose inaccuracy leading to either inefficacy or toxicity.[18–20] The low amounts of PLP solubilised in some products are particularly dangerous, given that non-response to these supplements can be taken to be diagnostically indicative of a seizure disorder that does not respond to PLP."

"It has been reported that some patients receiving this aqueous form of PLP develop deranged liver function tests (LFTs) and, with time, hepatic cirrhosis.[11,12] Transient LFT increases were shown to occur in 14/28 patients treated with PLP for infantile spasms, these were resolved on cessation of PLP supplementation.[13] In addition, one reported homocystinuria patient treated with 1000 mg/day of PLP developed hepatitis and deranged LFTs within 4 days of his dose being raised.[14] The cause of this liver toxicity is not clear but is hypothesised that it may occur as a result of either the high doses of PLP itself (30–100 mg/kg/day in 4–6 doses) or ingestion of compounds arising as a result of degradation of PLP when in solution. Importantly, hepatic disease is not seen in PNPO patients supplemented with high dose of pyridoxine or in other B6 responsive disorders treated similarly."

"Several dietary PLP products (Biocare, Bonusan and Food Science) did not comply with the B.P guidelines with regard to weight uniformity. This increases the risk of dose inaccuracy. Furthermore, some of the tablets (Solgar and Vitacost) are enteric coated making them difficult to crush and cause the generation of residues that can impair administration."

"When used clinically as a liquid formulation, carers usually only take the supernatant after solubilising PLP and leave any insoluble excipients behind, not knowing what is left, but in this context pragmatism prevails. This study has replicated the clinical scenario by only measuring PLP in the supernatant of the solutions prepared for analysis and has not measured any PLP that may be sequestered in the insoluble fraction. It is possible (indeed likely given its reactivity) that additional PLP is bound to other insoluble excipients (Appendix 1). If these products are taken as a dietary supplement it is likely the acidic conditions found in the stomach will release all PLP found therein. Moreover, it is also thought that these experiments being performed in the laboratory possibly improved the preparation methods of these PLP liquids and are not strictly what an inexperienced parent would do."
@Blossom

"Pyridoxal 50-phosphate is known to be unstable in aqueous form and undergoes photodegradation." "All of the extemporaneous liquids prepared from the tested marketed PLP products showed degradation when exposed to light even for short periods of time (4 h). This was consistent with the studies of Morrison and Long[15] and Ubbink,[21] which showed that pure PLP solutions were unstable after 4 h incubation in simulated daylight (66.5 +- 4.3% drug remaining). Morrison and Long[15] observed that pure PLP dissolved in air-free water completely photolysed after one hour in bright summer sunlight. Our advice is that PLP should always be made up immediately before administration. However, if this is impossible, it is imperative to protect PLP aqueous liquids from light when prepared in advance to avoid risk of dose inaccuracy and potential toxicity from any degradation products that may form. Unfortunately, this might be difficult to implement in the patient’s home."

"Several photolysis products of PLP were first postulated nearly sixty years ago.[15] This photochemical reaction is irreversible and the degradation compounds formed are oxygen concentration-dependent and PLP concentration-dependent.[16] One of the degradation products has been identified as 4-pyridoxic acid 5'-phosphate (PAP), formed by the oxidation of the aldehyde at the 40 position of PLP (Figure 2). In the presence of O2, PAP is readily formed when PLP is present at low concentrations, however, at high concentrations other yet unidentified species, with a peak absorbance of 288 nm are also formed, these are postulated to be dimers of PLP.[16]"

View attachment 10824​

"Analysis of a PLP solution by HPLC-UV/VIS after exposure to light revealed the presence of degradation products (Figure S2). In particular, a major product was seen to elute at 3.5 min. There were also two more minor photoproducts found to elute after PLP between 6.5 and 10 min HPLCUV/VIS analysis (Figure S2)."

"For light stability studies, the liquids were exposed to light with 2 Philips TL 8W/35 fluorescent lamps[.]"
"The PLP liquids were exposed for 4 h along with a solution of pure PLP as a control."

"Most of the extemporaneous liquids prepared from the tested marketed PLP products and pure PLP were stable at room temperature when protected from light (~90% drug remaining). This was not consistent with the study of Shephard and Labadarios,[22] who have reported that 95% of a solution of pure PLP was degraded (mostly by hydrolysis to PL) after storage at room temperature in the dark for 24 h. The concentration of PLP is known to affect its degradation pattern.[14] This might explain the different findings in Shephard and Labadario’s studies in which PLP was assessed at low concentrations (1 mg/ml), while in our studies a higher concentration relevant to the clinical setting was investigated (5 mg/ml)."

"The photodegradation products of PLP were further characterised using LC-MS/MS and showed that after 24 h exposure to light 27.4% of degraded PLP had been converted to PAP with a further 72.6% degraded to other products including a diketone dimer of PLP. This is crucial as these degradation products could cause toxic side effects. PAP, naturally not present in humans, has been shown to inhibit PLP-dependent enzymes and thus theoretically could be a cause of the hepatotoxicity seen in PNPO patients on high-dose PLP supplementation.[23] However! In vivo it is likely that PAP is hydrolysed and subsequently excreted as pyridoxic acid in urine.[24,25] It is known that the B6 vitamers are mostly absorbed in their non-phosphorylated form and do not cross the gastro-intestinal wall in appreciable amounts before hydrolysis.[26] In addition, upon measurement of the B6 vitamer blood levels of patients on PLP supplementation, PAP is not detected in significant amounts (Unpublished data Laboratory of Mills P, 2016)."

"While it seems unlikely that PAP is a major toxic degradation product, other structural analogues of the B6 vitamers are already known to have toxic effects. Gingko toxin (40-O-methylpyridoxine), a naturally occurring plant extract, causes seizures thought to be because of inhibition of the pyridoxal kinase enzyme, responsible for phosphorylation of the B6 vitamers: pyridoxal, pyridoxamine and pyridoxine.[27,28] If other structural analogues of PLP are also capable of inhibition of B6-metabolising or PLPdependent enzymes, the effects could be wide ranging and could indeed result in hepatic dysfunction."

"Coman et al. postulate that the hepatic cirrhosis seen on high-dose PLP supplementation results because of the aberrant purinoceptor activation of hepatic stellate cells (HSC).[11] P2 receptors of HSC are linked with a fibrogenic response through increased collagen production. PLP itself acts on P2 receptors in an antagonist role but other PLP analogues show both agonistic and antagonist effects. It is possible that degradation products or metabolites of PLP may cause the hepatic fibrosis and deranged LFTs seen in PNPO deficient patients on high doses of PLP by purinoceptor activation."

"Pyridoxal 50-phosphate from Solgar, Thorne, Bonusan and Vitacost are the most stable products at room temperature, protected from light. Bonusan tablets are of non-uniform weight. Throne and Vitacost contain higher than stated amounts of PLP [~ 60 mg] which increases the risk of dose inaccuracy and toxicity. Although Solgar was of the best quality, none of the currently marketed products are truly suitable for long-term use at high doses because of possible liver toxicity. There is a need for a more stable pharmaceutically licensed treatment that is easily prepared and administered to PLP-responsive patients."

@haidut

Thanks. We did send an Energin bottle to our lab for analysis more than a year ago and they did not find anything other than P5P in it. It was at least 2 months old so by then it should have formed some P5P metabolites if there was indeed notable degradation due to O2 exposure.

 

[Amazoniac]

- Disorders affecting vitamin B6 metabolism

Vitamin B6 is present in our diet in many forms, however, only pyridoxal 5′‐phosphate (PLP) can function as a cofactor for enzymes. The intestine absorbs nonphosphorylated B6 vitamers, which are converted by specific enzymes to the active PLP form. The role of PLP is enabled by its reactive aldehyde group. Pathways reliant on PLP include amino acid and neurotransmitter metabolism, folate and 1‐carbon metabolism, protein and polyamine synthesis, carbohydrate and lipid metabolism, mitochondrial function and erythropoiesis. Besides the role of PLP as a cofactor B6 vitamers also play other cellular roles, for example, as antioxidants, modifying expression and action of steroid hormone receptors, affecting immune function, as chaperones and as an antagonist of Adenosine‐5'‐triphosphate (ATP) at P2 purinoceptors. Because of the vital role of PLP in neurotransmitter metabolism, particularly synthesis of the inhibitory transmitter γ‐aminobutyric acid, it is not surprising that various inborn errors leading to PLP deficiency manifest as B6‐responsive epilepsy, usually of early onset. This includes pyridox(am)ine phosphate oxidase deficiency (a disorder affecting PLP synthesis and recycling), disorders affecting PLP import into the brain (hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects), a disorder of an intracellular PLP‐binding protein (PLPBP, previously named PROSC) and disorders where metabolites accumulate that inactivate PLP, for example, ALDH7A1 deficiency and hyperprolinaemia type II. Patients with these disorders can show rapid control of seizures in response to either pyridoxine and/or PLP with a lifelong dependency on supraphysiological vitamin B6 supply. The clinical and biochemical features of disorders leading to B6‐responsive seizures and the treatment of these disorders are described in this review.

 

[Velve921]

Do most people use B6 in the morning or in the evening before bed? What dosages are people experimenting with?