Why lipoic acid should never be supplemented

The sodium-dependent multivitamin transporter transports biotin, pantothenic acid and lipoate (Prasad et al. 1997). The three vitamins competitively inhibit transport of each other. Lipoate inhibits the transport of biotin and pantothenic acid (Prasad et al. 1998). Biotin is taken in microgram quanties while lipoic acid is taken in 600 milligram and higher quantites. What is more lipoate is synthesized on proteins whereby there is no need for free lipoic acid. All supplemental lipoic acid would be doing is blocking the transport of biotin and pantothenic acid.

IRP1 and neuropathy

thiamine

Hypoxia-inducible factor 1alpha (HIF-1α) induces transcription of thiamine transporter 2 by binding to the promoter of thiamine transporter 2. HIF-1α and hypoxia-inducible factor 2alpha bind to the same hypoxia responsive elements is promoters of hypoxia regulated genes. Hypoxia-inducible factor-2alpha is also called endothelial PAS domain-containing protein 1 (EPAS1).

EPAS1 mRNA has an iron response element in the 5′ untranslated region. When iron regulatory proteins (IRPs) bind to an iron response elements in the 5′ untranslated region of mRNA transcripts mRNA transcripts are destabilized reducing translation of iron responsive genes.

EPAS1 could like HIF-1α bind to promoters of the gene for thiamine transporter 2. However increased activity of IRP1 could destabilize EPAS1 mRNA transcripts reducing transcription of thiamine transporter 2 in response to hypoxia.

Neuropathy could result from increased activity of IRP1. With increased activity of IRP1 there could be low levels of EPAS1. Overtime with hypoxia not inducing thiamine transporter 2 the gene for thiamine tranpor 2 could become hypermethylated. Taking only RDA amounts of thiamine is then no longer sufficuent.

For neuropathy a combination of iron from carbonyl iron, thiamine and biotin could be of assistance. Iron decreases IRP1 activity which would stabilize mRNA transcipts of EPAS1 so thiamine transporter 2 can be induced by EPAS1. Thiamine and biotin supplementation can treat mutations in thiamine transporter 2.

When biotin is supplemented biotin is supplemented three times a day while pantothenic acid is supplemented once a day also but away from biotin.  Intestinal absorption of biotin is via the sodium-dependent multivitamin transporter (SMVT) where the SMVT also transports pantothenate. High dosages of pantothenic acid taken at the same time as biotin could inhibit transport of biotin. Biotinylation of the SMVT locus inhibits transcription of the SMVT gene so biotin cannot be taken at the same time as pantothenic acid.

The SMVT also transports lipoic acid. Supplementing with lipoic acid must be avoided as lipoic acid supplementation would competitively inhibit the transport of biotin and pantothenic acid by the SMVT.

There is no genetic defect nor is there a systematic thiamine deficiency where there is neuropathy arises due to high levels of IRP1. Only some thiamine transporter 2 genes are hypermethylated. Localized thiamine deficiencies do not have the symptoms of generalized thiamine deficiences, however, one of the symptoms of localized thiamine deficiencies could be neuropathy.

Synthesis of thiamine diphosphate by thiamine pyrophosphokinase requires ATP. Creatine buffers ATP. Creatine taken four times a day can be of asssistance in the treatment of neuropathy due to high levels of IRP1 as long as creatine is taken with iron from carbonyl iron, thiamine and biotin.

Vitamin B6 will worsen a neuropathy due to increased levels of IRP1 likely due to an effect on glutamic–pyruvic transaminase and serine-pyruvate transaminase which can not be supported due to dysregulation of aconitase 1 in the TCA cycle. Supplemental vitamin B6 could be of assistance given iron from carbonyl iron is supplemented.

Supplemental carbonyl iron, thiamine, biotin and pantothenic acid could be a more effective treatment for a lot of cases of neuropathy where supplemental vitamin B6 could also be assistance. Supplements and drinks on the list of ‘too be avoided supplements and drinks’ on the Treatment Page would have to be avoided.

Pyruvate carboxylase and metabolic syndrome

Pyruvate carboxylase is a biotin-dependent enzyme involved in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitters, and in glucose-induced insulin secretion by pancreatic islets. Pyruvate carboxylase is a key to beta cell adaptation to insulin resistance where pyruvate carboxylase reduction can lead to beta cell failure. In Agouti-K mice reduction of pyruvate carboxylase in pancreatic islets could play a role in the development of Type 2 diabetes.

Biotin deficiencies both by decreasing metabolism of branched-chain amino acids and decreasing activity of pyruvate carboxylase could lead to the development of metabolic syndrome in humans. Both biotin and pantothenate would have to be taken to treat metabolic syndrome where biotin would be taken three times a day and pantothenic acid taken once a day away from biotin. Both biotin and pantothenate are transported by the the sodium-dependent multivitamin transporter (SMVT). Pantothenic acid taken alone could competitively inhibit transport of biotin by the SMVT while biotin taken alone could decrease transport of pantothenic acid by biotinylation of histones at the SMVT locus.

The SMVT and iodide

The sodium-dependent multivitamin transporter (SMVT) also transports iodide. How important the SMVT is for iodide transport is not clear. Supplementing with biotin and pantothenic acid, however, could competitively block the transport of iodide by the SMVT. There is another transporter of of iodide, the sodium/iodide cotransporter, (SLC5A5) which is largely expressed in the thyroid. The SMVT is expressed in the digestive tract.

Coenzyme A as a supplement

Coenzyme A could be a very useful supplement. Pantothenic acid is supplemented to increase coenzyme A levels. Supplementing with coenzyme A could directly increase coenzyme A levels. There are supplements labeled as coenzyme A that do not contain any coenzyme A.  For example  Coenyzme-A Technologies has a supplement labeled as Pure Coenzyme A that contains no coenzyme A where the actual ingredients of the product are ingredients that should not be supplemented.   Apparently there are no supplements on the market that contain coenzyme A.  There may be a reason why coenzyme A is not sold as a supplement but I have seen medical journal articles where coenzyme A was prescribed for patients. Coenzyme A should not be confused with coenzyme Q10 or with vitamin A.

Pantothenic acid and acetylcholine in Alzheimer’s disease

Synthesis of acetylcholine requires acetyl-coenzyme A which donates an acetyl group to choline. With dysregulation of the transsulfuration pathway in Alzheimer’s disease, marked by high levels of homocysteine,  L-cysteine is not synthesized at sufficient levels. See my paper A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway. With low levels of l-cysteine coenzyme A, which is synthesized from pantothenic acid and which requires l-cysteine for synthesis, is not synthesized at appropriate levels. With low levels of coenzyme A the E2 subunit of the pyruvate dehydrogenase complex is underactive. Acetyl-coenzyme A required for the synthesis of acetylcholine is derived from the pyruvate dehydrogenase complex. Dysregulation of the pyruvate dehydrogenase complex could lead to shortages of acetylcholine in Alzheimer’s disease. Shortages of acetylcholine are a hallmark of Alzheimer’s disease which could be due decreases in the synthesis of coenzyme A is Alsheimer’s disesae.

Pantothenic acid and iron-sulfur cluster formation

Supplemental pantothenic acid increases levels of fatty acid synthase and the acyl carrier protein. Pantothenic acid donates a 4′-phosphopantetheine moiety to the acyl carrier protein. The mitochondrial acyl carrier protein (ACP) of fatty acid synthase is required for iron-sulfur cluster biogenesis.

Supplemental pantothenic acid is then of assistance both in increasing activity of the citric acid cycle and of assistance in increasing iron-sulfur cluster biogenesis.

Treating the negative symptoms of schizophrenia

The negative symptoms of schizophrenia are at least partly due to a shortage of coenzyme A which is used by the E2 unit of the 2-oxoglutarate dehydrogenase complex and the E2 unit of the pyruvate dehydrogenase complex in the citric acid cycle. What is needed is to increase levels of coenzyme A which can be done by supplemental pantothenic acid.

Why are coenzyme A levels low in schizophrenia? L-cysteine is required to synthesize coenzyme A. Due dysregulation of the transsulfuration pathway in schizophrenia, as explained in my paper Treatment-resistant schizophrenia: focus on the transsulfuration pathway, intracellular levels of L-cysteine can be low in schizophrenia which will decrease synthesis of coenzyme A.

Supplementation with L-carnitine from carnitine tartrate is needed as L-carnitine reverses the inhibition of pantothenic kinase by coenzyme A and acetyl-coenzyme A. Pantothenic kinase is the rate-limiting enzyme in coenzyme A synthesis. Supplementation with acetyl-l-carnitine is avoided as palmitonylcarnitine , which is what actually reverses the inhibition of pantothenic kinase, is synthesized from L-carnitine not acetyl-L-carnitine. For reasons I will not go into here the L-carnitine must be L-carnitine from L-carnitine tartrate. L-carnitine fumarate must be avoided.

Supplementation with sulbutiamine will also be helpful in the treatment of the negative symptoms of schizophrenia. Sulbutiamine is a fat-soluble form of thiamine which can greatly increase thiamine diphosphate levels . Thiamine diphoshpate is used by the E1 unit of the 2-oxogularate dehydrogenase complex and the E1 subunit of the pyruvate dehydrogenase complex.

Supplementation with sublingual biotin would be useful. The sodium-dependent multivitamin transporter (SMVT) transports pantothenic acid, biotin and lipoate. Biotinyalition of histones associated with with the sodium-dependent multivitamin transporter silences transcription of the sodium-dependent multivitamin transporter gene. High dosages of pantothenic acid could competitively biotin transport in the gut but this would be avoided with sublingual biotin. Very surprisingly coenzyme Q10 must be taken when biotin is supplemented. Biotin apparently can have a large effect on the TCA cycle. If the TCA cycle hangs up at the succinate dehydrogenase step supplemental biotin is not of assistance.

Acetyl-coenzyme A can be synthesized from fatty acids. EPA + DHA where EPA makes up 65 to 70% of the EPA + DHA combination will be helpful. A EPA + DHA combination has been extensively studied and has good safety profile.

Supplemental coenzyme Q10 is also required. Succinate dehydrogenase which is an iron-sulfur protein in the citric acid cycle, requires coenzyme Q10. Biotin is not useful without coenzyme Q10. If the citric acid cycle gets hung up at the succinate dehydrogenase step biotin is not helpful.

Activities of the E3 subunits of the pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex, which have NAD+ as substrates, unstimulated by supplements are  completely acceptable as is.

If niacin, niacin derivatives,  riboflavin and/or lipoic acid are supplemented pantothenic acid and thiamine will not work against the negative symptoms of schizophrenia.  A B-50 supplement is a terrible supplement. What not to supplement with is as important as what to supplement with.  Lipoic acid increases l-cysteine levels by reducing cystine to L-cysteine but cystine must be present to enter cells by way of the cystine/glutamate antiporter. Once in cells cystine is rapidly reduced to L-cysteine.  In any case lipoic acid is synthesized on lysine residues of proteins so supplemental lipoic acid would not boost activities of the  E2 subunit of the pyruvate dehydrogenase complex and E2 subunit of the 2-oxoglutarate complex. Do not supplement with pantethine. Pantethine depletes cystine.

The supplements must be taken with food. Taking the supplements with food makes a huge difference.

Can pantothenic acid, sulbutiamine, sublingual biotin, EPA + DHA, coenzyme Q10 and l-carnitine be effective against  the negative symptoms of schizophrenia when taken alone? I don’t know. Minimally, to be avoided supplements as listed on the Treatment page should be avoided.