View Full Version : Here's an Intriguing Idea: ADHD as Inborn Error of B6 Metabolism?


20thcenturyfox
11-15-16, 03:18 PM
Where is the follow-up to this astounding piece of Israeli research? Vitamin B6 supplementation resolved ADHD behaviour problems completely? Do these guys sound like flakes to you?

http://www.omicsgroup.org/journals/2167-065X/2167-065X-S1.004-031.pdf

Sounds exceedingly cheap and relatively easy to test, though apparently there is some challenge with fast degradation of these by-products in urine. Are we really this dependent on drug companies to sponsor trials? Even if this would not help everyone or resolve 100%, how hard can it be to determine who would be helped by it? How many of us are walking around with these excess pyrrols and therefore stripped of Zn and B6? Could it reduce the amount of medication required?

Caution: 200/mg of B6 per day is 200% of the Daily Upper Limit of B6, which was selected out of an abundance of caution because of neuropathies reportedly developing below 500mg per day. But 200mg/day is used without reported incident for treating various other problems.

But making sure you are getting the DUL of at least 100mg per day (50 times the RDA) might be a no-brainer.

Lunacie
11-15-16, 05:44 PM
I have tried supplementing with both B6 alone and in a multi-B supplement.
Didn't seem to improve my symptoms in the least.

I find it confusing that the study refers to improvement in "behavior." Do they
mean symptoms? Is poor working memory a behavior or a symptom? Not all
of us are hyperactive after all.

namazu
11-15-16, 05:51 PM
"Astounding" in the sense that this conference presentation abstract makes an extraordinary claim but does not provide the extraordinary evidence needed to support it.

I tracked down the paper, which the authors eventually published in a journal called Medical Hypotheses (https://www.ncbi.nlm.nih.gov/pubmed/24321736). Medical Hypotheses is a general biomedical journal that strives to "that foster the diversity and debate upon which the scientific process thrives" and will publish pretty much anything that has some possible theoretical basis and hasn't been soundly disproven yet. (I'd be curious to know how often these hypotheses are borne out by later data.) Unfortunately, the paper itself is behind a paywall.

In the paper, the authors report that they studied a total of 13 untreated kids with ADHD, 10 kids with ADHD treated with Ritalin, and 41 healthy controls. They did not mention the sex distribution of the children, nor how their ADHD was diagnosed/ascertained, nor how they were selected/recruited into the study, all of which are major methodological omissions.

They studied these kids' urine samples to test for metabolites. They found differences in group averages -- but also substantial overlap -- in three proposed biomarkers, such that their ability to diagnose ADHD reliably based on those biomarkers would be slim.

They also showed that these biomarkers were not notably changed in children treated with Ritalin (vs. no treatment). The authors suggest that this means that Ritalin does not fix the underlying problems in vitamin metabolism. (Alternatively, this could suggest that effective treatment does not necessarily involve the vitamins or metabolic pathways that the authors suggest are involved.)

The authors did not test for genetic markers of inborn errors of B6 metabolism, and as far as I'm aware, no such markers have been associated with ADHD in numerous genome-wide association studies (http://www.omim.org/entry/143465). This casts doubt on the authors' speculation that ADHD is generally underlain by an inborn error of B6 metabolism, though it's possible that some people with ADHD may have problems with B6.

The authors assert -- as they did in the abstract you posted -- that they saw great improvements in children treated with B6 and no side effects. But nowhere in the paper do they provide data to support that bold claim. The methods section only describes the urine testing (by referring to an earlier paper the authors had published in Med Hypotheses), not any treatment or follow-up protocol. The results section describes only biochemical parameters of one-time urine testing in their small sample of children, with nothing about symptoms or functioning.

The study was funded by Advanced Neuroprotective Systems, a for-profit company that markets diagnostic and drug-monitoring test kits.

So... Intriguing ? Yes. Evidence? No.

The US RDA (recommended daily allowance) of Vitamin B6 is 2mg/day, and that's what's in most typical multivitamin supplements. But taking 50x the US RDA (recommended daily allowance) of a vitamin that can cause problems at higher levels? Use caution.

For what it's worth, from a different review paper (https://www.ncbi.nlm.nih.gov/pubmed/25137514): "Supplementation with pyridoxine at doses greater than 50 mg/d for extended duration may be harmful and should be discouraged." (That's based on a 1987 case-control study of patients with and without neuropathy; in some cases, neuropathy occurred at doses of 50-75mg/day taken for 6 months or more, and resolved after B6 was discontinued. There were some healthy controls who took higher doses without problems, so there may be other underlying susceptibility issues. Some women who discontinued B6 supplements and then developed low B6 levels re-started 50mg/day of B6 and their neuropathy symptoms returned. So it's not clear that it's always safe to take high levels of B6, even with a demonstrated deficiency.)

So, my gut sense:
You probably have little to lose by trying B6 at modestly higher-than-normal levels (<50mg/day), especially for a short period of time.
Maybe it could help, and that would be great!
But clear it with your doctor, if you have one; don't overdo it (more is not always better); and don't be surprised if you don't see any miracles, because there's no reason to expect one.

BellaVita
11-15-16, 05:55 PM
I took B6 for a year or two.

I take a B-complex daily.

They both didn't improve my symptoms of ADHD.

At most they just help me feel a little better.

20thcenturyfox
11-15-16, 09:17 PM
Thanks, Namazu, for that critique. I had tried to find the original article, and had seen the NIH abstract you linked, but the convention summary I posted was the most complete report I could find.

But would you really go so far as to criticize metabolic research for not testing for genetic markers? I wouldn't have considered this a problem on its own. Testing and measuring metabolites--especially ratios of metabolites-- is no less valid for being cheap and (usually) low-tech. The bigger problem is that it is rare to get the clear results that would point to an IEM. And I didn't think they were trying trying to diagnose ADHD, as they seemed to be assuming it had already been diagnosed. But I agree that not saying how diagnosis and selection were determined/made, or how behaviour was defined are major methodological omissions.

So of course they did not test for genetic markers because this was not genetic research per se, nor does it have to be to study "inborn errors of metabolism"--many of which I believe were known through study of "Mendelian genetics" and metabolites in blood & urine long before genomic research was possible: from the Online Molecular and Metabolic Bases of Inherited Disease:

3: The Inborn Error and Biochemical Individuality
Barton Childs; David Valle; Gerardo Jimenez-Sanchez
Abstract: Archibald Garrod recognized that alkaptonuria was a disorder reflecting Mendelian inheritance in the human population. In 1902, that was an observation with remarkable insight. Garrod called this and three other Mendelian disorders (cystinuria, pentosuria, and albanism) examples of human biochemical individuality. Another 50 years would elapse before our understanding of the inborn errors of metabolism would lead to a field of inquiry called “human biochemical genetics.” The growth of knowledge in this field, in the latter half of the 20th century, is reflected in the expansion of information in The Metabolic and Molecular Bases of Inherited Disease.

AFAIK for obvious reasons most classic IEM's show up early in the life of an infant, and many are fatal. Those known to be survivable and related to Vitamin B6 apparently cause a range of problems including certain anemias and epilepsies. (Vitamin B6 and Inborn Errors http://ommbid.mhmedical.com/content.aspx?bookid=971&sectionid=62646411 ). So there are reference ranges for both normal and abnormal metabolites of B6, and this is how these genetic IEM's were traditionally diagnosed without reference to any genetic markers.

Of those which are not fatal in infancy, and merely cause suboptimal functioning, presumably not all have been identified. And B6 being known to be involved in the synthesis of neurotransmitters like dopamine, there is nothing inherently inconsistent between the ADHD brain research on abnormalities in dopamine circuits in the brain and someone being curious about whether any recognizable abnormalities show up in the metabolites of ADHD kids or adults.

One such B6 abnormality, pyroluria, has some familiar-sounding behavioural symptoms (The symptoms of excess urinary kryptopyrrole first manifest themselves as behavioral abnormalities. Although children tend to be more easily diagnosed than adults, the symptoms are consistent: poor tolerance of physical and emotional stress, mood swings, depression, noise and other tactile sensitivities. Later symptoms can range from severe depression to chronic schizophrenia. Accompanying physical symptoms can include pain, seizures, even complete physical debilitation.There is a myriad of other symptoms, including severe inner tension, ongoing anxiety, fearfulness, and sometimes episodic anger.)

So up to this point I take it there would appear to be a solid basis for this type of metabolic research--even with ADHD--unless it has already been done and metabolic errors ruled out. If properly done, I could see it yielding useful information no matter what the outcome, if only to confirm there is no detectable IEM element

Two obvious problems come to mind. One, we know ADHD is very diverse as to symptoms and severity, so you would expect any metabolic correlates to be diverse, or at most clustered into subgroups--which could still be very helpful. Two, I also gather the overall incidence of ADHD would be many orders of magnitude more prevalent than any single one of the IEM's. I couldn't find which IEM is the most common so far, so just guessing ADHD is a much bigger more diverse population than these other conditions. Still if metabolism errors are even a part of the ADHD picture, teasing this out should add significantly to our knowledge of subgroups and treatments.

Finally, it is one thing to take mega vitamin doses above the Safe Upper Limit after testing to establish some systemic reason why you would be short of Vitamin B6 and to try to normalize it while being monitored, but quite another to just self-dose experimentally above those limits knowing nothing of your B6 status. But if you actually do have pyroluria or something like that, normal amounts of B6 are not going to relieve it.

namazu
11-15-16, 10:51 PM
My comment about the authors not doing genetic testing was not a critique of their paper specifically. You can only look at so much in a given study, and I understand that. And yes, there is value to considering IEMs and their neuropsychiatric implications.

But what makes an inborn error of metabolism "inborn" is that is it is genetically-inherited.

Many, many genetic testing studies (in both large and small populations with various comorbidities), including genome-wide association studies, have --as far as I can tell -- failed to identify B6 metabolism-related genes or markers associated with ADHD. Yes, it's possible that there are subgroups of people with ADHD who do have some B6 metabolic error that would not have been picked up by those studies, or perhaps the identified genes affect B6 pathways in some heretofore unknown way, and perhaps those B6 metabolism problems could even contribute to ADHD symptoms in some people.

But my big objection here is that the authors go well beyond that in claiming that B6 metabolic errors underlie ADHD and epilepsy in general:
"Almost identical parameters of TRP degradation in untreated ADHD and epileptic patients allow to assume that inborn disorders of vitamin B6 metabolism are the common biochemical background of both diseases. [...] If vitamin B6 disorders are the core biochemical disturbances inherent in ADHD, then the long-term pyridoxine treatment is pathogenetically based replacement therapy of the disease."

In other words, the authors are suggesting that B6 metabolism errors are the primary factor underlying ADHD in the population [!] and that treatment with B6 supplementation corrects this problem [!] without any side effects.

I would love for that to be true; it would revolutionize ADHD treatment, and make it much cheaper. The problem is that they have demonstrated none of this. Not even in the small sample of 23 kids with ADHD whose urine they tested.

I wish the full text were freely available -- and that the reviewers had been more diligent. If I had reviewed this paper for publication, I would've send it back to the authors with a request for them to revise their abstract so as not to substantially misrepresent what they actually reported in the study.

I agree with you that it is plausible that unidentified IEMs (some possibly related to B6) may contribute to some portion of ADHD cases. As you noted, ADHD is diverse and multifactorial. Numerous genetic studies have revealed multiple contributing genes already (many of which are not clearly related to B6 metabolism) -- and many more are likely unidentified.

And that's precisely why incredibly broad suggestions that "vitamin B6 disorders are the core biochemical disturbances inherent in ADHD" are extraordinary. This small and inadequately-described study does not convince me.


In your OP, you wrote...
But making sure you are getting the DUL of at least 100mg per day (50 times the RDA) might be a no-brainer.
...which suggested that ADHDers -- without even considering their actual B6 status or the presence/absence of metabolic deficiencies -- far exceed the recommended daily intake of 2mg and instead use the "tolerable upper limit" of 100mg as a floor rather than as a ceiling. I would respectfully suggest that that's not sound advice for most people, especially given some reports of adverse health effects occurring at far lower doses taken over time. Your more recent, more nuanced statement strikes me as more appropriate:
Finally, it is one thing to take mega vitamin doses above the Safe Upper Limit after testing to establish some systemic reason why you would be short of Vitamin B6 and to try to normalize it while being monitored, but quite another to just self-dose experimentally above those limits knowing nothing of your B6 status. But if you actually do have pyroluria or something like that, normal amounts of B6 are not going to relieve it.



Again -- I'm not saying that IEMs or B6 problems in particular could not or do not contribute to some cases of ADHD, nor that they're not worth studying, nor that people should never experiment judiciously with vitamin supplementation. I'm just saying that the "astounding" study referenced in the OP does not come close to supporting the extraordinary claims made in the abstract, and that jumping into a B6 megadose regimen primarily on the basis of this study is not justified (and may be detrimental).

20thcenturyfox
11-16-16, 02:20 AM
Well, you're probably right that the abstracts go too far, though I read them both as merely saying "If B6 disorders are the core biochemical disturbances in ADHD, then," etc. But they clearly have skipped over far too much in the selection/diagnosis criteria to know what population they were studying, and too much in the behaviour outcomes to know what results they were reporting. Even the metabolite data was overgeneralized and hard to follow.

But speaking of metabolite data, before I gave up tonight, I was trying to figure out the rather bizarre not quite random differences in the 2 reports we posted, namazu's from PubMed is shorter than the one I posted from the OMICS Group Conference.

In trying to figure out what was omitted from the former, it seems it was primarily the more striking points of comparison in results between the patients and the controls, namely that 4 compounds were elevated 2-4 times in the ADHD group, while 6 compounds or ratios were conspicuously reduced in the patients, as determined by high-performance liquid chromatography. The PubMed version only mentions 3 ratios out of the above 10 findings in the OMICS report, and contains nothing specific enough to replicate or compare to other studies.

The Ritalin results are also much more clearly distinguished from the controls in the OMICS report.

Of course paying $12 or $36 for the full text would not be much of a hurdle for anyone interested in following up these results. The company which sponsored the study still seems to be clearly focused on epilepsy, so maybe if they were considering a foray into ADHD treatments, in the end they weren't sufficiently impressed with the results, either.

I'm out of brain cells to give this any more thought right now. But I think out of curiosity, at least, I will consider pricing out some of these specialized urine tests (now that I know what HPLC is!) and see what it would cost to further my education in this regard. It would be nice to know if I have little kryptopyrols busily stripping B6 and zinc from my blood and starving my brain. Wouldn't it?

sarahsweets
11-16-16, 05:19 AM
I take the following vitamins for reasons other than adhd :
c, b6,b12,d,e, folic acid,iron,calcium,chelated magnesium,biotin, fish oil and melatonin. I have taken them for 8 years and never had them work or affect my adhd one way or another. I know its antecdotal but wanted to share.