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Critical Response to Study of MB12 Injections

Letter to the editors Dr. Richard Deth of Northeastern University sent a letter to the editor at Toxicological and Environmental Chemisty pointing out flaws in a published study criticizing the injectable form of MB12. 

press release about the study begins with:  " A new study, “An Autism Cohort Study of Cobalt Levels Following Vitamin B12 Injections”, published in the most recent issue of the peer-reviewed Toxicological & Environmental Chemistry1, confirms a significant association between the frequency of methylcobalamin (vitamin B12) injections and blood/urinary cobalt levels in subjects diagnosed with an autism spectrum disorder as well as a significant association between cobalt exposure and damage to human neurons. 

Here is Dr. Deth's letter:

Dear Dr. Frank
 
Having read the paper “An Autism Cohort Study of Cobalt Levels Following Vitamin B12 Injections”, I feel it necessary to write a follow-up “Letter to the Editor”.  I hope such letters are published by the Journal. The text follows:
 
To the editor:
 
While I have a great deal of respect for the overall work of David and Mark Geier, their recent article “An Autism Cohort Study of Cobalt Levels Following Vitamin B12 Injections” misuses findings to create an unjustified level of fear about the use of methylcobalamin (methylB12) to treat autism. Since this treatment is widely recognized as being effective in a significant number of autistic individuals, it is critical to not allow a scientifically flawed paper to undermine its use. The authors found a mean plasma level of cobalt of 0.82 ug/liter for subjects receiving methylB12 injections, which corresponds to a concentration of 14 nM, and they found that neuroblastoma cells exhibit a toxic response to cobalt(II)nitrate hexahydrate with an LC50 of 559 uM. As a first significant problem,  their comparison of cobalt in vitamin B12 with the free heavy metal form of cobalt is an inappropriate and misleading comparison. It would be as if supplements containing vitamin B12 actually contained the heavy metal cobalt, which is obviously not the case. The authors have an obligation to characterize the chemical form of cobalt, which is highly likely to be overwhelmingly in the form of vitamin B12, not in the form of free cobalt. Secondly, the difference between the plasma concentration and the toxic concentration is 40,000-fold, but the authors fail to make this comparison. If indeed the plasma form of cobalt is in the form of vitamin B12, the difference in free cobalt concentrations is actually much higher than 40,000-fold. These discrepancies make this article scientifically invalid and as such it should be withdrawn. Studies directed toward identifying optimal dosing regimens for methylB12, with minimal toxicity, are indeed important. Unfortunately, this is not such a study.
 
Sincerely,
Richard C. Deth, PhD
 
Professor of Pharmacology
Northeastern University
360 Huntington Avenue
Boston, MA 02115
USA
 

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M Hari Krishna,

Prof Sudhakar's contact address is posted at the end of his comment.

Best regards,

John Stone, UK Editor

please send us the contact details of professor sudhakar k JNAFA University, Hyderabad India posted comment on may 19 2012
as my son is autistic and we stay in hyderabad

my 5 year is diagnosed with PDD. He's been on: Mb12, Phospholipids, Glutathione & Folic Acid (All injected IV)
The Results are nothing less than amazing.
He's been on this treatment for 7 months now and I could assure you that the GFCF diet it important too. If your child is not on this diet, I highly suggest getting him/her on the diet for faster results.

I have an autistic teenage son here in India and am engaged in fixing his problems last few years and am have been keenly following all the pronouncements and recommendations of Dr. Nuebrander in this regard, living in a remote geographical location and implementing his line of treatment. today I can say with full confidence that his observations and notings regarding the autistic subjects their metabolism and behavior done in real time are 100% accurate and no lab research in the world can match that. (he has spent a life time doing it). His now well documented methods, prescriptions, responses of children to his treatments and his conclusions are earth shaking and in fact he is playing god to the unfortunate lesser children of the world whose life is greatly enriched by his noble contributions.

Even a Nobel prize to him will be less of the honor he richly deserves. Pl. note: Parents of autistic children can mail me for further sharing of my experiences.

Prof. Sudhakar. K
(Parent of ASD child)
JNAFA University, Hyderabad,
India

What is the difference biochemically between the three forms of Vit B12 - cyanocobalamin, methylcobalamin, & hydroxycobalamin?
Could this oxidative stress problem, and the inactivation of methionine synthase be a problem in persons with ADHD?associated with learning disorders? and emotional instability? My stepson deals with these issues since a very young age & was born via an emergency C Section for fetal distress (cord wrapped around neck several times & meconium aspiration on a ventilator for a day.) There is however ADHD in the family on the paternal side & possibly on the maternal. Has any link or similarity been drawn between these two groups of disorders which are epidemic at this time?
Thank you for addressing this in any form possible. Suzanne M. Picinich, DO

Regarding hydroxy-B12, methyl-B12 and bad reactions...

Hydroxy-B12 can be converted in the body to adenosyl-B12 or methyl-B12. These two forms of B12 have very different functions. Adenosyl-B12 is a cofactor for the enzyme Methylmalonyl-CoA mutase, import for mitochondrial function. Methyl-B12 is a cofactor for the enzyme methionine synthase, important for cellular methylation.

The reason to give methyl-B12 instead of hydroxy-B12 is that the body requires glutathione to make the conversion. Many studies have shown glutathione is low in kids with ASD and low glutathione has suspected involvement in many chronic conditions (chronic fatigue, fibromyalgia, ASD, etc.). Dr. Deth has also shown that thimersol blocks the conversion to methyl-B12. By giving the methyl-B12 directly, you aren’t relying on the presence of glutathione (and a lack of thimerisol) for the transition. You also aren’t using up valuable glutathione stores to make the methyl-B12, important since glutathione is probably low already and has many other anti-oxidant and detox tasks within the body.

I think methyl-B12 “toxicity” is the wrong word to use unless you are specifically referring to the cobalt issue presented by the Geiers and Dr. Deth demolishes that argument in the comments below. The fact that some kids react negatively to methyl-B12 is probably explained by the Yasko “over-methylator” argument. Dr. Yasko hypothesizes that a minority of ASD kids are over sensitive to methyl groups already loose within their bodies due to genetic mutations. This can cause issues with neurotransmitters as methylation is used as a method of regulating neurotransmitters (along with many other tasks). Supplying even more methyl groups to these kids exacerbates the situation. Yasko suggests checking the COMT enzyme (used to methylate neurotransmitters) for mutations to determine if your child is an over or under methylator. COMT - - (no mutation) is an undermethylator, COMT + + (mutations from both parents) are over methylators. My son is COMT - - and he responded very well to methyl B12.

I should add that Dr. Neubrander has stated many times he thinks we don’t understand the whole over/under methylator business well enough to exclude methyl-B12 based on genomic testing. He recommends a trial regardless of genomic test results. He also states that hydroxy-B12 might be better for some kids, but thinks methyl-B12 is a better first choice. Dr. Neubrander has some good write-ups on his website if you want to learn more. Dr Deth’s papers and presentations are also available if you google his name.

Can someone address B12 toxicity? Why do some kids develop seizures and get B12 toxic? Why does giving P5P or Methyl Folate help MB12 absorption?
The compounding pharmacist told me Hydroxy B12 was the more bio-available form of B12 and my son has responded well on it but he doesn't really have a problem with MB12 if it is given with P5P and Methyl Folate. Once we gave him a Revitapop (just B12) and he didn't sleep for almost 72 hrs so I learned that he cannot tolerate just B12.
It's unfortunate that for parents we have to do so much trial and error here. I agree with earlier posts that there clearly needs to be much more research in this area. HELP!

Not so fast said:

“One way to test your own child, if you have the means and motive to do so, is to ask for an MMA urine test at each doctor visit. MMA stands for methylmalonic acid. MMA in urine is considered to be a marker of Vitamin B-12 deficiency.”

“If someone is receiving Vitamin B-12 injections, and that marker does not change (or does not change enough) it would certainly be sensible to shift over to sublingual tablets and try them out.”

This shows a clear misunderstanding of Dr. Deth’s work. MMA is a marker for adenosylcobalamin deficiency, not methylcobalamin. There are huge differences as adenosylcobalamin will not activate methionine synthase (MS) that has been deactivated by oxidative stress. We are not talking about a simple vitamin deficiency here, but as using MB12 (methylcobalamin) as a something akin to a pharmacological agent.

Dr Deth has shown that MS in the brain does not have the same ability to reactivate itself once oxidized (MS can do this in the rest of the body). Under oxidative stress, the cobalamin attached to MS changes from the active Cob(I)alamin form to the inactive Cob(II)alamin form. This renders MS inactive and completely stops methylation. In the rest of the body, MS contains a SAM domain that is used to reactivate MS. The oxidized cobalamin is reduced by flavodoxin and then remethylated with SAM from the SAM domain. This process coverts cobalamin to the active Cob(III)almin form and methylation restarts.

In the brain, for reasons that are unclear, MS lacks (or has in greatly reduced quantities) the SAM domain and the ability to remethylate itself, it requires a new methylcobalamin molecule. When methylcobalamin is present in high amounts in the blood, MS will discard the oxidized Cob(II)alamin molecule, and replace it with methylcobalamin. Methylation restarts. Methylation of the neuron membrane is critical in allowing neuron synchronization (via proper calcium channel operation). Proper calcium channel operation also protects the neurons against excitotoxicity.

MB12 is not for everyone, but it has caused dramatic improvements in many children, including my five year old son. Now we are working on resolving the oxidative stress, once that is improved, MS will function as intended without needing MB12. In the mean time, MB12 has dramatically improved my son’s quality of life. By the way, we use a daily nasal spray instead of the shots with dramatic results.

Dr. Deth and Dr. Neubrander, thank you both for your incredible work. It has changed our lives.

@Mattea. No our DAN doc did not try Hydroxyl B12 first. Our experience was five years ago, and I'm not sure if that nuance was understood back then or not. However, upon investigation of Yasko's Protocol and the understanding of the probability that my son has COMT, I tried an oral Hydroxyl B-12. Works beautifully for both of us (I have NVLD & Methyl B12 was a problem for me too).

the only thing I would watch out for is severe anemia, as cobalt binds to iron. In some cases for our autistic kids, that would actually be a good thing, but for others not so good. Also Cobalt is used in doping athletes. Not sure the mechanism, but I looked it up, something to do with oxidation and enhance performance of muasles, again, could that be a bad thing for our kids? Just sayin..

I am certainly very familiar with the cobalt-containing corrin ring structure of vitamin B12. The cobalt is held within the ring by four bonds, very similar to the way iron is held within its heme ring in hemoglobin. This is how nature harnesses the intrinsic oxidative potential of these heavy metals and puts them to critical metabolic use.

In the case of B12, the tail portion of the molecule bends back to bond to the cobalt via the lower face of the corrin ring. When B12 is bound to the enzyme methionine synthase the tail is displaced and instead a portion of the enzyme reversibly binds to the cobalt from the underside. This on and off binding from below controls the tendency of the cobalt to either pick up a methyl group (from methylfolate) or donate a methyl group (to homocysteine) on the upper surface of the corrin ring. Its a very clever piece of biochemistry.

There is undoubtedly some breakdown of the corrin ring, just like there is breakdown of the heme ring, and it would be important to know how much of this occurs after methylB12 administration. However, I'm not aware that anyone has measured this, although the vast majority of the dose is undoubtedly excreted as unchanged B12. When the Geier's paper compared the toxicity of free cobalt with measurements of total plasma or urinary cobalt, which is likely to be vitamin B12, they ignored this obviously important issue. Methods exist for specifically measuring cobalamins, which should have been done to see what proportion of the cobalt was still B12.

As I pointed out, even if 100% of the cobalt was released from the B12, the concentration the Geiers found in plasma was 40,000-fold below the toxic level they reported. So if 1% of the B12 was broken down and released its cobalt, the difference would be more than a million-fold. Even though zero would be better, this is a very big margin of safety. However, there should be a direct measurement of the cobalt-containing species to see what proportion was free.

In any case methylB12 is obviously not for everyone, even though many do appear to benefit. Genetic testing may indeed be a useful predictor of who will benefit, and different dosage schedules and routes of administration may allow individualization of its use. Its unfortunate that methylB12 has not yet been studied in this manner, but hopefully this may occur in the future.

I am seeing a lot of posts on B-12 shots and kids not tolerating them, Did at any point, your DAN think to prescribe Hydroxy first! That is what Dr. Stoller does to bypass all this mess of children having adverse reactions to methyl groups. Then once the child's mutation tests comes back, then you can give methyl b-12 if they do not have "comt" mutation, or if the yeast is not under control,b-12 will aggravate yeast.

The Geiers study clearly shows that more work is needed in this area. After initially responding very well, my daughter crashed on MB12. There is a doctor in NJ that commented to me she has a large number of patients that have come to her because they crashed on MB12. Dr. Neubrander's email about 'organic' vs 'inorganic' cobalt should send up red flags. We've been haggling over this terminology about mercury for close to a decade.

This post is not meant to slam Dr. Neubrander or fall firmly on the side of the Geiers. This study raises a concern that should be investigated further. Just like everything else we try in autism - some things are miracles for our children and other things cause serious side effects or have no effect.

If some children can't handle MB12 shots, then its a great opportunity to find new insights into this disorder.

My son reacted horribly to the Methyl B -12 injections. He went from a calm Autistic preschooler to being a flapping, hyper stim machine. Unfortunately the stimming and hyperactivity didn't go away once we got off the B-12. DAN docters need to be more precise about to whom they prescribe Methyl B-12. For some kids it can be a complete miracle while in others it can create problems. Then need to follow Dr. Yasko's lead and test for genetic mutations first, then individualize treatment protocols. My son shows all the signs of a COMT mutation and such a person should never be given Methyl B-12 because they are undermythelators.

Sorry Jack, I would disagree with the opinion you have expressed above. With all due respect, in my view the Geiers work receives an unjustified recognition in an audience of non specialists. This is particularly relevent with regard to their work on testosterone and Lupron therapy. This is sad but a critical caution must be observed by all in order to make the best choices for their autistic loved ones. Until fair and informed guidelines on interventions are being produced, parents will remain vulnerable and highly influenced. I would suggest that it should be one of AoA’s priorities to continue to demand that suitable research in intervention is being conducted, not solely by Autism Speaks but also by the many practitioners involved in autism treatment.

I stopped giving my son MB-12 after he tested high for cobalt. His cobalt level returned to zero.

Dr. Neubrander's email to patients

That this article and content was to be published was nothing new to me because it first came to my attention when the Geirs presented their theory at Cherry Hill a year ago. I lecture to physicians about the flaws in this study when doing training seminars. A full discussion would take an hour or more to write so I will only list a few key points here.

It is the cobalt inorganic salts that are toxic, not the organic form of cobalt that is bound on all four binding sites in the corrin ring. The more we take of B12 by any route of administration, the more that passes unchanged from the blood to the urine. If one did not find it to be high in the urine, then that would indicate a problem.

Laboratories do not differentiate between organic and inorganic amounts of cobalt but report the total amount of cobalt present along with a reference range that was created for the inorganic toxic form for miners and "old fashioned beers" (no longer used). An analogy would be to consider the total number of eggs one will be adding to a cake mix before and after it is baked and then try to compare the taste and texture of eggs to a cake. As an environmental physician, we see fairly rapid cause and effect for truly toxic agents, only one of which are heavy metals or metals in general. The effects of mercury or lead or arsenic are just as rapid and severe after exposure as are the effects from toxic amounts of poisonous chemicals. Therefore, common sense dictates that from the thousands of children I have treated, added to that the tens of thousands of children who have now been treated worldwide, if there really was a problem we would have seen it by now and that the effects would be pronounced. Exactly the opposite is what we as clinicians and parents see to be the case. Add to that incredible amount of clinical data that has and continues to be accumlated the fact that other published "clinical" studies (not quoted in the Geir article) support the fact that higher doses are safe and possibly more effective than lower doses.

All of that should be taken into account and weighed against the findings of the recent 2010 Okada rat study. In that study whereby rat's nerves were transected, they found that the methyl analog of the B12 family was significantly more biologically active than any other form of B12. They also documented that it is the shortest lived analog and therefore clinicians should consider giving it by injections instead of the usual routes of administration. In addition, they found the greatest benefits at high to very high doses. What occurred in the rat's nervous tissue under these conditions (organic cobalt plus the cobalamin molecule) was that it increased the length of axons, increased formation of neurites, increased resistance to apoptosis, was involved in kinase signaling pathways, and helped repair the transected nerves.

Therefore, what you do with "this study" is up to you but "published studies show" that mercury and vaccines are safe and not related to the autism epidemic. Many other "published studies" have proven many things we believe to not be true but are passed along as fact. Therefore, the final thing that any parent has to do, you just being one of them, is to decide for yourself what you choose to believe and after that follow your heart. I have no qualms with that. However, as for me, after observing thousands of my own patients do so well on injectable MB12, and where the majority of them do even better with daily shots than every two or three day shots, I can confidently say I've read the study and do not agree with its implications.

Sincerely,

Jim Neubrander, M.D.

Dr. Deth says,
"Their comparison of cobalt in vitamin B12 with the free heavy metal form of cobalt is an inappropriate and misleading comparison.
It would be as if supplements containing vitamin B12 actually contained the heavy metal cobalt, which is obviously not the case."

Not so fast. The Geiers are probably correct.

Nonetheless BOTH parties, the Geiers and Dr. Deth, are on your side. This is not a question of whether there is a benefit from Vitamin B-12, only a question of the delivery method.

Dr. Deth may or may not know this: Vitamin B-12 does contain cobalt -- the substance which he calls "the heavy metal cobalt." And cobalt is a heavy metal, an element, he is correct about that. Cobalt is found on the Periodic Table as #27, with iron on its left and nickel on its right.

However, Vitamin B-12 is classified as both "vitamin" and "mineral." This is because it is a vitamin -- and please look up the definition of "vitamin" -- and it also contains cobalt at its core.

Vitamin B-12 is a very large molecule, and you can see a drawing of it (with cobalt at the center) here: http://en.wikipedia.org/wiki/File:Cobalamin.png

It looks like Dr. Deth is not opposed to the idea of Vitamin B-12 injections, but thinks that injections cannot raise the level(s) of cobalt, the element.

However. There is a school of thought, and I am not going to provide cites and "evidence" here (look it up yourself!) which feels that when methylcobalamin is injected and then circulates through the bloodstream, the body "strips off" the methyl group for other uses. And as a consequence, perhaps the entire molecule disintegrates, leaving cobalt (the element) and other detritus. Which raises the levels of cobalt in the body.

On the other hand, this school of thought believes that when methylcobalamin is given sublingually -- in tablets which dissolve under the tongue -- this does not happen. Why there would be this difference may be known in some quarters, but will not be answered here.

It is possible to obtain methylcobalamin in tablets of 1,000 mcg (micrograms) or 2,000 or 5,000. They are available without a prescription, in health food stores and perhaps ordinary drugstores. There is no reason to give injections, and especially if they do not work as well as the sublingual tablets.

One way to test your own child, if you have the means and motive to do so, is to ask for an MMA urine test at each doctor visit. MMA stands for methylmalonic acid. MMA in urine is considered to be a marker of Vitamin B-12 deficiency.

If someone is receiving Vitamin B-12 injections, and that marker does not change (or does not change enough) it would certainly be sensible to shift over to sublingual tablets and try them out.

This really is unbelievable. When Geier and Geier publish a retrospective study using the VAERs database that links thimerisol to autism, the medical establishment labels them as unqualified quacks, hired shills for the trial lawyers of desperate parents. When they publish a study that mistakenly associates methyl-B12 with heavy metal cobalt poisoning, they are now dedicated researchers exposing the snake oil methods of (other) quacks taking advantage of (again) desperate parents, who unwittingly poison their children.

MB12 (methylcobalamin) is one of a very small list of interventions that truly works, and importantly, we understand why it works. Thanks to the tireless work of Dr. Deth, Dr. Waly and Dr. Nuebrander, we understand that MB12 reactivates methionine synthase (MS) in the brain that was deactivated by oxidative stress. We understand that phospholipid methylation can resume thus allowing proper neuron membrane permeability/flexibility and neuronal signal synchronization. In any other disorder, these three men would be viewed with admiration; MB12 would be considered a godsend.

Unfortunately, all three men have publicly stated they think thimerisol plays a key role in the inactivation of MS in the first place. They have stated thimerisol depletes glutathione, this preventing reactivation of MS on its own. They must be destroyed.

Thanks for posting this. I had not heard of the warning or the subsequent letter. I have been giving my autistic triplets MB12 injections for 6 years now without any problems.

Way to go, Professor Deth!

The Geiers, aside from Gallagher et al. from SUNY Stony Brook, are the only people to have produced good epidemiology of thimerosal's toxicity to date and the only people outside the CDC to have conducted any kind of epidemiological research on thimerosal at all. They also did ground-breaking hormonal research of the disorder.

What a disappointment that they have now produced a paper so badly flawed.

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