The B12 Protocol: 10 Foundational Principles

10 Concepts That You Must Understand If You Want The B12 Protocol to Work for Your Child!

 

Here are 10 concepts that will give some context into the use of vitamin B12 in autism.  This article will help you understand why and how B12 has been a foundational staple in autism and related metabolic disorders for over 20 years.

 

Concept #1: Vitamin B12 must be obtained from the environment

Vitamin B12 is a water-soluble substance that the body cannot synthesize on its own.  It is synthesized by bacteria that live in the intestines of animals and humans.  It is therefore absorbed into the bloodstream and found in their tissues.  Plants cannot synthesize Vitamin B12, nor is it absorbed through a plant’s root system, therefore it is not found in plant tissue.  In order to obtain Vitamin B12, humans must consume a diet that includes animal flesh.  The amounts synthesized by our intestinal bacteria are insufficient to meet our metabolic needs.  Furthermore, metabolic stress increases the requirements for Vitamin B12, and modern living conditions have placed increased demands on our metabolic state.

Concept #2: Vitamin B12 plays two cofactor roles in the body

Before specifically getting into the role of Vitamin B12 in the body, it is necessary to first explain what a vitamin is in a general sense.  A vitamin is a substance that cannot be synthesized by the organism but is required for the proper functioning of an enzyme within the body.  Therefore, vitamins must be obtained from the diet or the environment.  Vitamins are part of a broader class of substances known as cofactors. 

To understand how a vitamin assists an enzyme, by analogy, scissors cannot cut without a hand operating the mechanism.  Scissors without a hand operating them would be akin to an enzyme without the necessary cofactor, with the hand being that necessary cofactor.  If you had many pairs of scissors, you would need many hands to operate all of them, and only the pairs of scissors with a hand operating them would be capable of cutting.  A state of nutritional deficiency, in the context of a vitamin deficiency, would be represented by plenty of scissors and a shortage of hands to operate them by way of this analogy.

Vitamin B12 has two known cofactor roles in the body – that is, vitamin B12 functions as a cofactor in two known enzymes involved in human metabolism.  The first is a mitochondrial enzyme known as methylmalonyl-CoA mutase which contributes to energy production.  This enzyme uses a form of Vitamin B12 (called a vitamer of Vitamin B12) known as adenosyl-B12.

The second enzyme that Vitamin B12 participates in is called methionine synthase, which is located in the nucleus of the cell.  This enzyme uses a vitamer of B12 known as methyl-B12.  This enzyme is part of the methylation cycle, which serves to maintain an adequate level of one-carbon groups to regulate energy production (via carnitine synthesis), energy storage (via creatine synthesis), neurotransmission (via phospholipid synthesis, direct action upon neurotransmitters, and regulation of transport proteins), cellular detoxification (via methylation of toxicants in the liver), and gene expression (via methylation at certain cytosine sites along the DNA double-helix).

Concept #3: Vitamin B12 can be supplied in a “nutritional dose”

A nutritional dose of a nutrient refers to amounts that can be obtained from dietary sources.  A nutritional dose can be obtained through food or dietary supplement, but what classifies a dose as a nutritional dose is whether that dose falls within the realm of what can be obtained from diet.  For example, the RDI for Vitamin B12 is ~6 micrograms, which can be obtained from eating about 7 ounces of beef, or it can be obtained from taking a dietary supplement containing that amount.  When a vitamin is consumed in amounts that are considered a nutritional dose, the vitamin substance is used by the body to fulfill its vitamin cofactor role(s) in specific enzymes, as mentioned earlier.

You might have noticed that many dietary supplements contain amounts that exceed what can be reasonably obtained from diet.  When the dose of a nutrient exceeds that which can be obtained from diet, it begins to enter the realm of a pharmacological dose.

Concept #4: Vitamin B12 can be supplied in a “pharmacological dose”

A pharmacological dose may result in a supraphysiological level of that nutrient in the body.  Though it is not clearly defined where a nutritional dose ends and a pharmacological dose begins, my general rule of thumb is around ten times the RDI.  This means that the amount of said nutrient greatly exceeds the needs that the body has for it as a cofactor in its specific enzyme functions.  Many people in the mainstream medical industry will tell you that this makes for “expensive urine”, insinuating that anything in excess of the RDI is simply eliminated via urine.

This is sometimes the case, but not always.  For instance, the body may become insufficient in some nutrients not because the diet is lacking in that nutrient but because of malabsorption, which is common in certain inflammatory gastrointestinal conditions.  Gastrointestinal malabsorption is disproportionately higher in autism than in the general population, so for this reason alone, nutritional testing may be needed in the autistic population to see if certain nutrients need to be supplied in supraphysiological doses to compensate for malabsorption.

In some cases, however, supraphysiological levels of nutrients obtained from pharmacological dosing is shown to have beneficial effects in spite of adequate absorption.  One mechanism by which this may work is that when a cofactor is supplied in amounts that exceed the availability to bind to the specific enzyme for which it is the cofactor, transcription of that enzyme is accelerated, resulting in more enzyme and increased metabolic activity.  This may be necessary in certain situations where metabolic testing shows that a certain enzyme is functioning below the optimal rate (which could be due to genetic factors or environmental factors) and requires acceleration to bring metabolism into balance.  What this means in simpler terms is that taking excessively high doses of a cofactor can increase production of the enzyme it functions with, thus accelerating the metabolic result of that reaction.

In the context of Vitamin B12, however, I would like to turn your attention to a novel mechanism of action that takes place in the presence of supraphysiological levels of a nutrient.  This mechanism is very novel because in the previously mentioned mechanisms, the nutrient still operated within its traditionally accepted role as a cofactor for an enzyme.

In the case of Vitamin B12, when it is supplied at supraphysiological levels, it begins to take on a new role that was not previously characterized by its known cofactor roles.  This is confirmed by laboratory testing specifically in the case of Vitamin B12!  Allow me to explain.

You see, if a person reports to the Emergency Department with symptoms of acute cyanide poisoning, the primary antidote is a megadose of Vitamin B12 given by injection, repeated if necessary.  This is not because methionine synthase or methylmalonyl-CoA mutase are involved in cyanide detoxification.  This is because when given in supraphysiological amounts, Vitamin B12 is able to directly bind to cyanide, neutralizing its toxic properties, while allowing it to be eliminated from the body.

Please understand that this use for Vitamin B12 has absolutely nothing to do with its function in the body as a vitamin and does not begin to manifest until the concentration of the nutrient greatly exceeds what is needed to load the molecule onto the enzymes it serves in a cofactor capacity.  This is why a pharmacological dose is required to observe the non-cofactor role just described.

Concept #5: Vitamin B12’s use in autism can be explained by its relationship to certain toxicants

Methylation and mitochondrial function are two very important areas of focus in the biochemical study of autism.  Since Vitamin B12 plays pivotal roles in both processes, it is logical to assume that the benefits of Vitamin B12 in autism come from its contribution to these metabolic pathways.  This is certainly true to some extent, but it is my personal opinion that the contribution of the B12 Protocol, in the context of these roles, are greatly overstated.

As explained in the previous concept, there is more likely a pharmacological role involved in the B12 Protocol that accounts for a significant portion of the benefits witnessed by thousands of parents who choose to begin this treatment with their children.

In 2000, a researcher from the University of Birmingham conducted a study that showed the autistic sample group was able to detoxify cyanide at only 12% the capacity of the neurotypical sample group (the enzyme involved in cyanide removal is called rhodanese).  This is likely NOT a genetic shortcoming of the autistic sample group, but rather a decrease in enzyme function as a result of oxidative stress in the mitochondria, which affects the function of MANY enzymes.

Because cyanide exposure is very minute in the general population, this reduced rhodanese activity would not be expected to result in acute poisoning symptoms.  Even with rhodanese working at only 12% capacity, the body can be expected to keep cyanide levels low enough to maintain vital functions, albeit with greater difficulty and loss of efficiency in the mitochondria.  Because cyanide blocks oxidative phosphorylation within the mitochondria, energy production is greatly reduced and oxidative stress is even further increased.  Over time, symptoms of mitochondrial dysfunction and developmental delays would be expected if the situation is not corrected.  The longer the damage is allowed to continue, the longer the road to recovery.

The B12 Protocol in autism, I speculate, owes a great deal of its success to the same mechanism employed in Emergency Departments around the globe treating acute cyanide poisoning.  The Vitamin B12 molecule sacrifices itself to neutralize the toxic effects of cyanide within the mitochondrial electron transport chain, allowing the process of oxidative phosphorylation to take place.  It is only with pharmacological doses of Vitamin B12 that this mechanism will work. 

An important distinction between chronic cyanide toxicity and acute cyanide poisoning must be made.  To clarify this distinction, chronic toxicity usually involves long-term exposure to amounts of a toxicant that are not likely to be lethal in a short period of time (or ever) but can result in a deterioration of health if not addressed.  Contrast that with acute poisoning, which is an immediately dangerous situation involving exposure to lethal levels of a toxicant over a short period of time, resulting in death or serious injury if immediate action is not taken.

We must acknowledge that in autism, the relationship with cyanide is a chronic toxicity situation – not an acute poisoning situation for which a visit to the Emergency Department is warranted – therefore the usage for autism symptoms should look a bit different from the therapeutic process used in an acute poisoning situation.  I will outline those differences later in this article.

Concept #6: The use of vitamin B12 in autism has been shown to result in global improvements

Every child will benefit from the B12 Protocol in somewhat different ways and to differing degrees.  A small percentage, roughly 5-10%, may not benefit from it at all.  However, the use of vitamin B12 in autism has been around for over 20 years, and there are some common effects that many parents have reported over and over.  The benefits I am about to list just happen to be the most common.  This does not mean your child will experience all of these (or any of these) or that these are the only benefits you can expect to attribute to this treatment.  Here are the most commonly reported benefits of Vitamin B12 in the context of autism:

·       Improved cognition

·       Reduced fatigue

·       Increased affection

·       Increased alertness

·       Improved mood

·       Increased appetite

·       More assertive

·       Increased desire to communicate verbally

·       Improved verbal expression, putting more words and/or ideas together

·       Improved receptive language

·       More age-appropriate behavior

·       More appropriate play

·       Better eye contact

·       Improved motor skills

·       Improved bowel function

·       Reduced anxiety

·       Understanding of cause and effect

·       Less rigid about routine

·       Less clumsy

·       Increased compliance

·       Improved comprehension

·       Reduced compulsive behavior

·       Increased concentration

·       More conversational or back-and-forth interaction

·       Improved allergy symptoms (such as dark circles under the eyes)

·       Better at following directions

·       Understands choices

·       Skin improves (eczema)

·       More engaged with others and less in their own world

·       Begins to have rational fears and begins to let go of irrational fears

·       Understands feelings

·       Calmer and less easily frustrated

·       May begin to sing for the first time, or increased interest in singing

·       Growth spurt

·       Ability to generalize is improved

·       Improved gesturing

·       Enjoys humor and begins to understand humor better

·       More imaginative and creative

·       Improved imitation skills

·       Improved immune system

·       Improved independence

·       Initiation of play or interaction with others

·       More inquisitive

·       Broader interests (less restricted to a singular obsession)

·       Learns with reduced requirement for prompts

·       Improved memory

·       Open to trying new things

·       Improved quality of sleep

·       Increased formation of opinions

·       Pays more attention to people

·       Improved reading skills

·       Makes more requests

·       Quicker response time (less time required to process)

·       Improved ability to retain what is learned and build upon previous knowledge

·       Less fidgety

·       Improved time, place, and space awareness

·       Improved prosody or tone inflection (speech is less monotone or robotic sounding)

·       Increased answering of questions, including yes and no questions

·       Increased asking of questions such as “what, where, who, when, and why” or answers with because.

Here I have listed 58 commonly reported benefits of Vitamin B12.  Your child WILL NOT experience all 58 right away.  But in five years, should you stick it out, I would be willing to bet that you will look back on where your child was when they began this therapy and where they are now, and can say that most if not ALL of the 58 listed benefits will be witnessed to varying degrees in your child.

Improving neurological development with the B12 Protocol is a long-term process, and many good things will be witnessed by those who are patient enough to continue through the seemingly uneventful developmental plateaus.  Rest assured, change is happening during those dull periods, perhaps only at the metabolic level, but the physical and mental development will follow suit when the genetic code dictates that it is the appropriate time.

 

Concept #7: There is no great way to predict who will respond positively and who will not

Naturally, we parents only want to subject our children to therapies that are likely to help them and ignore any therapies that may not be useful (or even detrimental).  The question is often asked about whether there is a litmus test, so to speak, that can be used to determine whether your child would likely benefit from the B12 Protocol so you can avoid a trial-and-error approach.

Some tests that people make claims about as litmus tests for using vitamin B12 are serum testing, genetic SNP testing (the most popular are COMT, CBS, and MTHFR), and many others that I won’t waste my time getting into.  None of those tests can predict a Vitamin B12 responder, but are there others?

The short answer to this question is “maybe in some cases…” but the cost of the testing must also be taken into consideration.  Therefore, a better use of time and money may be to simply begin a B12 Protocol trial to assess whether your child is likely to see continued benefits from it, as the cost of the protocol supplements is often far less than the testing itself.  Statistically, there has been a 90-95% chance that vitamin B12 will be useful, so a protocol trial is a lower wager to gamble than a battery of predictive tests.

But for those who must know, or have unlimited funds and don’t mind making a decision based on equivocal results, these are the tests most likely to indicate whether your child will benefit from the B12 Protocol:

·       Organic Acids Testing

This panel measures 76 organic acids that serve as functional assessments of vitamin status, mitochondrial function, and methylation potential.  The panel can be used to assess vitamin B12 functional status.  If you can afford to purchase a baseline panel, this is great to have.  If this test breaks the bank, it is more useful if employed some time after beginning the B12 Protocol as a way of adjusting dosages.

·       Thyroid Panel

A thyroid panel will not assess B12 status.  However, thyroid hormones directly and indirectly regulate MTHFR activity, which is essential for proper usage of vitamin B12 in the body.  To put it simply, if a person is hypothyroid, their functional B12 status will be compromised.  Like the organic acids test, this panel is great to have at baseline (even more important than a baseline OAT), but if money is tight, it may be best to save the thyroid panel for some time after beginning the B12 Protocol.  It can then be used to adjust dosages.

Additional specialty testing:

·       Urinary sulfur panel

This urinary test panel looks at the same biomarkers used in Rosemary Waring’s 2000 study comparing an autistic sample population to the neurotypical control population.  By comparing thiocyanate and thiosulfate ratios, an indirect measure of intracellular cyanide level can be estimated.  If only one test could be used to predict probability of therapeutic success, this test panel is it.  However, it does not account for other benefits of Vitamin B12 (such as its known vitamin roles and how supraphysiological levels may be needed to get it to cross the blood-brain barrier) and therefore should not be used to predict success in all cases.

·       MitoSwab testing

This test panel is conducted on a buccal swab that measures the activities of several mitochondrial enzymes found within the cells collected on the swab.  Particularly, the rate of respiratory chain complex IV is important to look at when considering the utility of Vitamin B12 therapy because cyanide binds to cytochrome C oxidase, which will then prevent the mitochondria from utilizing oxygen, and this will be seen as decreased activity of respiratory chain complex IV.  It is important to note that there are many toxins that exert their toxic properties by interfering with cytochrome C oxidase and/or respiratory chain complex IV and is not specific to cyanide.  This test panel is very useful for monitoring treatment effectiveness and guiding your practitioner on other necessary areas of support but should not be used as a standalone test to determine whether Vitamin B12 has therapeutic potential for your child.  Used in conjunction with the other tests mentioned here, it can provide some clues as to whether Vitamin B12 has therapeutic potential in your child.

·       Methylation panel

This test panel looks at the metabolites within the methylation cycle, the folate cycle, and the sulfur antioxidant pathways.  Because mitochondrial dysfunction will reduce redox capacity, this can be seen in the sulfur antioxidant pathway results.  Methylation capacity is also negatively impacted by mitochondrial dysfunction, so this will be seen as a reduced SAM/SAH ratio, reduced methionine/homocysteine ratio, elevated or reduced adenosine, and/or reduced intracellular folate levels.  Though this panel is very useful for monitoring treatment success and guiding your practitioner on other nutritional supports that might be needed, much like the MitoSwab testing above, it cannot be used to directly or indirectly measure intracellular cyanide levels.  Used in conjunction with the other tests mentioned here, it can provide some clues as to whether Vitamin B12 has therapeutic potential in your child.

An experienced guide can interpret these tests holistically and gauge the degree of dysfunction in oxidative phosphorylation, which is probably a good predictor of whether there is therapeutic potential with Vitamin B12 therapy.  I would honestly much rather know for certain based on trial-and-error, thus eliminating the lengthy turnaround time, costly labs, and possibly incorrect prediction of a lab-based guess.

Furthermore, if your child is diagnosed with autism, I will buy you a Cadillac if all of the above lab panels show no irregularities that I mentioned in the section above.

Concept #8: Clearing chronic cyanide toxicity is likely NOT the only pharmacological benefit to the B12 Protocol

Though cyanide neutralization is one proven pharmacological benefit of vitamin B12 therapy, that is likely not the only toxicant that vitamin B12 is capable of neutralizing.  For instance, it has been demonstrated experimentally that hydrogen sulfide is neutralized by Vitamin B12 in a nearly identical manner as cyanide.  Hydrogen sulfide, though it behaves as a beneficial nutrient in appropriate quantities and in specific compartments of the body, similar to cyanide, it has the ability to inhibit the activity of respiratory chain complex IV, thus contributing to mitochondrial dysfunction.  Hydrogen sulfide levels are often elevated in autism, along with other abnormalities in sulfur metabolism.  Though I have chosen to focus the previous sections on the very likely beneficial effects of Vitamin B12 therapy on cyanide metabolism, the same principles can be applied to hydrogen sulfide toxicity.  In fact, Vitamin B12 is administered in Emergency Departments across the globe in a similar fashion as that used for cyanide poisoning when a patient presents with hydrogen sulfide poisoning.  Research on animals shows that novel forms of Vitamin B12, such as cobinamide, may be more effective than cobalamine (the most abundant natural form of Vitamin B12) and is a topic of current research.

As mentioned previously, there are known enzymatic roles for Vitamin B12 in methylation and mitochondrial metabolism, which are often (if not ALWAYS) compromised in autism.  Providing supraphysiological levels of Vitamin B12 may allow it to cross the blood-brain barrier more effectively

Concept #9: A high vitamin B12 serum test is not a good way to disqualify the need for supplementing it

If you have read this far and understand what I have written, you already know that Vitamin B12 is not being given to correct a nutritional deficiency situation, therefore laboratory reference ranges that are obtained using the general population who is consuming nutritional doses of Vitamin B12 are entirely useless for our purposes.  Though the B12 Protocol was not designed to correct a nutritional deficiency per se (the intents and purposes of the treatment goes way beyond nutritional roles as explained earlier), if a nutritional deficiency situation does exist, it would be quickly corrected with the very first application, since each 8 drop dose is hundreds of times the RDI.

One of the situations that the B12 Protocol was designed to correct is a functional B12 deficiency, meaning there is plenty of B12 in circulation, but it is not being properly imported and utilized in cells.  This situation can result in elevated serum levels.  This is why a high serum level may actually be indicating a paradoxical situation where there is plenty of B12 available but cells lack the other necessary cofactors to import it and put it to use.

Rest assured that Vitamin B12 is a water-soluble nutrient and has been demonstrated to be free of toxicity in any dose that has been administered to humans.  For your reference, the amount administered as a treatment for cyanide poisoning is thousands of times higher than what is conventionally administered in standard autism protocols and has been used safely for many years.

Non-toxic and free of side effects are not synonymous, however.  We will discuss potential side effects of Vitamin B12 therapy later in this document.  Suffice to say there have not been any life-threatening symptoms reported from Vitamin B12 therapy related to toxicity.

Concept #10: Transdermal application is superior to oral administration

Explaining this concept thoroughly requires that I compare and contrast the pharmacokinetics of Vitamin B12 when it is administered orally and when it is administered transdermally.

Oral absorption of Vitamin B12 is a complicated process, involving several steps.  First, Vitamin B12 must be separated from proteins in food via digestion.  Very little of this freed Vitamin B12 can be absorbed passively through the small intestine, rather, most of it must be bound to a special protein called intrinsic factor, produced by cells in the stomach.  Intrinsic factor-bound Vitamin B12 can then be absorbed by the small intestine, but since only limited amounts of intrinsic factor are produced, the amount of Vitamin B12 that can potentially be absorbed orally is quite limited (most sources say 1.5-2 mcg per meal).  From there, the metabolism of Vitamin B12, whether delivered orally or via injection, is the same.  The limitations on oral absorption likely prevents oral dosing from achieving supraphysiological levels necessary to exert Vitamin B12’s pharmacological role(s).

That said, let’s hypothetically say we are able to achieve similar levels of Vitamin B12 administering the nutrient orally as we are when administered transdermally.  This is where the pharmacokinetics comes into play.  Pharmacokinetics is an area of medicine that can be used to characterize the absorption, distribution, metabolism, and excretion of an administered substance.  In this particular thought experiment, we are assuming that the absorption of orally administered Vitamin B12 is the same as that administered transdermally.  However, in an orally administered substance, the blood level of the nutrient will generally peak within a predictable range of time (depending on various factors such as whether it was taken with food, the degree of liver processing, etc) and be eliminated in a predictable range of time as well.  This peak and elimination interval for orally administered Vitamin B12, if concentration is followed over time, appears as a sharp peak in comparison to transdermal Vitamin B12.

A generous estimation of the half-life of Vitamin B12 is 24 hours, meaning essentially all orally ingested Vitamin B12 is eliminated from the body in roughly a 48-hour period.  Keep in mind we are also giving a very generous (and likely dubious) concession that orally administered Vitamin B12 is fully absorbed, even when given in pharmacological doses.  I’ve explained the complex mechanism of Vitamin B12 absorption that makes that assumption very unlikely, as scientific studies have estimated that the limit of absorption via intrinsic factor is likely only 2 micrograms in a single feeding, whereas the amounts given transdermally or via injection in autism protocols are typically ~1000 times that amount and have a much higher bioavailability.

In contrast, when Vitamin B12 is administered transdermally, its slow passage through the skin serves to slow down the rate of absorption into the blood.  This is important because a single transdermal dose may take a full 24-48 hours to completely make its way into the blood supply, which means that the peak concentration and elimination are leveled out in comparison to an equally absorbed oral dosage.  Visually, it results in a flattened level of Vitamin B12 over time, whereas the orally administered Vitamin B12 would be visually represented by a series of mountains and valleys day after day.

If the absorption rate were the only difference between oral B12 and transdermal B12, theoretically you could space the oral B12 every few hours around the clock and mimic the pharmacokinetics of Activated B12 Oil.  However, at the risk of sounding like a broken record, the height of the B12 peak is likely much higher in transdermal B12.  I suspect that orally ingested B12 is not able to reach supraphysiological levels needed for it to perform its non-cofactor roles in the mitochondria.  To my knowledge, no studies have yet been conducted to compare the blood levels of Vitamin B12 from oral ingestion versus transdermal application.

Summary

Vitamin B12 is more than a basic dietary nutrient. In the context of the B12 Protocol, it is used at pharmacological levels to support the metabolic systems most often under strain in autism: methylation, mitochondrial energy production, redox balance, sulfur metabolism, neurological development, and cellular detoxification.

The central idea is simple: a child may have adequate B12 circulating in the bloodstream while still experiencing a functional need for higher-dose B12 support at the cellular level. This is why serum B12 alone is not a meaningful measure of whether the protocol is appropriate, and why a child’s response cannot be reliably predicted by diet history, genetic SNP reports, or a single laboratory value.

The B12 Protocol is designed to provide sustained, supraphysiological exposure to B12 rather than merely correcting a conventional nutritional deficiency. At these levels, B12 supports its established cofactor roles in methylation and mitochondrial metabolism while also providing pharmacological activity that may be especially relevant when mitochondrial stress, impaired oxidative phosphorylation, sulfur abnormalities, and reduced resilience to environmental toxicants are present.

Progress is rarely limited to one symptom or one developmental domain. Meaningful changes often begin with greater alertness, improved sleep, steadier mood, better bowel function, increased energy, reduced anxiety, and greater engagement with the environment. From there, many children show gains in communication, receptive and expressive language, attention, social interaction, play, motor skills, flexibility, learning, independence, and emotional awareness.

The protocol works best when it is approached as a consistent long-term developmental intervention. Development is not always linear. Periods that appear uneventful are often followed by new gains in function, language, learning, behavior, and social awareness. The goal is not to force development, but to provide the metabolic conditions that allow the child’s own developmental potential to emerge more fully.

In short, the B12 Protocol is built around a foundational principle: when cellular metabolism is better supported, the nervous system is better able to learn, regulate, communicate, adapt, and develop.  The 10 concepts described above are the foundations of why and how this protocol works.