… It’s important to choose the right type of B12 for your individual genetics before taking methylfolate to treat the MTHFR gene mutation for depression and anxiety  

How you choose the right  
type of B12
for your individual Genetics

B12 comes in 4 different types cyanocobalamin, methyl-B12, hydroxo-B12 and adenosyl-B12 choosing the right type for your individual metabolism based on your genetics or your symptoms and health goals can make a difference.
Best type of B12 for MTHFRImbalances in folate-methylation metabolism have received a lot of interest as more people learn about the MTHFR gene mutation but folate is only one part of the complex interconnected methylation metabolic system and there are several other nutrients required to run the system including B12. To understand more about what methylation metabolism is see below.
Your ability to metabolise B12 can also be affected by genetic variations, the MTHFR gene mutation tells us you have an increased need for methylfolate (natural or active form of folic acid) but it is not tell you which of the 4 types of B12 you need to take to suit your individual body, it is the COMT V158M and VDR Taq not the MTHFR gene variations that tell us which type of B12 will suit you.
If you have the MTHFR gene mutation and you start supplementing methylfolate before you have provided sufficient quantities of the right forms of B12 and the other nutrients that work in tandem with methylfolate you may either not make progress or experience unwanted treatment or healing reactions.

Use the table below to determine which type of B12 to take:
COMT V158M VDR Taq Best tolerated type of B12
- - + + (TT) All 3 types
- - + - (Tt) All 3 types but possibly Methyl B12 may be less well-tolerated
- - - - (tt) Hydroxo B12 and Adenosyl B12
+ - + + All 3 types but possibly Methyl B12 be may be less well-tolerated
+ - + - Hydroxo B12 and Adenosyl B12
+ - - - Hydroxo B12 and Adenosyl B12
+ + + + Hydroxo B12 and Adenosyl B12
+ + + - Hydroxo B12 and Adenosyl B12
+ + - - Mainly hydroxo B12 should be best tolerated



Why methyl B12 may make you anxious, agitated and have difficulty sleeping

When you have the COMT [COMT +/+] your ability to break down and deactivate dopamine is compromised, elevated dopamine and norepinephrine are central features of bipolar disorder and having the COMT variation is believed to be a risk factor for bipolar disorder[i]; in other people elevated dopamine and norepinephrine could cause over excitation in the brain producing feelings of agitation, aggravating anxiety and having difficulty sleeping.
Fully functioning VDR Taq genes are needed to manufacture dopamine and norepinephrine and people with the VDR Taq mutations do not make enough dopamine/norepinephrine.
What this means is if you have unhealthy DVR Taq genes with working COMT genes you will not be making enough dopamine and norepinephrine in the 1st place and breaking it down in a normal way causing issues of too little dopamine and norepinephrine.
Conversely if you have working VDR Taq genes but unhealthy COMT genes you can make enough dopamine and norepinephrine but will have difficulty breaking them down causing issues of elevated dopamine and norepinephrine levels.
We think that these people with working DVR Taq genes making enough dopamine and norepinephrine but unhealthy COMT genes meaning they can’t break them down are the people that experience increased agitation, anxiety and difficulty sleeping when they take remedies that increase methylation by donating methyl groups. There are ways around this by avoiding high dosages of methyl B12 and using hydroxo and adenosyl B12 instead and if necessary further controlling methylation with the use of niacin. Niacin soaks up excessive methyl groups in people that over methylate is and for some rare individuals very high doses of niacin and have powerful therapeutic effects.
something I want to make absolutely clear is this issue of over methylation or sensitivity to methyl donating remedies is very very uncommon, only seen a handful of times in 30 years practice, if you have an anxious brain and your mind latches onto this scary possibility remind yourself that the anxiety is messing with your mind and giving you a distorted and exaggerated perception of risk. Methyl B12 is not dangerous, make you feel worse it hasn’t caused any permanent damage and supplementing it may actually help you.

VDR Taq COMT and Bipolar Disorder

If you have both unhealthy VDR Taq and COMT genes then you can’t break down dopamine and norepinephrine that well because of the COMT mutation but you don’t make that much in the 1st place so hypothetically you might think these 2 things would cancel each other out but unfortunately it’s not going to be that simple, you going to have complex metabolic problems with your brains ability to regulate its dopamine and norepinephrine levels, this looks like classic bipolar disorder, but more scientific studies needed to connect this combination of mutations to bipolar disorder.
The treatment for such situation is going to be consequently complicated too involving a combination treatment whereby you will be taking things to support and overcome your VDR Taq issues with making dopamine and norepinephrine whilst at the same time taking things to control and down regulate dopamine and norepinephrine excess.
Developing effective combination treatments for simultaneously up regulating dopamine and norepinephrine production whilst at the same time down regulating them is something I have been doing for years, long before we ever talked about genetics and nutrigenomics (genetics applied to nutrition). My 1st successes in treating my own bipolar disorder involved aggressively up regulating dopamine/norepinephrine production and at the same time aggressively inhibiting it and was able to keep my bipolar disorder fully under control for 10 years by adjusting the strength with which I did these 2 things and use the same technique in my practice modifying it for each individual patient of course. It was like controlling the speed of a car by having your foot on the gas pedal and the brake pedal at the same time (see my pages on treating bipolar disorder). Since 2012 however I have developed an improved strategy based more upon controlling neuroinflammation and promoting neuroplasticity. If you would like me to look at your individual case and develop an tailor-made combination of natural remedies and therapy techniques I’m available for consultations either at my London clinic or via Skype for people that live too far away.

The discussion above may make you think that you shouldn’t take methyl B12 if you have bipolar disorder because of the risk of it over activating dopamine and norepinephrine production but that’s not necessarily the case; brains and bipolar disorder in particular are incredibly complicated and is a lot of evidence which you can easily find yourself showing that generally bipolar brains including the brains of people with recurrent mania suffer from under methylation in which case encouraging methylation with methyl B12 will be an overall helpful treatment in my practice I generally do prescribe methyl B12 to my bipolar patients but I never ever give any remedy but has potential antidepressant effects to someone with bipolar without also giving them mood stabilising or counterbalancing antimanic remedies. For information about bipolar disorder, methylation and methyl B12 see How to Choose the Right Type of B12 for Depression Bipolar and Anxiety

You will notice in the table Hydroxo B12 is suitable for all types and a simple strategy is to start with this type, after you have improved and stabilised your health you could then try experimenting with different types to see if they improve your health further.

Here are some more pointers:

With MTR & MTRR mutations you may do well with methylcobalamin & adenosylcobalamin supplementation.
If you have B12 deficiency coupled and an MTHFR gene mutation the B12 deficiency will exasperate the effects of the MTHFR mutation contributing to depression[ii][iii] and other mental health problems, and B12 deficiency is surprisingly common you may well have it without even knowing it; B12 deficiency is found in as many as 1 in 25 people and suboptimal levels may be present in as much as 40% of people, furthermore B12 deficiency has been found to be more common i.e. above-average in people with mental health problems so if you’re interested in my work you should probably be supplementing B12 to eliminate the possibility you have B12 deficiency see B12 Deficiency Depression Anxiety and More to learn the best way to deliver B12, swallowing it is not the most efficient way to go.

Don’t over rely on genetics to guide your choices

You mustn’t make the mistake of think that genetic testing is anywhere near providing us with precise definitive rules as to what we should or should not eat and supplement, I think the precision of so-called nutrigenomics is grossly overstated at this point in time. Genes are not binary we don’t just have one single on off switch for one thing, there are often multiple genes involved in causing condition, you could have 2 genes out of for increasing your chances of having a thing and 2 not so it’s a split committee decision rather a single command decision and then there are epigenetic overrides that can switch off genes encoding for unwanted things like cancer; it could take decades to map genetic and epigenetic interactions. The point I’m wanting to make here is you can use the above table as a starting point but listen to your body and experiment, remember do not dogmatically stick to the guidelines in the table above, you may for example do well by supplementing large amounts of either adenosyl B12 for hydroxo B12 but with the addition of moderate amounts of methyl B12 because methyl B12 is the primary methyl donating form.
Another way to choose which type of B12 supplement to use to help you achieve your health goals is learning about the unique properties of the 4 different types of B12 and safely experimenting to see how they affect you.

3 other of the things you need to know about using B12 supplements beyond choosing which type of B12 to takeOnce you’ve chosen which type of B12 to take there are 3 other things you need to know about how to deliver or absorb B12 in therapeutic quantities:

  • The 1st thing you need to know is B12 can be so poorly absorbed from the digestive system that it can be surprisingly difficult to get therapeutic benefits from regular supplements, you need to know how to get around the problem of poor absorption via the digestive system to deliver enough B12 to have therapeutic effects.
  • The 2nd thing that might surprise you is it appears being deficient of lithium can impede B12 utilisation and so to get the most out of your B12 supplements you may want to pave the way with a safe micro dose of lithium from lithium orotate.
  • The 3rd thing you need to know is you may not receive the benefits from supplementing methyl B12 you are looking for without also raising your glutathione levels. 
See B12 supplements 4 things you need to know.

Why methylation matters so much for mental health

A lack of methylation doesn’t just have one single effect but can cause a wide variety of health problems in different areas.

MTHFR treatment supplementsI discuss methylation in more detail elsewhere but briefly it’s a natural chemical process occurring in every cell of your body whereby a small molecule called a methyl group consisting of just 1 carbon and 3 hydrogen atoms is added or attached to other molecules and in so doing it transform them into something else, for example we need methylation to manufacture serotonin, we use it to break down homocysteine, methylation is such a basic chemical process the body uses to transform numerous substances that compromised methylation have profound widespread health consequences including anxiety and depression.
In the brain specifically methyl groups are required to manufacture chemicals critical to brain function including:-
  • Serotonin
  • Norepinephrine
  • Epinephrine
  • Melatonin (needed not just for sleep but melatonin is a potent antioxidant used in the brain and digestive system)
  • Glutathione (the main antioxidant the brain and liver used to protect against free radical damage, an inability to protect the brain from oxidative damage due to a lack of glutathione accelerating brain degeneration and ageing, and is believed to play a significant role in some mental health problems)
  • Cysteine (another important antioxidant for the brain)
  • Nitrous oxide (which acts as a neurotransmitter)
  • Taurine (an amino acid especially critical for maintaining and regenerating the health of the hippocampus involved in depression, bipolar, poor memory and other mental health problems)
Lack of methylation can cause health problems throughout the body but I specialise in treating brain and mental health problems with natural remedies and since a lack of methylation can have such a significant impact in this area treating methylation imbalances has become a critical part restoring health to the brains of some of my patients.

Why the MTHFR gene mutation matters so much

Furthermore methylation changes epigenetic proteins that in turn change the expression of every other gene in your body, other genes unrelated to MTHFR. Genes are made of DNA and DNA itself can be methylated and DNA methylation as it is called changes how active a gene will be, whether it is expressed (switched on) or not. Therefore an MTHFR gene mutation influences the activity of all the other genes in the body which is why it is such a key mutation causing so many widespread and diverse health complications and problems; with regard to the brain for example there are genes that control the manufacture of molecules the breakdown serotonin and if those genes are overexpressed you will be breaking down serotonin too quickly and by increasing methylation you can dampen down the overexpression of these genes and therefore increase serotonin activity in your brain producing an antidepressant and antianxiety effect.

Treating the MTHFR Gene Mutation

Micro dose lithium orotate to utilise B12

Lithium orotate for B12 absorptionYou should supplement micro dose of lithium from lithium orotate as part of your MTHFR gene recovery treatment because you could be lithium deficient and it appears lithium changes the body’s utilisation of B12, I have taken B12 when not taking low-dose lithium orotate and it produces no noticeable effects, however when I am already on lithium orotate and I add methyl B12 it has significant effects on my health increasing my energy. There is insufficient scientific evidence connecting lithium to B12 [iv] to backup this assertion I base it on my own personal and clinical observations and those of Dr Amy Yasko.
You may be surprised at the suggestion that you should supplement lithium as part of your MTHFR treatment recovery lithium has a bad reputation for producing harmful side-effects but this only relates to the high dosages of lithium carbonate used in psychiatric medicine not micro doses of lithium from lithium-orotate (see Lithium Orotate Many Health Benefits).
When you start your MTHFR gene mutation recovery treatment your body and brain will have been under-methylated for a long time and it is not recommended simply to jump in with high doses of methylfolate, doing so can produce a healing reaction and worsening of symptoms. When you supplement methylfolate the body will clear a backlog of incomplete metabolic processes resulting in increased mobilisation and discharge of toxins and to avoid a healing reaction the 1st thing you should do is ensure the detoxification systems in your body are functioning well and able to cope with the increased workload they will receive. Knowing how and when to do this is a skilled job and you should work with a qualified practitioner will become a qualified practitioner yourself!
In addition to paving the way for detoxification you should use supplements to build up the other essential mineral and vitamin methyl donors (mentioned above) needed for complete methylation before supplementing methylfolate.
Sometimes it’s a good idea to start with phospholipids such as phosphatidylserine, phosphatidylcholine, pure choline et al, these provide a shortcut to supplying methyl groups to where they are needed compared to the long methylfolate metabolic path; this can speed up the healing process and can actually be better tolerated and less likely to produce healing reactions in people with poor health and highly sensitive systems.
Some types of depression since there are signs that methylation is kickstarted I may quickly transition from phosphatidylserine/choline to CDP choline and Alpha CGP for methylation and to up-regulate dopaminergic and acetylcholine systems in the brain; for low dopamine bipolar depression this may be effective but must be properly managed and counterbalanced with antimanic remedies including still low but not Microdoses of lithium from orotate to avoid producing excess dopamine and triggering mania.
For anxiety, agitated depression and mixed bipolar states I may use high doses of TMG (betaine). TMG produces a sedating and tranquilizing effect on the brain, even used it myself during a period of life-threatening bipolar mixed state and a high dose to make myself so sedated that it reduced the risk of death from suicide I found it very effective and obviously I’m still writing so it :-)
TMJ is also an effective shortcut to delivering methyl groups and it up-regulates liver detoxification particularly following excessive drinking which as you may know invariably leads to B12 deficiency.
Surprisingly it takes many months (say 5 to 9 months) of treatment to fully supply all the metabolic systems in the body that require methyl groups and for them to clear out any backlogged in completed metabolic processes, once you’ve reached this stable stage or as you’re going along you can experiment to establish the ideal dose of folate, B6 and B12 to achieve your optimum wellness; for some people one or more of these 3 methylating vitamins can have profound effects on mental health problems such or even specific mental health symptoms. To use myself as an example supplementing additional B6 with breakfast literally switches off the social withdrawal/anxiety state I experience when I don’t take it, it also contributes an antidepressant effect.

For a more detailed explanation on How to Treat the MTHFR Gene Mutation click here

There are 7 additional nutrients required for methylation metabolism besides methylfolate:-

  • Active forms of B12
  • Active forms of B6
  • Active forms of B-2
  • Magnesium
  • Trimethylglycine also known as betaine
  • Vitamin D3
Furthermore as mentioned above to enhance B12 utilisation you should micro-dose lithium orotate.
Best type of B12 for depression
Besides choosing your B12 based on your genetic profile you can determine the ideal form or combination of forms of B12 to help you achieve your health goals through personal experimentation and trial and error. Learning about the different properties of the 4 types of B12 can help you work this out, see The 4 Types of B12 and How to Choose the Best One 
Further reading:-
I specialise in treating and coaching people with mental health problems how to obtain better mental health with natural remedies and self-help techniques. If you would like me to look into your individual case and develop a tailor-made programme of natural remedies, dietary advice and brain training exercises I’m available for private consultations at my London clinic and online for people that live too far away.
I also run regular meditation classes in London and online.
Click on the 
bookings tab to make an appointment.
I’m passionate about treating mental health and I’d be very happy to work with you.

[i] Sci Rep. 2015; 5: 8813. Published online 2015 Mar 6. doi:  10.1038/srep08813 PMCID: PMC4351536 PMID: 25744938 A potential interaction between COMT and MTHFR genetic variants in Han Chinese patients with bipolar II disorder Liang-Jen Wang, et. al.
[ii] Arch Gen Psychiatry. 2003 Jun;60(6):618-26.
Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Bjelland et al, PMID: 12796225 DOI: 10.1001/archpsyc.60.6.618
[iii] J Psychopharmacol. 2005 Jan;19(1):59-65.
Treatment of depression: time to consider folic acid and vitamin B12.
Coppen et al. PMID: 15671130 DOI: 10.1177/0269881105048899
[vi] Biol Trace Elem Res. 1992 Aug;34(2):161-76. Lithium in scalp hair of adults, students, and violent criminals. Effects of supplementation and evidence for interactions of lithium with vitamin B12 and with other trace elements. Schrauzer GN, et al PMID: 1381936 DOI: 10.1007/BF02785244 
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Hi my name is Peter Smith I specialise in treating and coaching people how to live well with mental health problems, digestive health problems/IBS, sleep problems and type II diabetes using natural therapies.
I used these techniques to overcome and live well with my own bipolar disorder and IBS. I've been in practice as a natural medicine practitioner since 1988.

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If you’d like treatment for any of the issues discussed in this article I specialise in treating and coaching people how to obtain better mental health with natural remedies and self-help techniques. If you would like me to look into your individual case and develop a tailor-made programme of natural remedies, dietary advice and brain training exercises I’m available for private consultations and I’m available for private consultations at my London clinic and online for people that live too far away.
I also run regular meditation classes in London and online.
I’m passionate about treating mental health and I’d be very happy to work with you.
Click on the
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