Could a Gene Mutation be causing your depression or bipolar?-With the MTHFR gene mutation you may not be able to make the enough of the active form of the vitamin folate needed to make the neurotransmitters serotonin and dopamine causing mental health problems-
PeterSmithUK.com © 2014
(Updated 1st Nov 14)
(Updated 1st Nov 14)
IntroductionThere’s a substantial body of evidence showing a significant connection between diminished folate and depression [i][ii][iii], there is good evidence showing diminished folate in people with bipolar syndrome and even their relatives[iv], however little or no relationship has been found between folate and anxiety.
The vitamin folate (commonly known as folic acid or B9) comes in different forms and people with a mutation of the MTHFR gene cannot properly convert folate into the biologically active and useful form called L-methylfolate which is needed for many essential body processes including the manufacturing of the neurotransmitters serotonin and dopamine. L-methylfolate plays such a central role in the production of neurotransmitters that being deficient of it can not only cause depression but it can create the type of depression that is resistant to other treatments until the deficiency is corrected. See treatment resistant depression (under construction).
As can be seen in the diagram on the left people with the MTHFR gene mutation can work around the inbuilt limitation of their metabolism by directly supplementing L-methylfolate. See how to supplement L-methylfolate below.
The MTHFR gene mutation which can be identified with from a saliva sample (see below), comes in many different degrees of severity from mild to severe, with the mildest version of the mutation the body’s ability to manufacture L-methylfolate is only partially affected and most people with this condition should be able to achieve good health simply by eating a healthy diet with plenty vegetables and natural sources of folate and maybe supplementing a modest amount of L-methylfolate, with the more severe versions however the body’s ability to manufacture L-methylfolate can be so compromised that even if you eat a good diet containing plenty of natural folate you may not be able to manufacture enough L-methylfolate to maintain good mental health; in fact with this severe form of the mutation even consuming the wrong form of folate (the folic acid used in most multivitamins and added to many ready-made foods) can actually make depression worse, because it ‘congests’ the already inefficient folate pathway so you end up with even less L-methylfolate in the brain, also with the severe form of the gene mutation people will generally need to supplement high doses (10 to 15 mg) of L-methylfolate to regain their health.
Information online on the MTHFR gene mutation can be really confusing I think one of the big problems is that we are not sure exactly what the effects of this gene mutation are; I’m going to give you a deliberately simplified version to try and help shed some clarity on this important subject.
N.B. Online I see many parents of autistic children interested in the MTHFR gene mutation but this is not something I treat or have any clinical experience with.
Folate and Depression especially Treatment Resistant DepressionNumerous studies have shown a link between low levels of folate and depression[v], so if you have chronic long-term depression, especially if your condition has shown itself to be resistant to standard antidepressant treatments you should definitely consider investigating the possibility that you have an MTHFR gene mutation and if you do then treating the problem with specific supplements that deliver L-methylfolate along with complimentary methylating supplements including methylcobalamin (B12), P-5-P (B6) and TMG, maybe the breakthrough you’re looking for. It’s important to get the right type of L-methylfolate so see below for more details on choosing the supplements.
Having insufficient levels of L-methylfolate in the brain can have such a negative impact on the brain’s ability to manufacture serotonin and dopamine that in my practice I always encourage patients with chronic depression to experiment with a high dose of L-methylfolate and other methylating vitamins and see if these specific substances have useful antidepressant effects for them. I think the important point here is that not only is L-methylfolate a useful remedy, but for some people it may turn out to be pretty much the onlyremedy that will resolve their depression, whether used on its own or as part of a combination prescription.
Folate and Bipolar SyndromeIt looks like elevated homocysteine with low folate and B12 may be an independent risk factor for the development of bipolar syndrome[vi] and supplementing L-methylfolate has been shown to assist the action of sodium valproate[vii] used to treat bipolar mania.
During phases of bipolar mania the persons chemistry and behaviour is very similar to that of a person high on cocaine, it’s like the brain has spontaneously flooded itself with excess dopamine activity. Now given that you need L-methylfolate to manufacture dopamine it’s hard to understand how it’s possible for a person with the MTHFR gene mutation to manufacture excessive amounts of dopamine and produce bipolar mania, however time and time again brain chemistry is confounding, contradictory and confusing. Despite this somehow from time to time their brains are able to muster together the resources to over activate dopamine pathways in the brain. What I would imagine however is that the dopamine pathways would quickly become depleted causing a rapid crash into bipolar depression and the combination of low L-methylfolate, inadequate methylation and high homocysteine probably conspired together to create a nasty inflammatory environment from which it’s hard to recover.
Why We Need L-MethylfolateOne of the main of functions-methylfolate is it supplies the body with what are called methyl molecules known as a methyl groups. Methyl groups are needed to perform a crucial process in the body called methylation. Methylation involves attaching methyl groups to other substances to change them, for example the amino acid tryptophan is changed into the neurotransmitter serotonin by methylation or adding methyl groups to it.
So a lack of methylation in the brain due to a lack of L-methylfolate can result in deficient serotonin and dopamine production causing depression including bipolar depression.
If you have depression due to a deficiency of neurotransmitters and the MTHFR gene mutation is the reason you cannot make enough neurotransmitters then standard antidepressant treatment may simply not be effective resulting in so-called treatment resistant depression.
The good news is you can obtain L-methylfolate as a supplement and it readily passes the blood-brain barrier so you can supply your brain with enough ready-made L-methylfolate to maintain mental wellness. Potentially this may be the solution for some cases of treatment resistant depression and bipolar depression (although bipolar syndrome is more complicated than simply not being able to make enough neurotransmitters). Supplemental L-methylfolate can also be taken at the same time as antidepressants and may significantly enhance their effectiveness[viii][ix]. If you are currently on antidepressants and obtaining unsatisfactory results ask your doctor about combining deplin a prescription form of L-methylfolate with your antidepressants to see if it enhances their effectiveness.
Besides the MTHFR gene mutation lack of methylation can also result from a diet that does not contain enough sources of methyl groups because it is deficient in folate, B12, B6 and the vitamin choline.
Another consequence of diminished methylation is the build-up of a chemical called homocysteine. Elevated homocysteine levels are associated with a wide range of health problems from depression and bipolar to cardiovascular and Alzheimer’s disease, however it now looks as though homocysteine doesn’t actually causethese problems but it just associated with them, I’ll say more about this later.
The body’s need for methyl groups increases at times of increased stress and as discussed elsewhere people with depression and bipolar syndrome often have hyperactive internal stress responses, therefore increasing their need for methyl molecules.
MTHFR and Brain InflammationLack of methylation causes inflammation and as I explain elsewhere chronic inflammation in the brain damages delicate brain structures and brain scans reveal damaged structures within the brains of people with chronic depression, bipolar and many other mental health problems. The brain has a tremendous ability to regenerate and regrow new connections, this is called neuroplasticity, to regenerate effectively the brain needs the right internal environment free from chronic inflammation, toxins (e.g. heavy-metal), allergens (e.g. gluten), excess stress hormones, chronic low-grade infections and elevated blood sugar; it also needs the right building blocks (e.g. omega-3 oils) and other key substances including BDNF. Chronic inflammation in the brain is one of those things which if not eliminated can prevent recovery, lowering elevated homocysteine and restoring adequate methylation by ensuring the brain has adequate levels of L-methylfolate can be an important part of eliminating inflammation.
MTHFR and NeurotransmittersThe brain needs the bioactive form of folate (L-methylfolate) for three critical roles:-
1) Firstly as you may already know lack of the neurotransmitters serotonin and dopamine may cause depression including bipolar depression. These neurotransmitters are made from the amino acids tryptophan and tyrosine respectively; for the enzymes that make serotonin and dopamine to work properly they require a cofactor compound called biopterin (BH4) to be present and we need L-methylfolate to make this cofactor.
The enzymes that make serotonin and dopamine (tryptophan hydroxylase and tyrosine hydroxylase) are what are called the rate-limiting enzyme, meaning they control the slowest step in the manufacturing process, i.e. the step that if slowed down will slow down or limit the whole process. This means that if you do not have enough L-methylfolate -whether from chronic deficiency in your diet or the presence of an active MTHFR gene mutation- you may be unable to synthesise adequate amounts of serotonin, dopamine and its derivative norepinephrine[x].
Inadequate intake of dietary folate or the MTHFR gene mutation ->
Lack of L-methylfolate ->
inadequate production of the cofactor biopterin (BH4) needed for the rate-limiting enzymes tryptophan hydroxylase and tyrosine hydroxylase to work ->
inadequate production of the neurotransmitters serotonin, dopamine and its derivative norepinephrine.)
The manufacturing of serotonin and dopamine also requires adequate levels of B6, as far as I’m aware no gene mutation has yet been identified blocking the metabolism of B6 in the same way that the MTHFR gene mutation blocks the metabolism of L-methylfolate; however I have often observed in some patients supplementing relatively high doses of the biologically active forms of B6 (pyridoxal-5-phosphate) to have a significant antidepressant effect whereas supplementing L-methylfolate makes no discernible difference, which just goes to show how different we can be and is the reason I always advocate personal experimentation to work out an individual prescription.
2) There’s a second way that a lack of L-methylfolate may decrease the production of serotonin and dopamine. You might already be familiar with the supplement SAMe that can be purchased and taken as a fast a natural antidepressant, SAMe is also naturally produced by our own cells, but only if we have adequate levels of L-methylfolate[xi].
Basically L-methylfolate breaks down homocysteine a chemical which every cell is continuously makings into the amino acid methionine which is needed to make SAMe and SAMe supplies the methyl groups required for the production of serotonin and dopamine.
L-methylfolate -> homocysteine -> methionine -> SAMe (methyl groups) -> serotonin, dopamine and norepinephrine.)
So there are 2 independent ways that lack L-methylfolate diminish neurotransmitter production, firstly you need-methylfolate to make the cofactor BH4 needed for the enzymes that manufacture serotonin and dopamine to work; secondly without L-methylfolate your brain will not be able to make enough of the SAMe needed to donate methyl groups to change the amino acids into neurotransmitters.
3) A third possible way that a lack of L-methylfolate may contribute to mental health problems is from the buildup of homocysteine. Elevated homocysteine has definitely been associated with an increased incidence of depression[xii], this has been dubbed the homocysteine hypothesis of depression[xiii], elevated homocysteine has also been associated with bipolar syndrome[xiv]. Research in 2013 connected high levels of homocysteine with acceleration degeneration of the brain, cognitive decline and Alzheimer’s disease.
It used to be thought that elevated homocysteine caused inflammation and heart disease however several studies have shown that lowering homocysteine does not reduce other signs of inflammation[xv] and therefore it seems that elevated homocysteine is something that occurs alongside inflammation rather than something that actually causes inflammation[xvi], you could say if inflammation is fire homocysteine is just the smoke and blowing the smoke away doesn’t put out the fire. You’ll still see lots of websites still suggesting that homocysteine causes inflammation, I used to say to myself, but since 2000 this has looked progressively incorrect and people need to keep their knowledge and websites up to date! So if lowering does not effectively extinguish chronic inflammation what does? Besides the things discussed elsewhere that you should eliminate because they provoke chronic inflammation you can increase the production of glutathione which is one of the brains primary antioxidants by supplementing NAC cysteine and ensuring you brain has enough ethyl groups from L-methylfolate which are also needed for glutathione production. Especially prepared Curcunim from turmeric with improved absorption is also an effective anti-inflammatory.
There is however some evidence that elevated homocysteine causes free radical like oxidative damage in the brain[xvii] and I suspect this does indeed contribute to the degeneration observed in the brains of people with depression and bipolar syndrome. As already mentioned preventing and reversing this degeneration is a central goal of overcoming mental illness using functional medicine. See Beyond Neurotransmitters Making the Brain Healthy.
Summary of MTHFR Gene MutationIn simple terms you need the biologically active form of folate (L-methylfolate) to make neurotransmitters, prevent depression and maintain mental health; people with the MTHFR gene mutation cannot make enough L-methylfolate so they essentially end up with folate deficiency diseases even if they eat well or take regular vitamin supplements, folate deficiency can have widespread negative health consequences particularly for mental health. The severity of the mutation and therefore deficiency can range from mild to severe.
To recover from a mental health problem and maintain wellness it’s important to be able to provide enough methyl molecules from L-methylfolate, B12 and B6. If you have depression or bipolar syndrome especially if your condition has turned out to be resistant to treatment you should explore the possibility that lack of methylation in your brain is part of your problem, later on I’ll discuss whether or not you need to have the genetic test in order to work this out?
Under-Methylation may be a cause of widespread Health ProblemsResearch is contradictory and I’ll update this page as the situation becomes clearer however under-methylation and elevated homocysteine may be involved in contributing to widespread health problems including an increased risk of coronary artery disease, venous thrombosis, strokes, type II diabetes, Alzheimer’s disease, recurrent miscarriage, stillbirth, neural tube defects and autism spectrum disorders; this site is focused on the treatment of mental health disorders so I won’t go into these conditions in any more detail.
The main known causes of under-methylation and elevated homocysteine are dietary deficiency of vitamin B12, B6, folate or an inbuilt inability to manufacture L-methylfolate due to the MTHFR gene mutation.
Choosing the Right Folate SupplementsBad Folic Acid vs. Good L-Methylfolate
The vitamin folate comes in several different formats:
Folic acid is a man-made synthetic form of the vitamin, folic acid is the form of folate almost always used in vitamin supplements, it’s also added to most mass produced flours to produce so called fortifed foods, if you have the MTHFR gene mutation you can’t process folic acid, in fact if you consume too much folic acid from supplements and flour based products (breads, pasta etc.) you may end up with unhealthy high levels of folic acid which may congest and diminish your body’s ability to process the natural folate that occurs in vegetables and therefore make your depression even worse!
Fortified flower with folic acid has no doubt helped prevent many poor people around the would suffer folate deficiency, but we want to improve on general government one size fits all health policy and work out if consuming folic acid is helpful or a harmful thing for your individual mental health problem. The internet is awash with claims and counter claims that too much folic acid may increase the risk of cancer, particularly breast cancer. For people that don’t take high doses of folic acid from supplements but only consume folic acid in fortified foods I think the evidence is clear that fortified foods do not increase overall mortality[xviii], when one looks at only breast cancer some studies found a link and some didn’t, but other studies however found reduced mortality from heart disease and all causes mortality was not increased.
My suggestions are:
1) avoid fortified flour and
2) choose supplements that use L-methylfolate instead of folic acid. With these two simple steps you avoid excess folic acid. Or alternatively
3) have an MTHFR gene mutation test to gain a greater understanding of your ability to process folic acid.
The concern with increased risk of cancer only applies to synthetic folic acid, indeed another form of folate called folinic acid shows promise as a preventative and supportive remedies during cancer treatment.
Folinic acid also called calcium folinate is a form of folate you can buy as a supplement, it does not cross the blood brain barrier and act as an antidepressant unless it’s converted into L-methylfolate, however it’s worth mentioning because it has been tested and shown to be an helpful adjunctive supplement for cancer therapy[xix], it may also possess cancer protective properties particularly for bowel cancer, if this condition was a particular concern of mine I would definitely supplement folinic acid 800 µg once or twice a day on a daily basis.
Our body turns all the other forms of folate into L-methylfolate, it’s the biologically active form of folate our body actually uses to make neurotransmitters and do the other things we need folate for.
As you can see from the diagram the MTHFR gene is needed to convert all the other forms of folate into the usable form L-methylfolate or 5-MTHFR which can pass the blood-brain barrier.
About 70% of the folate naturally occurring in vegetables like broccoli is in the form called dihydrofolate (6(S)-5-MTHF) which requires less conversion turn into l-methylfolate than synthetic folic acid; the rest may come in a format that may presents a problem for people with the most severe form of the gene mutation. In these severe cases even vegetables should only be consumed in moderation to avoid overloading their metabolism with a type of folate that they cannot metabolise and they will also need to take large doses of L-methylfolate to compensate for the limitations of their metabolism.
Have you noticed methyl in the name methylfolate? This is the methyl molecule or group that folate donates to the process of making neurotransmitters.
Obtaining the Right Types of Methylfolate SupplementJust to make things even more complicated L-methylfolate comes in different formats itself and because they do not all work as well as each other you need to pick the right format.
Sometimes the name methylfolate is replaced with MTHF, methylfolate calcium,-5-methylfolate or methyltetrahydrofolate.
Choose supplements with the letters L or 6(S) in the name, for example the following are good formats to use:-
i.e. L-methylfolate, L-methyltetrahydrofolate, L-MTHF, L-methylfolate calcium.
L-5- forms: L-5-methylfolate.
The following named formats are also good formats to use:-
Deplin Thisis a high dose prescription form of methylfolate you could ask your doctor to prescribe alongside your antidepressants to increase and enhance their effectiveness.
You can also buy the equivalent high dose Deplin (7.5 or 15 mg) from the www.methylpro.com and www.methyl-life.com
Avoid supplements with the letters D or 6(R) in the name for example the following supplements are not good formats:-
If you don’t see the letter L or 6(S) in the name you can’t be sure exactly what you’re getting so always choose supplements that state L or 6(S); exceptions to this are Metafolin, Levomefolic Acid, Quatrefolic and Deplin which are good supplements.
Recommended brands include: Life Extension Optimised Folate (available at a good price from www.iherb.com), Seeking Health, Jarrow, Solgar folate and for a high dose (7.5 or 15 mg) use MethylPro.
In the long run you may want to take a multi-vitamin/mineral formula or a multi-B complex that uses the bioavailable L-methylfolate form instead of folic acid; so far only a few manufacturers have started to produce such products. A good multi-vitamin mineral containing the ideal form of folate I take myself is:
Doctor's Best, Best Multiple, Fully Optimized Vitamin-Mineral Complex. This is the only brand I can find that does not include the trace mineral vanadium which is helpful for stabilising blood sugar and may be OK to take for people with unipolar depression but should be avoided by people with bipolar syndrome, see vanadium toxicity and bipolar syndrome.
For a B complex I recommend:
Jarrow Formulas, B-Right.
You can buy all of these products at www.iherb.com and if you use the discount code HUK817 you can get $10 off your first order.
In the UK the only brand I can find using L-methylfolate is Thorn Research.
Testing for the MTHFR Gene Mutation
The MTHFR gene mutation is not a simple on/off switch, there are several versions of the mutation with varying degrees of inability to produce L-methylfolate; in the mildest version just eating well and modest supplementing with the biologically active L-methylfolate may be sufficient to work around the problem, however in the more severe versions of the gene mutation not only will high doses of L-methylfolate be required to restore and maintain health but consuming the wrong type of folate (folic acid) could actually make your health worse. If your body only has a very limited capacity to process naturally occurring folate from food into L-methylfolate what you don’t want to do is flood your system with synthetic folic acid which is the least bioactive form and ‘congest’ your limited metabolic pathways.
Epigenetics and EpistasisAnother thing you should understand is the very real limitations of our current understanding of how these gene mutations actually affect us. As already mentioned the MTHFR gene mutation is not a simple on/off switch, genetics is often far more complex than a single gene switches on or switches off a particular effect in the body, genes often work together so you may have a gene that switches something on then another modifier gene that switches the original gene off again. This type of interaction between genes is called epistasis and the subject of much research.
In addition to genes interacting with each other they also interact with outside influences in our environment such as your diet, exposure to toxins, exposure to stress, the quality of the nutrition a mother consumes during pregnancy has also been shown to influence the expression of the genes of her children and even her grandchildren. This is called epigenetics, in practice it means that simply having the gene for a particular thing does not necessarily mean you will develop that particular thing, for example you may carry the genes that encode for the development of breast or prostate cancer but the lifestyle and diet you lead influence these genes so that they are never expressed and you do not develop breast or prostate cancer.
[A request for help do you know whether a lack of methylation from the presence of the MTHFR gene mutation has been shown to have a significant effect on DNA methylation and if it does affect DNA methylation does this significantly increases the expression of genetic diseases; and if so would folic acid be a toxic or negative epigenetic influence for people with the MTHFR gene mutation because it diminishes methylation and L-methylfolate be a beneficial epigenetic influence because it increases methylation? What are the long-term epigenetic consequences of having the MTHFR gene mutation and lack of L-methylfolate during pregnancy on the future health of the child? I’d love to hear from you.]
Is It Worth Testing for the MTHFR Gene Mutation?So because of epistasis and epigenetic influences an MTHFR genetic test is not going to give you an absolutely clear-cut black or white understanding of the involvement of folate-dependent methylation in your mental health problem; at best it can indicate a possible involvement and suggest it would definitely be worthwhile trying some personal experimentation with L-methylfolate. Even if you do need to supplement L-methylfolate different people with the same level of gene mutation can respond very differently to supplements so you’re still going to have to conduct your own personal real-world testing to find the right combination of methylation supplements to treat your condition. This is so often the case and the reason why I do not use many medical tests in my practice.
There aren’t that many good things about mental illness but one of them is that you can tell for yourself if the treatment is helping or not, in contrast to conditions like say hypertension or high cholesterol which you cannot feel changing and have to rely upon medical tests to determine if the treatment is working. As soon as someone invents a medical test that can tell me what to prescribe a patient with depression, anxiety or bipolar syndrome more accurately and reliably than I can work out by taking a good case history I’ll use it, but until then I believe basing the initial prescription on the presenting symptoms then conducting personal experimentation is an effective medical methodology. For variable conditions such as rapid cycling bipolar syndrome or variable anxiety I argue real-world testing is by far superior to any lab tests because it has the advantage of developing one’s intuitive understanding of how to use the remedies and be in control of your daily prescription.
So instead of having the MTHFR gene mutation test you could simply buy some L-methylfolate, B6, methylcobalamin (B12) and TMG and supplement them at a high dose for a few months whilst at the same time avoiding all forms of folic acid and see how it affects your mental health, see below for the full prescription. After a few months on such a regime you should be able to tell if lack of methylation is involved in your problem, if you do feel better try lowering the doses of the various remedies to find minimum required dose to maintain the improvement, thereafter you could continue at a dose a bit above the minimum.
If you’re not on a budget, or if you like having tests or if you’re just starting out in your treatment and have never taken any supplements before it’s probably worth testing for the MTHFR gene mutation to gain information, you could even start doing your real-world personal treatment trial while you’re waiting for the results.
In summary I believe if you have a chronic mental health problem you should test the possibility that lack of folate and methylation is contributing to your problem, however I believe that having the MTHFR gene mutation test is optional and in the end you’re still going to have to conduct a personal treatment trial by taking the treatment protocol and seeing how it affects you.
However if you’re concerned with preventing cognitive decline or miscarriages or just planning on getting pregnant on the other hand I would recommend having the gene test to determine if lack of L-methylfolate production is something you suffer from.
The purpose of my website is to provide information about effective solutions for mental health problems, I’m not in the business of selling genetic tests and thus far I’m not completely convinced of the superior usefulness of having this particular test over simply conducting personal treatment trial, but please write to me if you know of good reason why having the MTHFR gene mutation test provides information that you could not work out and change my mind.
Having said that I understand that some people feel reassured by scientific tests and I can see that it contributes some information and if you want to have the MTHFR gene mutation test I can organise it for you.
MTHFR Test CostsIn the US and Australia I’ve seen saliva and mouth swab test available for about $100, In the UK you can now have your DNA tested using a saliva test kit via the post for £125 from 23andme (23 and me). The test often only provides you with raw data (a file of meaningless numbers) and you to need to put the raw data through a program to convert it into something that you can read and interpret. Getting the raw data converted into something useful is not difficult however you will need to be fairly confident with downloading and using computer programs, but it can be done for free.
Since you can now purchase and obtain a DNA test for yourself in the UK I no longer organise them through my clinic.
Once you have obtained your results however if you want assistance interpreting the results and developing a personal treatment protocol you can consult with me either at my London clinic or via my Skype coaching service, see bookings and fees.
The MTHFR gene mutation comes in Different FormsThe most common mutations occur on the C677 and A1298C positions of the gene.
Having one mutation in either position is called heterozygous.
Having two mutations (one from each parent) in either position is called homozygous.
If you are homozygous MTHFR C677TT (i.e. 2 mutations in the C677 position) your ability to manufacture L-methylfolate is probably reduced to less than 30%.
Having a mutation in both positions i.e. one mutation in the 677 position and another one in the 1298 position is called compound heterozygous.
So one mutation is heterozygous, 2 mutations in the same position is homozygous and a single mutations in each position is called compound heterozygous.
Having more than 2 mutations i.e. 2 mutations in one position and another mutation in the other position or even 2 mutations in both positions is almost unheard of.
Your test results may be written in the following format:
MTHFR 677 CC = no mutation
MTHFR 677 CT = 1 mutation i.e. 677 heterozygous
MTHFR 677 TT = 2 mutations i.e. 677 homozygous
MTHFR 1298 AA = no mutation
MTHFR 1298 AC = 1 mutation i.e. 1298 heterozygous
MTHFR 1298 CC = 2 mutations i.e. 1298 homozygous
MTHFR 677 CT + MTHFR 1298AC = 2 mutations one in each position i.e. compound heterozygous.
Interpreting Your ResultsSome people claim about 30% of the population are heterozygous (i.e. one mutant gene) which causes a 30% inability to process folic acid and 12% of the population are homozygous (i.e. two mutant genes) which causes a 70% inability, however I don’t think we can be that precise yet and I’ve found such conflicting information about the significance of the MTHFR gene mutations that I’m not going to provide any specific claims myself, what I suggest is if you have a persistent mental health problem and any level of this gene mutation you conduct an individual treatment trial by applying the full treatment protocol and see what happens.
Treatment Protocol to
If you’ve been living with a lack of methylation in your system for some time whatever the cause it’s possible that when you first start supplementing methylfolate and other methyl donors (B6, B12, choline, TMG) you may experience what is called a healing crisis i.e. an initial worsening of your symptoms. Imagine there being a backlog of all the processes in the body that require L-methylfolate in every cell of the body and this backlog suddenly getting cleared en masse, the result can sometimes be a toxic sick feeling. If this happens to you simply stop or reduce the prescription for a few days and allow the symptoms to subside before restarting the protocol.
Compensate for the MTHFR Gene Mutation
Diet for MTHFR Gene MutationYou must avoid flour and flour products unless you can be sure that they were made with flour that was not fortified with synthetic folic acid, you can for example continue to eat rice or source and fortified flour and make your own flour based products.
Unless you have the stronger versions of the mutation (heterozygous i.e. 2 mutations in the 677 position or compound heterozygous i.e. one in each position) it’s healthy for you to eat a high vegetable diet which not only supplies natural folate but also an abundance of fibre, potassium and antioxidants. However it’s possible with the stronger versions of the mutation that a high vegetable diet may overload your system with types of folate other than L-methylfolate and be a problem. I do not believe there is a hard and fast rule about this and you should combine personal experimentation and monitoring of your homocysteine levels to work out your optimum health regime.
Supplements for MTHFR Gene MutationL-Methylfolate (one of the good formats see above)
Start with 400-800 mcg just for the first few days just to gently clear that some of the backlogged undermethylation and test your system to see if you’re super sensitive to this supplement. If you are okay on this dose and most people are I would suggest going up to 5 mg a day for a week, if you tolerate this taking 10 mg a day the next week and if you tolerate this taking the maximum dose which is 15 mg a day thereafter for 3 months. By the end of 3 months on the maximum dose -and probably much sooner- you should be able to tell L-methylfolate is beneficial for your mental health problem, if after 3 months you feel no benefit I would give up treatment and move onto something else.
Continue taking 15 mg a day as long as you feel it is continuing to improve your condition, once you feel the benefits either plateauing or you are completely well you can consider reducing the dosage to try to find the maintenance dose which you need to continue taking long-term to maintain wellness; you may for example find that you only need somewhere between 2.5 to 7.5 mg a day on an ongoing basis.
Divide your daily dose into 2 half with breakfast and half with dinner.
PLEASE NOTE: Folate is a water-soluble vitamin and the likelihood of producing a toxic effect is considered to be every low, however a dose over 1.5 mg is considered to be a high dose so 15 mg is an exceptionally high dose, I would always recommend working with a suitably qualified medical professional experienced in using nutritional supplements before consuming such high doses. The only notable contraindications to taking high doses of folate are that it can mask the existence of B12 deficiency, so in theory if you took a high dose folate and were deficient of B12 no one would be able to work out what was going wrong with your health; but then on this protocol you’re going to be supplementing B12 anyway. Also supplementing folic acid can increase the mortality of children under 5 with malaria, I don’t notice also applies to L-methylfolate but I just thought I’d mention it.
B6, B12, SAMe and TMG also Methylate and Lower HomocysteineIn addition to taking L-methylfolate you should take the following supplements because as you can see from the diagrams folate metabolism is just one part of an interconnected chain of metabolic cycles and processes which require other key methyl donating nutrients such as B6 and B12.
Vitamin B6 is a another important vitamin involved in relaying methyl groups through our metabolism. There’s little scientific evidence that B6 is involved in mental health problems however my personal and clinical observations are that it is a helpful antidepressant remedy for some people. B6 comes in different formats the most useful is pyridoxyl 5 phosphate (P-5-P)
P-5-P: 100 to 200 mg, this could be taken as part of a multi-B complex.
Vitamin B12: 1000 to 5000 mcg. B12 must be in the form of methylcobalamin not cyanocobalamin. B12 is very poorly absorbed from the intestines and to obtain a high therapeutic dosage you need to bypass the intestines, there are several ways to do this including injections and transdermal patches (i.e. through the skin)or under the tongue as a sub-lingual lozenge which is cheap and available. To get this method to work you need to hold a crushed sublingual lozenge under the tongue for several minutes once a day. A really cool trick is to give yourself a dose of bright light therapy using one of the modern blue LED devices at the same time as you hold B12 under the tongue, research in Japan showed that this combination significantly increases the rate at which your pineal gland produces melatonin later in the day after dark to give you a better sleep. See my book Sleep Better with Natural Therapies for more details. Research has been unable to establish a toxic dose for B12 meaning to say it’s basically totally non-poisonous, so take as much as you want for as long as you want, try to establish the dosage that gives you could energy.
SAMe is a molecule the body naturally makes but can also be bought and taken as a supplement. SAMe is a well-researched, effective and very fast acting antidepressant, it’s believed it increases the production of serotonin and dopamine, SAMe is also an effective anti-inflammatory useful for a wide range of therapeutic effects including inflammation in the brain, liver, cardiovascular system and joints. There are however some problems with SAMe, firstly it's quite expensive, secondly it can cause stomach ache and thirdly like all antidepressants it can potentially cause mania in people with bipolar syndrome. This last effect does not preclude its use as a remedy for bipolar depression and I often prescribe it, but only when adequate anti-mania counter measures have been put in place and thoroughly practised. See Managing Mania.
Another crucial thing to understand about SAMe is that for it to work properly and process methyl molecules we must have adequate levels of B12 (methylcobalamin), B6 and methylfolate, without adequate levels of these vitamins SAMe will actually end up producing more homocysteine and inflammation; to prevent this happening and get SAMe to work as a helpful medicine is easy, all you have to do is combine it with B12 B6 and methylfolate or folic acid if you don’t have the MTHFR gene mutation.
TMG Trimethylglycine was originally called betaine it’s a naturally occurring compound that we both obtain from plant foods in our diet and manufacture in our body. TMG is a significant general methyl donator and can be used to lower homocysteine, detoxify the liver especially for fatty liver and excessive alcohol consumption, it also has useful antidepressant effects. The latter is probably because TMG increases the production of SAMe a powerful natural antidepressant.
TMG also tends to have a significant relaxing effect on the autonomic nervous system, it tends to produce a very calming and sedating antidepressant effect as opposed to SAMe which tends to be a rather stimulating and energising antidepressant, making TMG a safer option for people with bipolar depression.
As you can see in the diagram right TMG breaks down homocysteine to produce SAMe via an alternative route to the L-methylfolate pathway and is therefore an effective work around for the MTHFR gene mutation in this regard, however it does not assists the body to make the cofactor BH4 needed for the enzymes that make serotonin and dopamine, so it’s not a complete fix for the MTHFR gene mutation; nevertheless I have regularly observed TMG to be a useful antidepressant.
It’s highly recommended you include TMG in your prescription at least for the first month or longer if you have poor liver function or a history of alcohol or drug abuse. Including TMG in the beginning of the treatment will help reduce detoxification healing reactions because it supports and enhances liver function.
Optional helpful remedies you could add to the above prescription:-Magnesium Citrate to supply 400 mg of magnesium twice a day divided between 2 meals.
Zinc 30 to 40 mg divided between meals.
Magnesium and zinc are often deficient in our diet and supplementing them assists general detoxification and regeneration.
Curcumin (e.g. Super Bio Curcumin from Life Extension) 1 capsule twice a day, or an equivalent highly absorbable form of curcumin as an additional supportive anti-inflammatory.
NAC cysteine 1200 mg once a day on an empty stomach as an anti-inflammatory, liver detoxifier, heavy-metal detoxifier and to increase the level of glutathione one of the brains primary anti-inflammatory free radical scavengers.
Include curcumin and NAC cysteine as anti-inflammatories when signs of inflammation are present or suspected.
Choline and Inositol 500-1500 mg of each. Choline is an additional methyl donor however it also assists liver function and detoxification as does inositol.
In the bipolar brain supplementing choline may have an anti-mania affect with the potential to worsen depression, inositol on the other hand may have an antidepressant effect with the potential to worsen mania, taking choline and inositol together seems to balance these two opposing effects however you should understand the potential effect of these remedies before supplementing them. In my medicine cabinet I have separate choline and inositol which is occasionally to assist me keep my rapid cycling bipolar syndrome under control. See Lecithin and Choline for Bipolar Mania, and the Inositol Theory of Bipolar Syndrome .
Add choline/inositol, NAC cysteine, magnesium with TMG when you want to focus on enhancing liver function and detoxification as part of your MTHFR treatment protocol.
If you have unipolar depression and want to supplement choline to assist liver detoxification, omega-3 oil transportation to the brain and the production of acetylcholine to improve cognitive function always combine it with antidepressant inositol for balance.
How Do You Know Which Remedies Working?It’s true that if you take all the above remedies together at the same time you don’t know if it’s just one of them that’s working and which one, but they all work together synergistically to produce a more powerful effect and in the beginning all that matters is getting a result. Gradually over time you can experiment and work out if one of the remedies is all you need, it’s also possible that it is not just one individual remedy but a combination that rebalances your brain chemistry. It perplexes me when I meet a patient that is reluctant to take so many remedies because they’re worried about not knowing which one worked, my thinking is that this stage let’s just worry about getting a result, we can worry about working out a minimum maintenance programme later on.
My Personal Experience with Methylating SupplementsUsing myself as an example I have not had the MTHFR gene mutation test, although I probably will just for the sake of experimentation; the reason I’m not rushing out to have the test is because I already tested the effects of all the methyl donating remedies mentioned on this page on my own bipolar syndrome years before I even heard of the MTHFR gene. I know for example that taking high doses of folic acid does not make me feel worse and that taking high doses of L-methylfolate has no noticeable impact on my condition; B6 on the other hand has an enormous antidepressant and antianxiety effect on me and is a key component of my daily prescription, B12 (methylcobalamin) has a mild antidepressant effect on me but noticeably increases my physical energy and improves my sleep, SAMe has powerful antidepressant effects so much so it can flip me into mania and when I used TMG during a prolonged depression and found that it soothed the pain of the depression but was very sedating, which at that time was a benefit because I was actively suicidal. So in a sense I’ve already worked out how all the major methyl donating and conveying remedies affect my mental health, what will an MTHFR gene mutation test tell me I don’t already know?
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Be WellToday I primarily use nutritional medicine, cognitive hypnotherapy, NLP and Bicom therapy to treat mental, digestive and functional health problems like chronic fatigue and IBS.
I have extensive experience (both professional and personal) and several forthcoming books in nutritional approaches to balancing brain chemistry treating depression, bipolar syndrome and anxiety. You’ll be able to read the most of the contents of these books for free on my balancing brain chemistry site.
In 2013 I published my first book Sleep Better with Natural Therapies
I practice at the Hale Clinic (central London) as a holistic medical practitioner and have been in practice since 1988.
Over the years I’ve trained in Nutritional /naturopathic medicine, Cognitive Hypnotherapy and NLP, body-centred psychotherapy, Chinese herbal medicine, Acupuncture, Bicom resonance therapy, meditation and Kundalini yoga.
Today combine the above techniques for a mind-body approach to health. I see clients for mental health problems (depression, bipolar syndrome, anxiety, drug addiction), digestive health (IBS, bloating, candida, constipation), chronic fatigue, imbalances in blood sugar, high cholesterol, high blood pressure, migraines.
For a more information on my practice and a list of conditions I treat click here About My Practice
For bookings call the Hale Clinic reception© Please feel free to download or print my work for personal use, I wrote it to help people. You can copy and distribute my work on your web pages and in literature but please give me credit for the fruits of my labour and don’t turn yourself into a plagiarist. When you copy my work please indicate where you got the information from (e.g. from or according to the website balancingbrainchemistry “…”) and include a reference/link to my name and the website or book you used. [#22]
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020 7631 0156
Mobile 07941 331 329
My other site:
© PeterSmithUK.com –Holistic Medicine Consultant-