Folate and BH4 Cycle111_CROPPED



Many people who are looking at their genetics are often motivated by the problem of depression.  Of course like many common health problems depression is now a big business in our society.  Pharmaceutical companies rake in billions of dollars producing drugs to try and treat this problem.  Unfortunately in the vast majority of cases the drug approach to depression simply masks the underlying causes.  As you will find in this post and the articles to follow, there are many different causes for us to experience depression.  In this video post I point out one very common cause of depression – a BH4 deficiency.  Many people are now aware that methylation support improves mood and effectively treats depression – the research has been clear on this for some time.  Yet few are aware that the reason methylation support is effective for treating depression is that folate increases levels of BH4 – the cofactor we all need to produce dopamine and serotonin.  So buckle up because you are about to learn how important BH4 is for treating and beating depression naturally.

Depression is not a Drug Deficiency

I often remind my patients that we aren’t depressed because of a drug deficiency.  We become depressed because that is a symptom of a brain that isn’t working correctly.  In fact, modern neurology and brain research now refers to depression as simply a brain that is not able to activate fast enough.  We now have functional MRI studies that compare healthy brain scans to depressed brain scans.  The obvious finding is that people with depression simply have a brain which is unable to activate fast enough.  Based on that we can say that depression is a slowed down neurological system.  The speed of the brain and nervous system is depressed, thus making us feel depressed.

I like to point out this definition of depression because we still live in a world where depression is a bit of a stigma and not everyone is willing to talk about it.  Once we realize the definition of depression is nothing other than a slowed down brain, then we can begin to learn what steps are necessary to speed the brain up.  And nothing is more effective at speeding up our brain than the methylation cycle and MTHFR-related genetic pathways.  To illustrate how powerful methylation-related treatment can be, listen to what my patient Sharon recently experienced:

Sharon contacted my office because she had seen our YouTube videos about gut health, methylation and optimzing genes.  She herself was in a decades-long battle with depression that didn’t let up no matter what.  Sharon already was doing many healthy things like yoga, organic eating, saunas, and more.  She was very confused why her depression wouldn’t lift and why she has required medication for her neurotransmitters year after year.  During our first consultation I explained to her that despite her best efforts and the effects of her medication that she simply didn’t have enough serotonin in her brain.  I shared with her how her MTHFR genes and related genetic imbalances were making it difficult for her body to provide the raw material her brain needed.  We also discussed how the gut supports brain function and that any imbalances of yeast or bacteria will be an obstacle to her recovery. We ended that conversation with a plan to have her perform an organic acid test and start a 10-day 4R gut repair program while we wait for the results.

Two weeks later we spoke again and she said she felt a little less depressed and her digestion was improving and her sinuses were clearing.  Reviewing the organic acid test together I showed her that our assumptions were spot on and that she was showing very low serotonin in her urine.  Sharon was pleased and expressed her excitement that finally she had evidence for why her depression was so persistent.  I explained to her that a lack of serotonin cannot be fixed by drugs because they don’t treat the cause of the problem.  Instead what she needed was to replace the vitamins, amino acids and cofactors her body needed to make serotonin all by itself.  The body wasn’t broken, it was just depleted.  Sharon agreed and started a targeted protocol to increase tryptophan, 5-HTP, and support MTHFR pathways with B9, B12 and B6.

We gave her four weeks to work with the serotonin support and then we reconnected with her.  Sharon’s face was beaming as she proudly shared with us that for the first time in over a decade she no longer needed to take her medication.  She was better than she had felt in years with her energy back and a renewed sense of focus and positive energy about life.  Last time we spoke Sharon concluded that she felt so good on the vitamins and supplements that she is planning on staying on them for the forseeable future.  I told her that makes perfect sense and that by supporting her methylation cycle and providing the serotonin precursors that depression would be a thing of her past.

One of the beautiful things about studying methylation and epigenetics is that is can accurately explain why things happen.  Methylation helps to explain not just why cancer and heart disease is common in certain families, but also why depression is a common finding as well.  The issue with depression and MTHFR has to do with biochemistry and the production of co-factors.  If you remember from biochemistry class, co-factors are ingredients that are required for certain chemical reactions to take place.  We couldn’t build a wooden house without screws or nails, because these are the co-factors necessary to hold the wood structure in place.  It is the same with our own biochemistry.  We cannot produce neurotransmitters which speed up our brain and cure depression without co-factors from the methylation cycle.

Folate and BH4

When we look at the methylation cycle its clear that optimum methylation is required to produce neurotransmitters like serotonin and dopamine.  But we cannot just focus on supplements and skip the diet part of the equation.  I published an article about how diet influences dopamine and adrenalin levels back in 2014.  That article lays out the scientific rational for why balancing blood sugar produces a more steady supply of neurotransmitters, reducing feelings of depression naturally.  For a review of that concept I suggest you follow the link above to the article and video on that topic.  As far as the BH4 and folate relationship goes, please see the chart below for a graphical representation of how folate and BH4 work together.

Folate and BH4 Cycle111

The reason that methylation support, esp. activated folate a.k.a. 5MTHF, is so important for depression is due to the fact that these vitamins increase BH4 levels.  Whether the folate comes from our diet or from our gut (remember gut bugs produce folate) doesn’t matter; the fact is that vitamin B9 is the vitamin required to recycle and increase BH4 levels.  Most of the BH4 in our body comes from the methylation cycle where a folate molecule is used to turn BH2 into BH4.  The methylation of BH2 into BH4 provides the co-factor necessary to turn tryptophan and tyrosine into their respective neurotransmitters serotonin and dopamine.  In this way the methylation cycle helps our brain manufacture serotonin.  Looking at the methylation cycle this way we can say it helps eliminate depression because it allows more BH4 to be produced which increases neurotransmitters, esp. serotonin.

The more BH4 we make the more our brain is able to convert tryptophan into serotonin.  And we want that because more serotonin means less depression!  Now there is more to it than this one reaction, but this is the real reason why MTHFR genes impact depression so much.  Studies show consistently that people who are born with MTHFR C677T genes experience a much higher risk of depression.  The science is very clear that MTHFR genes are a risk factor for depression, increasing risk of depression by a whopping 500%!  But what isn’t as well understood is how that process happens and what we can do to fix it.  And that is why this article is helpful.  For a good visual on how BH4, BH2 and folate levels are related, take a look at the slide below.

BH4 and Folate Cycle1

Because BH4 levels are the required co-factors to produce serotonin and dopamine and prevent depression, anything that lowers our BH4 levels will increase our risk of depression.  MTHFR genes like C677T and A1298C are a big problem because they reduce the amount of folate available and active within our cells.  Without a strong MTHFR system in our cells, we cannot activate folic acid and other folate molecules into the form of B9 our body needs – MTHF.  This leads to a folate deficiency which can impact all areas of our body and esp. our brain.  As the body struggles to activate folate through the slowed down MTHFR pathways, we produce less BH4 as less vitamin B9 is available in our cells.  Since most of our BH4 is produced by recycling BH2, the bottom line is that without folate we just don’t make much serotonin or dopamine.

Science has known this for some time but only now are people learning about the power of the methylation cycle to influence how our brain feels.  I meet patients every week who are depressed, sleeping poorly, have low libido and chronic fatigue.  Some of these individuals are aware of the role MTHFR and methylation plays in their condition while others are not.  I explain to each patient that one of the main causes of their depression is they have a slowed down pathway and that we can bypass the blockage with activated nutrients.  We know that insulin and blood sugar are key players for healthy brain balance, but so too is adequate methylation support for anyone who is dealing with depression.

Methylation Support in Depression

In order to overcome depression, one must figure out which neurotransmitters are in excess and which are deficient.  In in my office, over 95% of the time, individuals are low in serotonin and relatively high in dopamine.  The research into brain chemistry has proven that low serotonin is a predictable cause of depression.  This is why drug companies use serotonin-reuptake inhibitors (SSRI’s) as their drug of choice to treat depression.  It is too bad that the modern medical answer is to use a drug, when in fact it is quite simple to fix this problem naturally.  Once you understand how your neurotransmitters are produced by the methylation cycle, one can easily select a natural supplement and make dietary changes to greatly improve neurotransmitter production.

I often hear the question about what is “enough” methylation support.  I don’t recommend extreme dosages like 7 or 15 mg per day of folate for most people. Too many times patients have told me how poorly they felt after taking high doses prescribed to them by practitioners who just look at genetic reports and nothing else.  The key with methylation is to give enough to saturate the pathways but not so much that there is a lot of extra, unused methylation vitamins lying around.  When that happens people tend to experience anxiety, insomnia, panic, worry and other kinds of symptoms.  For my patients I have found that mild dosages ranging from 1.6 mg to 5 mg per day is much more effective. Now remember my patients are also working heavily on their diet and lifestyle and most of them are also getting chiropractic care, massage and other treatments to improve their healing potential.  This full spectrum approach is very helpful in overcoming depression.


Recommended Supplementation to Support BH4 and Serotonin Levels:

Serosyn – If there was a natural alternative to an SSRI drug, this supplement would be it.  Providing amino acids, vitamins, and herbs in a synergistic formula to increase serotonin naturally, this product is a big help to individuals struggling with low serotonin and low melatonin levels.†

Vessel Care – My favorite methylation-specific supplement which has helped many patients overcome depression caused by low BH4.  Instead of taking dangerously high doses of folate by itself, better results are found by using all the other vitamins that work with tandem with folate – B2, B12, choline, and TMG.  Use 1-4 per day as needed to keep the production of serotonin and other neurotransmitters in an optimum range.†

UltraMeal Advanced Protein –Originally designed to prevent muscle loss in elderly individuals, this product provides a complete amino acid profile in a hypoallergic, non-GMO, and great tasting form.  Provides protein necessary to produce neurotransmitters as well as optimize muscle synthesis, gut health, brain function and more.†

UltraFlora Spectrum – Given that gut bacteria produce amino acids which help us make serotonin, we need to make sure our gut is populated with healthy gut bacteria.  This 7-strain probiotic is the best all-around formula I have seen and for long-term daily support.†

DHA:900 – Our brain is over 80% fat by weight and requires high levels of Omega 3 polyunsaturated fats to perform optimally.  DHA is the most difficult Omega 3 for our body to produce and it is also the main Omega 3 needed inside the white matter of our brain.  Depressed brains often have an imbalance of Omega 6 to Omega 3’s and benefit from daily support of high quality DHA.†


All supplements in this nutritional protocol can be purchased online through Dr. Rostenberg’s online pharmacy. Getting the supplements shipped to your door is very easy. Just follow the instructions below:

These supplements are available from our Metagenics web store and we extend a 20% discount plus free shipping to all new patients who order online. We also give you free shipping and 10% off all recurring orders. You will find our prices are competitive with other outlets.

Just click on “Create an Account” in the top right corner to get started. The practitioner code is RedMountain.

Metagenics batch tests every single raw ingredient. Meaning, they test every batch, every time before it is processed into a supplement. I’m not aware of any other company that puts that kind of expense and effort into product quality.


Even though the link between MTHFR genes and depression is complex, we can clearly see one reason we get depressed is from low BH4 levels.  Lack of folate causes low BH4 which causes low serotonin (and dopamine).  After reading the article above I think that all makes solid scientific sense.  However this just scratches the surface of the depression question.  There is more to the depression story that I will share with you in future posts.

In addition to what I have shared with you in this post, I have also been looking closely at how the immune system changes how much serotonin we produce.  The research on depression is incredible and strongly suggests that under any condition of stress – which we have an epidemic level of in our society – we are going to lose serotonin.  After studying this research for years and working with thousands of patients, it now appears to me that we are programmed to be depressed.  That statement may sound illogical or hard to believe, but I assure you the evidence is there.  I will share with you the latest cutting-edge scientific research on why our bodies are predisposed to have low serotonin when things get out of balance.  Depression, like all disease, has a specific cause and effect.  Continue to search, read and learn…and of course stay tuned for my upcoming posts on this most important subject!



For More Videos on Methylation and Brain Health I Recommend:

Leaky Gut, Leaky Brain: How Gut Problems Create Brain Problems

How Blood Sugar Influences Dopamine/Adrenalin Levels – COMT and MAO

A Genetic Cause of Pain and Anxiety – COMT, MAO and MTHFR


In Health,

Dr. Rostenberg

By studying the current peer-reviewed research, Dr. Rostenberg has discovered powerful, natural strategies to optimize gut  and methylation function to heal the body.  He can help you uncover the genetic or root causes of your health problem and find a natural solution!  If you would like help balancing your oxalate levels to improve your methylation cycle and reduce/eliminate your symptoms, please contact Dr. Rostenberg at Red Mountain Natural Medicine today. Phone 208-322-7755. Email Website

†This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.


  • May 9, 2016 Reply

    Carmen Domer

    Do you have any recommendations on doctors near Santa Rosa, CA or Sebastopol, CA? Thanks Carmen Domer

    • May 27, 2016 Reply


      Someone just made an appointment with a naturopathic physician in Santa Rosa, but I cannot get to her link right now! Her name is Dr. Grusecki! I heard she knows all about MTHFR and other genetic polymorphisms!

    • May 27, 2016 Reply


      Dr. Grusecki is a naturopath in Santa Rosa!

  • May 10, 2016 Reply


    Can these supplements be used with medications prescribed by the doctor

    • May 12, 2016 Reply


      Hi Andrea,

      You should always consult a physician regarding your medications and potential interactions. That said the only supplement that would be a potential issue is Serosyn. The other nutrients have no known interactions with anti-depressants, etc. If anti-depressants or MAO inhibitors are being taken, Serosyn should not be taken. Hope that helps!

      In Health,

      Dr. Rostenberg

  • May 10, 2016 Reply

    Lynn fick

    Would these suppliments help Parkinson s. I am scheduled for deep brain stimulation surgery June 2. I am still open to other options

  • May 10, 2016 Reply


    About the gut-brain connection … how many patients have you seen who have a headache the whole day, and 5 minutes after a toilet visit that’s all gone?

  • May 11, 2016 Reply


    Wondering if BH4 is tied up to detox NH3 when there is CBS up-regulation.

  • May 12, 2016 Reply

    mthfr gene mutation treatment

    This article helps everyone to understand something about MTHFR and Depression. It also clarifies many important underlying causes of depression and the link between MTHFR and depression.

  • May 22, 2016 Reply


    Hi! Do yoy know if Inositol it’s a mao inhibitor? THANKS

    • June 2, 2016 Reply


      Hi Beatriz,

      To my knowledge inositol is absolutely not an MAO inhibitor. Hope that helps.

      Dr. Rostenberg

      • June 18, 2016 Reply


        Thank you for taking the time to answer !

  • June 27, 2016 Reply


    Can you recommend a naturopath in the New Orleans, La area or Mississippi Gulf Coast area?

  • July 12, 2016 Reply


    I have had very severe and frequent headaches for about 12 years now (2004 to 2016). Quite a while ago, I was given the diagnosis of “Migraine with Aura.” I have used about 8+ different pharmaceutical drugs during the past 12 years; some of the drugs were used as a migraine preventive, and some of the drugs were used as a migraine abortive. Some of the drugs I have used are the following: bupropion (Wellbutrin SR) [preventive] {did not help me}; butorphanol nasal spray (Stadol NS) [abortive] {helped me the most among the abortive drugs, but I still had to “feel” the migraine, as is the case with any abortive drug}; divalproex (Depakote ER) [preventive] {helped the most among the preventive drugs, but I had to stop it right away, due to an interaction with other drugs I was taking}; topiramate (Topamax) [preventive] {did not help me, but is an excellent preventive drug for some people, just not me}; prochlorperazine (Compazine) [abortive] {helped me moderately well}; isometheptene/acetaminophen/dichloralphenazone combination drug (Midrin) [abortive] {helped me moderately well, but the pain relief did not last very long at all}; butalbital/aspirin/caffeine combination drug (Fiorinal) [abortive] {helped me a little, but not much}; metoclopramide (Reglan) [abortive] {helped me a little, but not much}; and a couple others. All of these drugs have helped me a little, but were unsatisfactory for some reason or another. I use and believe in dietary supplements to help us to live healthy and more-productive lives. Doctor, would you please point me in the right direction, so that I could find supplements that might help me with my “Migraine with Aura?” Thank you very much.

  • July 14, 2016 Reply


    Is it the same when in comes to anxiety? That MTHFR cause lack of folate and that lead to lack of BH4, and again lack of serotonin, and that can result in anxiety? Or is it like with the estrogen and MAO, that it is the oppersite in the case of anxiety vs. Depression?

    • July 18, 2016 Reply


      Hi Gitte,

      Thanks for your comment. MTHFR causes low BH4 which reduces the rate at which we make serotonin. Of course it can slow down dopamine production as well, but for many reasons which I will be explaining in a future post, we are much more likely to have low serotonin vs. dopamine. All these factors combine to make us feel anxious – low serotonin w/ high(er) dopamine will drive much of the feelings of anxiety we all experience. Hope that helps and stay tuned for the next post in August!

      In Health,

      Dr. Rostenberg

  • September 3, 2016 Reply


    You stated, “Whether the folate comes from our diet or from our gut (remember gut bugs produce folate) doesn’t matter…”

    I would challenge you to investigate this supposition further. What you might discover, could be game changing.

  • October 5, 2016 Reply


    Hi, you recommend taking the UltraMeal Advanced Protein.

    How would you respond to this statement –
    “…the body makes ammonia when it processes protein, and the BH4 pool is depleted when it detoxes that ammonia. Limiting dietary protein to the RDA is the most effective way to keep ammonia levels reasonable.”

    Thank you!!!

    • October 7, 2016 Reply


      Hi Claudia,

      Thanks for you comment! This is a good question and one that needs some clarification. It is true that all protein contains nitrogen, which when metabolized can become ammmonia. However, you must understand that most ammonia issues come from INSIDE the body, not the diet. Liver issues cause ammonia to elevate. Bacteria in the gut can also increase ammonia in the blood because they break down dietary protein and release the nitrogen into circulation. Those are the two most common causes of elevated ammonia. The third cause is created when the body goes into a catabolic state, when muscle tissue is broken down to supply the mitochondria and liver with amino acids. Yes, if you are protein deficient in your diet your ammonia goes UP inside your body because you start to eat your own muscles, ligaments, tendons, etc. and this raises ammonia. Can you eat too much protein? Of course you can, but that is RARELY the cause of increased ammonia. The causes of increased ammonia are in the following order – Catabolism (chronic stress), Liver and then Gut. Fix those and ammonia problems will usually resolve.

      Ultra Meal Advanced Protein is a fantastic product that helps people who have crappy digestion, poor stomach acid, and have lost muscle tissue due to chronic stress and disease. Muscle mass is the number one indicator of healthy aging, so anything that helps you build and maintain lean muscle mass is going to help you age well. Hope that helps!

      In Health,

      Dr. Rostenberg

Leave a Comment

Error: Please check your entries!