Tetrahydrobiopterin, also known as BH4, is essential for many body processes. It helps with the heart, brain, and the digestive and reproductive systems. Supplements can help prevent many disorders.

Introduction to Tetrahydrobiopterin (BH4)

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Tetrahydrobiopterin (BH4), also known as sapropterin (INN), plays a key role in a number of physiological processes. It is involved in the formation of neurotransmitters, heart, and endothelial dysfunction, the immune response, and pain sensitivity (R).

BH4 is essential for the action of several enzymes, including ones responsible for neurotransmitter synthesis, host defense, and formation of lipids (R).

BH4 helps in the biosynthesis of the neurotransmitters serotonin, melatonin,dopamine, norepinephrine, epinephrine, and is important for the production of nitric oxide (NO).

A large body of evidence implicates a reduction in vascular BH4 bioavailability as a central mechanism for the development of impaired NO-mediated microvascular function in a wide variety of conditions, including diabetes, hypertension, hypercholesterolemia, atherosclerosis, and aging (R).

Tetrahydrobiopterin has clinical trials on autism, ADHD, hypertension, endothelial dysfunction, and chronic kidney disease (R).

The aforementioned disorders also are associated with elevated vascular oxidative stress, and BH4 is particularly susceptible to oxidation by peroxynitrite (ONOO), a reactive oxygen species byproduct of the NO and superoxide anion (O2·−) reaction (R).

Oxidation of BH4results in promoting the transfer of electrons to molecular oxygen resulting in the production of Superoxide rather than Nitric Oxide (R).

One hypothesis is that exogenously administered BH4 is oxidized rapidly to BH2  upon entering circulation, diffuses into the cell as BH2, and then is recycled back to BH4 via the “salvage” pathway enzyme DHFR (R).

My Experience With BH4 One That I Recommend

BH4 puts me in a Zen state that can be characterized as a calm/relaxed alertness. It certainly has mood boosting properties and I enjoy taking it.  Since I don’t have any condition that is benefited by it and I don’t have anxiety or depression, the benefits to me are small.  Since it is expensive, it’s not a regular tool in my arsenal, but it’s a good product to try to see how it makes you feel.

Health Benefits of Tetrahydrobiopterin

1) BH4 Prevents Heart Failure

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Nitric oxide synthases (NOS) needs BH4 for the production of nitric oxide. When there is low BH4 concentration, NOS generates superoxide instead of NO, which increases oxidative stress and causes endothelial dysfunction (R, R1)

Oxidative stress can contribute to many complications, such as heart disease, high cholesterol, diabetes, high blood pressure, and stroke. Supplementation with BH4 may restore BH4 concentrations and prevent these diseases (R).

Infusion of BH4 could restore the heart conditions in patients with high cholesterol, type II diabetes, congestive heart failure and heart disease (R, R1, R2).

A single oral therapeutic dose of a synthetic BH4 improved reflex skin vasodilation during whole body heat stress by augmenting NO-mediated dilation (R).

Blood flow restriction (ischemia) decreased cardiac BH4 content by 85, 95, or 97% after 30, 45, or 60 min of ischemia, respectively. Paralleling the decreases in BH4, reductions of eNOS activity were seen of 58, 86, or 92%, and NOS-derived superoxide production was greatly increased (R).

Thus, BH4 depletion contributes to postischemic eNOS dysfunction, and BH4 treatment is effective in partial restoration of endothelium-dependent coronary flow. Supplementation of BH4 may therefore be an important therapeutic approach to reverse endothelial dysfunction in postischemic tissues (R).

2) BH4 Has Antidepressant Activity

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Depression is associated with an inflammatory response as well as activation of the anti-inflammatory reflex system. It is also accompanied by oxidative and nitrosative stress (R).

Elevated levels of inflammation and oxidative damage can subsequently lead to a depletion of tetrahydrobiopterin levels (R, R1).

The depletion of BH4 reduces the synthesis of neurotransmitters like serotonin, melatonin, dopamine, norepinephrine, and epinephrine. These compounds are essential for controlling daily body functions including mood, sleep cycle, memory, and appetite (R).

Loss of BH4 might explain some of the symptoms of depression. If BH4 levels increased, then it can be an effective treatment for depression (R).

3) BH4 Might Improve Autistic Symptoms

Levels of BH4 in cerebrospinal fluid are 42% lower in children with Autism Spectrum Disorder (ASD) (R).

It is possible that metabolic pathways that need BH4 are dysfunctional in children with ASD. Children with ASD can have excessive inflammation, excessive oxidative damage, and overactivation of the immune system, which also reduces BH4 levels (R, R1).

This suggests that BH4 supplementation might improve ASD pathology. BH4 treatment might improve specific autistic symptoms including adaptability, verbal expression, social responsiveness and interactions, communication, cognitive abilities, hyperactivity, and inappropriate speech (R, R1, R2, R3, R4).

4) BH4 Helps Treat Diabetes

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Diabetes is characterized by glucose intolerance and insulin resistance, which can be caused by endothelial nitric oxide synthase (eNOS) dysfunction. Diabetes can also cause gastroparesis, and its symptoms include pain, nausea, and vomiting (R, R1).

BH4 helps regulate eNOS activity and prevents it from dysfunction. Administration of BH4 in mice lead to less glucose intolerance and insulin resistance; it has potential to help alleviate symptoms of diabetes (R, R1).

5) BH4 Supports Digestive System Function

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Tetrahydrobiopterin is essential for serotonin synthesis. Serotonin works in the digestive system and helps prevent dysfunction (R).

In mice, BH4 supplementation can help bring serotonin levels back to normal and steady digestive function (R).

6) BH4 Can Help Prevent Problems During Pregnancy

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During pregnancy, the maternal blood total cholesterol levels increase in order to ensure normal development of the baby. However, cholesterol levels can exceed normal levels and cause maternal supraphysiological hypercholesterolemia (MSPH), which leads to hardening of the arteries (R).

Since maternal cholesterol can pass through the fetal barrier to the developing fetus, MSPH can have serious consequences including the development of hardening of the arteries during childhood and later in life (R, R1).

MSPH is associated with reduced levels of BH4 and reduced NOS activity in the human umbilical vein (R, R1).

BH4 supplementation could improve BH4 levels and NOS activity hence preventing the potential consequences in the health of the newborn and in its adulthood (R).

7) BH4 Can Prevent Phenylketonuria

Tetrahydrobiopterin deficiency can cause excess phenylalanine concentration, or phenylketonuria (PKU). PKU can cause severe brain damage, mental retardation, seizures, and other abnormalities (R).

Treatment with BH4 can help normalize phenylalanine levels and brain neurotransmitters, and correct a deficiency of other chemicals (R,R1).

Treatment of BH4 deficiencies is usually very efficient especially if initiated at an early stage (R, R1).

Side Effects and Interactions

  • Headaches (R)
  • Runny nose (R)
  • Diarrhea (R)
  • Vomiting (R)

No interaction studies have been conducted. Because of its mechanism, tetrahydrobiopterin might interact with dihydrofolate reductase inhibitors like methotrexate and trimethoprim, and NO-enhancing drugs like nitroglycerin, molsidomine, minoxidil, and PDE5 inhibitors. Combination of tetrahydrobiopterin with levodopa can lead to increased excitability.

Dosage

The effects of oral administration of BH4 are dose dependent and further studies are required to investigate its long-term effects (R).

Additionally, the combination of BH4 with other antioxidant compounds is not yet tested (R).

Biosynthesis and Genetics of Low BH4

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There are a variety of genes that can cause lower BH4.  You must get your genetics tested and sign up to SelfDecode to see if you have SNPs that are not as effective in these genes.

The first step is conversion of GTP (guanosine triphosphate) to dihydroneopterin triphosphate via the GCH1 gene.

Dihydroneopterin triphosphate and magnesium are then converted to 6-pyruvoyl-tetrahydropterin via the PTS gene. Dihydroneopterin triphosphate can also degrade into neopterin.

6-pyruvoyl-tetrahydropterin and NADPH are converted to tetrahydrobiopterin (BH4) and NADP via the SPR gene. 6-pyruvoyl-tetrahydropterin can also degrade to sepiapterin and then dihydrobiopterin (BH2).

Dihydrobiopterin (BH2) and folate also convert to tetrahydrobiopterin (BH4) via the DHFR gene.

The GCHFR gene acts as feedback mechanism for GCH1 activity. GCHFR normally inhibits GCH1, but in the presence of phenylalanine it stimulates GCH1.

What Increases BH4

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http://www.elsevier.es/en-revista-revista-portuguesa-cardiologia-english-edition–434-articulo-statins-oxidative-stress-in-chronic-S2174204915003013

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What Decreases BH4

Questions

Any advantage on going straight for bh4 versus trying to get there through improved methylation?

People have different blockages for BH4, as discussed above.  Some people might do perfectly fine on just methylfolate, while others will need the real thing.

If you take it, will it stop your natural production of it?

Probably not by that much, but surely to some degree.  When you stop taking it, production should resume to normal.

Technical

  • The production, salvage and regeneration of BH4  involve the action of a series of enzymes: GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), sepiapterin reductase (SR), dihydrofolate reductase (DHFR), pterin-4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR) (R, R1,R2).
  • In vitro experiments with electron paramagnetic resonance spectroscopy have demonstrated that BH4 both stabilizes and donates electrons to the ferrous-dioxygen complex in the oxygenase domain, as the initiating step of L–arginine oxidation (R).
  • Five types of tetrahydrobiopterin deficiencies are GTPCH deficiency, PTPS deficiency, PCD deficiency, DHPR deficiency and sepiapterin reductase deficiency (R).

Buy BH4

The site says it’s only sold for research purposes, but anyone can buy it and it’s pure (the company tests for purity).

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

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22 COMMENTS

  • Ben Wa

    I guess through the methylation cycle.

  • bernadette

    Is this beneficial to someone who has the fast MAO gene rs4623 since the fast enzyme tends to use the neurotransmitters quickly ????

  • Michael Merritt

    How does one get their BH4 levels tested? Is there a publicly available test? Also, I don’t think my general doc will think it’s necessary.

  • deejayvj

    How does sam-e increase bh4?.

    Amy Yasko’s mthfr 1298 capsules contain biopterin, a precursor and several ingredients that support bh4 recycling fwiw

  • Sarah

    So does the BH4 cycle occur in the gut or in all cells of the body? I’m trying to understand the big picture

    Thanks

  • Ari

    Since irc is out of stock of BH4, can anyone recommend another reliable source?

  • Julia

    Dear Joseph,
    as I read, BH4 does not cross the bloodbrainbarrier. That’s why docs supplement with 5htp and L-Dopa and Carbidopa. You say, that you felt a reaction in your Brain (more focus, relaxation). Do you know any studies, that the neurotransmitters in the brain will increase by themselfes, by taking only BH4?

  • EFFECTIVEMOM

    I’m purchasing the BH4 from irc.org. My son’s physician wants him to take 10-15mg of BH4. irc.org only sells BH4 compounded with ascorbic acid, with 50mg BH4 per 1,000mg. So, how much should I give my son for the equivalent of 10-15mg of BH4? My poor math tells me 1/3 of a gram of the compounded formula to get 10-15mg of BH4. Is that correct?

    1. Jack Hammer

      For 10mg use 200mg (0.2grams) of product.
      For 15mg use 300mg (0.3grams) of product.

  • Maddy

    Question: I am heterozygous for two separate CBS mutations. Genetic Genie said in the little blurb about them that CBS mutations are often upregulations rather than down-regulations or loss of function. It said that upregulation of CBS genes can also deplete BHR, and that these CBS genes are risks for mast cell activation….which check, I have some symptoms of – but not as bad as many people probably because they are heterozygous for me. Do you concur? CBS mutations can also lead indirectly to low BH4? Going to do your self-decode next because GG doesn’t tell you all that much….but was first one I encountered…

    1. Joseph M. Cohen

      No studies on CBS mutations

  • Michael (NW)

    If one were to buy BH4 from IRC.bio, how much do you take for 1mg, or 2mg, or….? What does 1/8 tsp equal to? Thank you.

    1. Joseph M. Cohen

      2mg

  • brittany

    What dosage would you recommend for someone with an MTHFR mutation

  • Anne

    How much of the bh4 did u take at a time? Thank you

    1. Joseph M. Cohen

      5mg, but you can start with less

  • Niki

    My doc is a biochemist and said I would likely do well on BH4 however the only proper BH4 is not available because a pharmaceutical company bought the patent and altered it slightly to use for Parkinsons treatment (I believe) . The patent is soon up and should hopefully be made available again – fingers crossed. Anything you can currently buy is chemically not the correct form of BH4 needed by the body- or so I’ve been advised.

    1. Joseph M. Cohen

      That’s false.

      1. Niki

        I’ll verify on my end as hopefully you are correct. I sent that exact website to him months ago and he was adamant it wasn’t the right form. Hopefully it was it dismissed without reviewing the specifics on the BH4 available and it is in fact the correct form made available!!!

      2. Niki

        Maybe what I say is valid only for commercial supplementation and my MD didn’t look at the link related to research sources. I’ll find out! Here is IRC’s reply:

        “BioMarin owns the marketing rights to BH4. Marketing rights apply to commercial use. We sell for research purposes only, which is a use exempt from patent law. This is how for example Sigma Aldrich is able to sell patented compounds.”

  • will

    Thanks for a great site and atricle. Can you tell us any more about your experience of bh4 (dosing etc)?

  • wormsweb

    How would this affect someone with a rs1801131 (MTHFR A1298C) mutation?

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