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Tetrahydrobiopterin (BH4): Role in the Body & New Research

Written by Persefoni Ioannou, PhD | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Persefoni Ioannou, PhD | Last updated:

Tetrahydrobiopterin, also known as BH4, is essential for many processes in the body. It helps with the heart, brain, and the digestive and reproductive systems. A synthetic version called sapropterin can help manage phenylketonuria and is under investigation for its potential in heart disease and autism. Read on to learn how it works.

What is Tetrahydrobiopterin (BH4)?

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 [1].

BH4 is essential for the action of several enzymes, including ones responsible for neurotransmitter synthesis, host defense, and formation of lipids [2].

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

Reduction in vascular BH4 bioavailability is a central mechanism for the development of impaired NO-mediated microvascular (smaller blood vessels) function in a wide variety of conditions, including diabetes, hypertension, hypercholesterolemia, atherosclerosis, and aging [3].

Tetrahydrobiopterin has clinical trials on autism, ADHD, hypertension, endothelial dysfunction, and chronic kidney disease [4].

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.

Oxidation of BH4 results in promoting the transfer of electrons to molecular oxygen resulting in the production of Superoxide rather than Nitric Oxide.

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.

Potential Health Benefits of BH4

Prescription Sapropterin for PKU

Before we discuss new research, it’s important to note that BH4, as sapropterin, has only been approved to help manage phenylketonuria, or PKU.

Tetrahydrobiopterin deficiency can cause excess phenylalanine concentration, or phenylketonuria. PKU can cause severe brain damage, mental retardation, seizures, and other abnormalities [5].

Treatment with BH4 can help normalize phenylalanine levels and brain neurotransmitters and correct a deficiency of other chemicals [6, 7].

Treatment of BH4 deficiencies is usually very efficient especially if initiated at an early stage. However, not everyone with PKU will respond to BH4 [6, 8].

If you have PKU, your doctor will determine if BH4 (sapropterin) is right for you.

Possibly Effective For

1) Heart Disease

In a meta-analysis of patients with heart conditions associated with high cholesterol, type II diabetes, and congestive heart failure, high-dose BH4 reduced symptoms and produced enough beneficial results for the authors to recommend its further use in clinical settings [9, 10, 11].

These results may be attributed to endogenous BH4 and its role in cardiovascular health.


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 [12, 13].

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 [14].

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

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 were greatly increased [15].

Thus, BH4 depletion contributes to postischemic eNOS dysfunction, and BH4 treatment partially restored endothelium-dependent coronary flow [15].

2) Autism

Levels of BH4 in cerebrospinal fluid are 42% lower in children with Autism Spectrum Disorder (ASD) [16].

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 [17, 18].

In clinical trials, BH4 treatment improved specific autistic symptoms in children including adaptability, verbal expression, social responsiveness and interactions, communication, cognitive abilities, hyperactivity, and inappropriate speech [19, 20, 21, 22, 23].

These results have been promising; however, we strongly recommend against using BH4 or giving BH4 to children without a doctor’s prescription.

Animal Research & Theoretical Uses (Lacking Evidence)

BH4 is involved in other biological functions; however, no clinical evidence supports the use of supplemental BH4 for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

3) Depression

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 [24].

Elevated levels of inflammation and oxidative damage can subsequently lead to a depletion of tetrahydrobiopterin levels [25, 26].

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 [25].

Loss of BH4 might explain some of the symptoms of depression. Some researchers have suggested that supplementary BH4 (as sapropterin) could raise BH4 levels and reduce the symptoms of depression [25].

4) Diabetes

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 [27, 28].

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 the potential to help alleviate symptoms of diabetes [27, 28].

5) Digestive Function


Tetrahydrobiopterin is essential for serotonin synthesis. Serotonin works in the digestive system and helps prevent dysfunction [29].

In mice, BH4 supplementation can help bring serotonin levels back to normal and steady digestive function [29].

6) Pregnancy

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 [30].

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 [30, 31].

MSPH is associated with reduced levels of BH4 and reduced NOS activity in the human umbilical vein [32, 30].

Some researchers have suggested that BH4 supplementation could improve BH4 levels and NOS activity hence preventing the potential consequences in the health of the newborn and in its adulthood [32].

Sapropterin has been safely used in pregnant mothers with PKU, but no studies have yet investigated BH4 in pregnant mothers with other conditions [33].

We recommend strongly against using BH4 during pregnancy without a specific recommendation and prescription from your doctor.

Side Effects, Interactions, & Dosage

  • Headaches [34]
  • A runny nose [34]
  • Diarrhea [34]
  • Vomiting [34]

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. A combination of tetrahydrobiopterin with levodopa can lead to increased excitability.

To avoid adverse effects and unexpected interactions, only use BH4 under the supervision of a medical professional.


The effects of oral administration of BH4 are dose-dependent and further studies are required to investigate its long-term effects [9].

Additionally, the combination of BH4 with other antioxidant compounds is not yet tested [11].

What Could Increase BH4?

Some lifestyle, diet, and supplement choices have been associated with increased BH4.

What Could Decrease BH4?

Likewise, some lifestyle, diet, and supplement choices have been associated with decreased BH4.

  • High homocysteine, possibly caused by certain MTHFR variants [39]
  • Sun/UV [40]
  • Oxidative stress [41]

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