Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN),[5][6] is a cofactor of the three aromatic amino acid hydroxylase enzymes,[7] used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases.

[10][citation needed] Tetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride (BH4*2HCL).

[19] The most common adverse effects, observed in more than 10% of people, include headache and a running or obstructed nose.

Therefore, a deficiency in tetrahydrobiopterin can cause a toxic buildup of L-phenylalanine, which manifests as the severe neurological issues seen in phenylketonuria.

The role of BH4 in this enzymatic process is so critical that some research points to a deficiency of BH4 – and thus, of nitric oxide – as being a core cause of the neurovascular dysfunction that is the hallmark of circulation-related diseases such as diabetes.

These include autism, depression,[30] ADHD, hypertension, endothelial dysfunction, and chronic kidney disease.

A 2015 BioMarin-funded study of PKU patients found that those who responded to tetrahydrobiopterin also showed a reduction of ADHD symptoms.

[35] In 2010, Frye et al. published a paper which concluded that it was safe, and also noted that "several clinical trials have suggested that treatment with BH4 improves ASD symptomatology in some individuals.

[37] Increasing tetrahydrobiopterin in endothelial cells by augmenting the levels of the biosynthetic enzyme GTPCH can maintain endothelial nitric oxide synthase function in experimental models of disease states such as diabetes,[38] atherosclerosis, and hypoxic pulmonary hypertension.

[41] GTPCH (GCH1) and tetrahydrobiopterin were found to have a secondary role protecting against cell death by ferroptosis in cellular models by limiting the formation of toxic lipid peroxides.

[42] Tetrahydrobiopterin acts as a potent, diffusable antioxidant that resists oxidative stress[43] and enables cancer cell survival via promotion of angiogenesis.