allopregnanolon

Allopregnanolone is a neurosteroid derived from progesterone, also known as 3α-hydroxy-5α-pregnan-20-one or tetrahydroprogesterone (THP). It is synthesized in the brain and peripheral tissues such as the ovaries and adrenal glands. In the brain, its levels vary with hormonal states, increases during pregnancy, and a rapid decline after birth has been linked to mood disturbances in some individuals.

Biosynthesis occurs from progesterone via 5α-reductase, which converts it to dihydroprogesterone, followed by 3α-hydroxysteroid dehydrogenase producing allopregnanolone. It is active in neuronal membranes and can diffuse across the blood–brain barrier, contributing to central nervous system signaling.

Pharmacologically, allopregnanolone is a potent positive allosteric modulator of GABA-A receptors, enhancing GABAergic inhibition. At higher concentrations it can directly activate GABA-A receptors. This action underpins its anxiolytic, sedative, and anticonvulsant effects and is thought to contribute to stress- and mood-related neurophysiology. It also has been studied for neuroprotective and anti-inflammatory properties in preclinical work.

Clinically, a formulation of allopregnanolone, brexanolone, is approved in the United States for the treatment of postpartum depression, administered intravenously. Other synthetic neurosteroids with similar mechanisms, such as zuranolone, are being investigated for major depressive disorder and related conditions. Potential risks include excessive sedation, dizziness, and respiratory depression, particularly with concurrent depressants. Allopregnanolone remains an active area of research for mood, anxiety, and neuropsychiatric disorders.