Allopregnanolone is a progesterone metabolite known for its antidepressant, neuroprotective, neurogenic, and anxiety lowering effects. When progesterone is supplemented via the oral route a large proportion is metabolized by the liver to allopregnanolone. This metabolite is a positive modulator of GABA action on the GABA receptor (a main inhibitory neurotransmitter in the brain), which usually can improve mood, calm anxiety, and treat insomnia

Low allopregnanolone levels have been associated with major depression, anxiety disorders, premenstrual dysphoric disorder (PMDD), and Alzheimer’s disease. Low levels of allopregnanolone during pregnancy have been associated with depression and a recent study found that infusion of allopregnanolone can rapidly treat postpartum depression (PPD). This led to the 2019 FDA approval of Brexanolone, a synthetic form of allopregnanolone, to treat PPD. Allopregnanolone is also being studied as a potential therapy for Alzheimer’s Disease. Murine research has shown that allopregnanolone can increase the generation of new brain cells.

Pretreatment of rats with allopregnanolone decreased the stress-induced release of cortisol. and ACTH.  This may be a mechanism to help protect the brain during stress and to help restore a calm state. 

Note that certain women may have paradoxical reactions to allopregnanolone exposure due to differences in the subunit on the GABA receptor called α-4. When too much α-4 is produced, the receptor’s capacity to use GABA is blunted, which can cause increased anxiety and a worsened mood for some. Up to 8% of women exposed to allopregnanolone paradoxically experience significant negative mood symptoms, so one should pay close attention to the response to oral progesterone therapy. 

Because of its calming and mood-lifting effects, oral progesterone supplementation is a consideration for treating anxiety, depression, and insomnia. Oral progesterone can be used concurrently with physiological doses of topical progesterone without causing excessively high salivary levels.