Allopregnanolone

Allopregnanolone is a neurosteroid—a steroid acting predominantly on the brain—synthesized from progesterone via the sequential actions of 5-alpha-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD). 3 It functions primarily as a potent positive allosteric modulator of GABAA receptors, producing sedative, anxiolytic, and antidepressant effects. 3 Unlike its precursor progesterone, allopregnanolone is considered devoid of classical hormonal activity through nuclear receptors such as the progesterone, estrogen, androgen, or glucocorticoid receptors, making it similar to pregnenolone in its neurosteroid profile. 2 The FDA-approved drug brexanolone (Zulresso) is simply an intravenous formulation of allopregnanolone for postpartum depression, though the steroid itself is openly sold as a research chemical. 3

Peat argued that supplementing progesterone reliably increases brain allopregnanolone concentrations, with a small oral dose tripling its levels, and that pregnenolone supplementation also raises it. 6 He viewed the pharmaceutical monopolization of allopregnanolone as a reductionist approach, noting that the drug industry profits from isolating a single metabolite when the parent steroid, progesterone, achieves the same effect. 6 Dinkov has written that the antidepressant effect of exogenous allopregnanolone is likely only partially explained by GABA agonism, as pure GABA agonists like benzodiazepines lack antidepressant properties; he suggests that at micromolar concentrations achieved through supplementation, allopregnanolone may also stimulate thyroid synthesis and metabolism. 2 He further notes that the first SSRI, fluoxetine (Prozac), was discovered to increase the activity and expression of 3α-HSD, leading to the hypothesis that allopregnanolone is the true antidepressant agent. 2

Dinkov has emphasized that allopregnanolone is one of the most powerful protective steroids in the brain, alongside its precursors pregnenolone and progesterone, and that 5-alpha-reductase is the crucial enzyme for its synthesis. 3 He has linked allopregnanolone deficiency during pregnancy to autism in offspring, interpreting this deficiency as an indirect marker of an energetic production deficiency in the mother, since steroid synthesis depends on adequate energy metabolism. 4 The steroid has also been described as neuroregenerative, synaptogenic, and a free radical scavenger, with clinical trials showing that once-weekly low-dose intravenous administration (as low as 4 mg) can reduce brain atrophy and increase neurogenesis in Alzheimer’s disease patients, though higher doses plateaued or reduced neurogenesis. 2 Its pro-dopamine effects, including increased dopamine release and dopaminergic response, have been documented in animal studies. 5

In practical application, Dinkov reports that allopregnanolone has a much more potent sedative effect than progesterone and was historically used as a general anesthetic. 3 He has noted that at higher doses, it produces the social disinhibition and mood improvement of alcohol without the hepatic side effects. 9 While Peat expressed that he did not see what allopregnanolone could do that progesterone could not, he considered it acceptable to try, and Dinkov has characterized it as a relatively benign steroid with no known hormone-imbalancing effects, making it a candidate for conditions like post-finasteride syndrome where 5-alpha-reductase activity is impaired. 3 The synthesis pathway requires that progesterone first be converted to 5α-dihydroprogesterone by 5-alpha-reductase before 3α-HSD can produce allopregnanolone; once progesterone undergoes 3α-HSD reduction directly, the resulting C-3-ol steroid cannot be processed by 5-alpha-reductase, though the bidirectional nature of 3α-HSD allows for potential reconversion. 11