Allopregnanolone
File:Allopregnanolone.svg
Abbreviation ALLO
Molecular formula C₂₁H₃₄O₂
Type Neurosteroid (progesterone metabolite, positive GABA-A modulator)
Administration IV (brexanolone, clinical); oral poorly effective
Bioavailability Poor oral, rapidly metabolized; IV form used clinically
Synonyms 3α-hydroxy-5α-pregnan-20-one, brexanolone (as drug)
Source Peripheral and CNS conversion from Progesterone via 5α-reductase and 3α-HSD
Ray's verdict Generally helps
A protective metabolite of progesterone; calms brain excitability, and low-progesterone states cut this protective path


Allopregnanolone is a neurosteroid made from progesterone that calms brain excitability by boosting GABA-A receptor activity. It is synthesized both peripherally and directly in brain tissue, and low progesterone states reduce the supply of this protective metabolite.

History

Etymology

The name combines "allo-" (Greek for "other," used in steroid chemistry to denote a specific stereoisomer) with "pregnanolone," itself from "pregnane" (the steroid backbone), "-ol" (hydroxyl group), and "-one" (ketone group).

Hans Selye described its sedative, anesthetic-like effects in 1941, coining the term "anesthetic steroid" for allopregnanolone and related compounds, decades before it was recognized as a natural modulator of GABA receptors.

The sedative and anesthetic effects of progesterone-derived steroids were first documented by Hans Selye in the early 1940s, who showed that certain steroid hormones could induce anesthesia in animals independent of any action on sex characteristics.[1] That line of research eventually identified allopregnanolone as the progesterone metabolite responsible for much of this effect. The term "neurosteroid" was coined decades later once it was established that steroids like allopregnanolone could be synthesized locally within the brain itself, not just delivered from peripheral glands.

Structure/Chemical properties

Allopregnanolone (3α-hydroxy-5α-pregnan-20-one) is a pregnane steroid formed from progesterone in two enzymatic steps: 5α-reductase first saturates the progesterone ring to form 5α-dihydroprogesterone, then 3α-hydroxysteroid dehydrogenase (3α-HSD) reduces the 3-position ketone to a hydroxyl group. This 3α-hydroxyl configuration is what allows it to bind the GABA-A receptor; the corresponding 3β-isomer largely lacks that activity.

Function/Mechanism of Action

Allopregnanolone is a positive allosteric modulator of the GABA-A receptor, binding a distinct site from benzodiazepines and enhancing chloride ion influx when GABA binds. This produces its calming, anticonvulsant, and sedative effects. Because it is synthesized directly in brain tissue as well as peripherally, it functions as part of the brain's own protective response to injury and stress.

Progesterone (and its metabolites, including allopregnanolone) protect against the harmful changes caused by a brain injury, but there are still important ideological and commercial reasons for not using it.

— Ray Peat[2]


TLR4 and inflammation

Allopregnanolone also curbs inflammation through a separate route: blocking TLR4, an immune receptor that sets off a strong inflammatory cascade when it senses bacterial toxins or tissue damage.

In cultured immune cells (RAW264.7 macrophages) challenged with a bacterial toxin (LPS), both allopregnanolone and its precursor pregnenolone cut activation of that TLR4 cascade by about 80%, lowering a whole panel of downstream inflammatory signals together (p-TAK1, TRAF6, several NF-κB species, HMGB1, MCP-1, and TNFα). The likely mechanism is direct: allopregnanolone appears to block TLR4 from pairing up with its co-receptor MD-2, the step that normally kicks off the cascade.

The effect also held up in live animals. In alcohol-preferring rats, an injection of allopregnanolone into a brain region tied to stress and addiction (the ventral tegmental area) lowered several inflammatory markers by 20-30% and cut TLR4's interaction with other signaling proteins by 40-60%.[3]

These are cell-culture and rodent neuroimmune findings, not a clinical trial of allopregnanolone for infection or systemic inflammation in humans.

Depression and PTSD

Allopregnanolone runs low in major depression and in PTSD. Post-mortem brain tissue from depressed patients shows reduced expression of 5α-reductase type I in the prefrontal cortex (Brodmann's area 9), the enzyme that starts the progesterone-to-allopregnanolone conversion.[4] In women with PTSD, progesterone fails to convert normally into allopregnanolone and pregnanolone, pointing to the same kind of block further down the enzyme chain; the size of the block tracks with symptom severity.[5]

Standard SSRI antidepressants raise brain allopregnanolone through a separate mechanism from serotonin reuptake blockade. Fluoxetine increases allopregnanolone at doses too low to inhibit serotonin reuptake at all, acting instead as a direct stimulant of the enzymes that make it, which led researchers to call this class of drug action a "selective brain steroidogenic stimulant."[6] That points to allopregnanolone itself, not serotonin, as a driver of some of the antidepressant effect credited to SSRIs.


Reviews of allopregnanolone agonist therapy summarize brexanolone (IV) reductions in HAM-D for postpartum depression and early zuranolone (oral, 14-day course) data for major depression, with sedation and dizziness as common adverse effects.[7] A 2021 mechanism review links lower allopregnanolone biosynthesis to depression, anxiety, and PTSD, frames allopregnanolone as a GABA-A positive allosteric modulator, and notes brexanolone approval for postpartum depression plus SSRI effects that can raise allopregnanolone.[8]

In healthy adults, oral pregnenolone 400 mg raised allopregnanolone and, versus placebo during an emotion-appraisal fMRI task, reduced amygdala and insula activity and increased dorsal medial prefrontal activity and amygdala-dmPFC connectivity during appraisal; higher allopregnanolone tracked with that connectivity pattern.[9]

Progesterone's calming and anticonvulsant actions run partly through this metabolite: allopregnanolone facilitates GABA inhibition that is low in some mood and movement disorders, and oral progesterone raises brain allopregnanolone.[10][11][12]

Progesterone versus MPA (mice)

In estrogen-primed ovariectomized mice, progesterone (but not medroxyprogesterone acetate) increased exploration, anti-anxiety, and social interaction in wildtype animals and raised prefrontal/hippocampal allopregnanolone; 5α-reductase type 1 knockout mice lacked those progesterone behavioral effects, while direct allopregnanolone worked in both genotypes. MPA does not convert to allopregnanolone the way progesterone does.[13]

Medical uses/Effects

Brexanolone, a proprietary IV formulation of allopregnanolone, was approved by the FDA in 2019 as the first drug specifically indicated for postpartum depression, administered as a continuous 60-hour infusion. In indirect comparisons against SSRIs for postpartum depression, brexanolone produced a larger drop in Hamilton Depression Rating Scale scores at every timepoint measured, worked within days rather than the 4-6 weeks SSRIs typically need, and showed a higher response rate.[14]

A randomized, double-blind, placebo-controlled phase 1 trial in early Alzheimer's disease patients (NCT02221622) tested once-weekly IV allopregnanolone over 12 weeks. The treatment was well tolerated, and low doses (as low as 4 mg weekly) were associated with reduced hippocampal atrophy, increased white matter integrity, and greater functional connectivity on MRI. Benefits plateaued or partially reversed at higher doses, suggesting a narrow effective concentration range.[15]

Dosing

In the Alzheimer's trial, doses ranged from 2-14 mg IV once weekly; the highest doses tolerated without excess sedation were 10 mg (male participants) and 14 mg (female participants), though 4 mg weekly appeared to be the more favorable dose for the neuroregenerative endpoints measured.[15] Brexanolone's approved postpartum depression regimen is a continuous IV infusion over 60 hours at escalating target doses, administered under monitored inpatient conditions due to sedation risk.

Allopregnanolone is not available as a practical oral supplement; oral doses are poorly and unpredictably absorbed, since it is rapidly metabolized on first pass.

Side/Adverse effects

The main dose-limiting side effect is sedation, consistent with its action as a GABA-A agonist. In the Alzheimer's trial, the most common reported effects were mild rash (22%) and fatigue (17%), with one case of non-serious dizziness; side-effect incidence did not differ meaningfully from placebo, and no adverse effects on cognition or MRI outcomes were seen.[15] Brexanolone carries an FDA boxed warning for excessive sedation and loss of consciousness during infusion, requiring monitored administration.

See also

References

  1. ↑ Selye H. "The anesthetic effect of steroid hormones." Proc Soc Exp Biol Med. 1941;46:116-121.
  2. ↑ Ray Peat Newsletter, "Progesterone, brain protection, and the 'science culture'," March 2016
  3. ↑ Balan I, Beattie MC, O'Buckley TK, Aurelian L, Morrow AL. "Endogenous Neurosteroid (3α,5α)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain," Sci Rep. 2019;9:1220. doi:10.1038/s41598-018-37409-6. PMID 30718548.
  4. ↑ Agis-Balboa RC, Guidotti A, Pinna G, "5α-reductase type I expression is downregulated in the prefrontal cortex/Brodmann's area 9 (BA9) of depressed patients," Psychopharmacology. 2014;231(18):3569-3580.
  5. ↑ Pineles SL, Nillni YI, Pinna G, et al, "PTSD in women is associated with a block in conversion of progesterone to the GABAergic neurosteroids allopregnanolone and pregnanolone measured in plasma," Psychoneuroendocrinology. 2018;93:133-141. DOI 10.1016/j.psyneuen.2018.04.024.
  6. ↑ Pinna G, Costa E, Guidotti A, "SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake," Current Opinion in Pharmacology. 2009;9(1):24-30. PMID 19157984.
  7. ↑ Walkerly A, Leader LD, Cooke E, VandenBerg A. "Review of Allopregnanolone Agonist Therapy for the Treatment of Depressive Disorders," Drug Des Devel Ther. 2021;15:3017-3024. doi:10.2147/DDDT.S240856. PMID 34267503.
  8. ↑ Chen S, Gao L, Li X, Ye Y. "Allopregnanolone in mood disorders: Mechanism and therapeutic development," Pharmacol Res. 2021;169:105682. doi:10.1016/j.phrs.2021.105682. PMID 34019980.
  9. ↑ Sripada RK, Marx CE, King AP, et al. "Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits," Biol Psychiatry. 2013;73(11):1045-1053. doi:10.1016/j.biopsych.2012.12.008. PMID 23348009.
  10. ↑ Ray Peat, "Serotonin, depression, and aggression: The problem of brain energy"
  11. ↑ Ray Peat, "Ask the Herb Doctor: Female Hormones, Progesterone", KMUD, 40:32
  12. ↑ Ray Peat, "Postpartum Depression, Brain Aging, and Reductionism", p. 1
  13. ↑ Koonce CJ, Frye CA. "Progesterone facilitates exploration, affective and social behaviors among wildtype, but not 5α-reductase Type 1 mutant, mice," Behav Brain Res. 2013;253:232-239. doi:10.1016/j.bbr.2013.07.025. PMID 23886595.
  14. ↑ "Using Matching-Adjusted Indirect Comparisons and Network Meta-analyses to Compare Efficacy of Brexanolone Injection with Selective Serotonin Reuptake Inhibitors for Treating Postpartum Depression," CNS Drugs. 2019;33(11):1039-1052. PMID 31642037.
  15. ↑ 15.0 15.1 15.2 "AAN2022 – Allopregnanolone Found Safe, May Ease Brain Atrophy," American Academy of Neurology 2022 annual meeting; trial NCT02221622, University of Arizona. https://index.mirasmart.com/aan2022/PDFfiles/AAN2022-001781.html