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Allotetrahydrocorticosterone (3α,5α-tetrahydrocorticosterone, or allo-THB) is an endogenous neurosteroid generated by sequential 5α-reduction and 3α-hydroxylation of the adrenal glucocorticoid corticosterone. It is the corticosterone-derived structural counterpart of THDOC (which is formed the same way from deoxycorticosterone) and behaves as a positive allosteric modulator (an enhancer that boosts a receptor's response without activating it directly) of the GABA-A receptor (the brain's principal inhibitory chloride ion channel); the additional 11β-hydroxyl group it carries, however, makes it a considerably weaker potentiator than THDOC or allopregnanolone. Beyond GABA-A it shows an unusually broad ion-channel profile, inhibiting glycine receptors (a second inhibitory chloride channel, prominent in the brainstem and spinal cord) and N-type calcium channels (presynaptic channels that gate neurotransmitter release), opening large-conductance calcium-activated potassium channels (BK or Maxi-K channels) in sensory nerves, and retaining residual glucocorticoid-receptor agonism. Clinically it appears mainly as a minor urinary corticosteroid metabolite that indexes 5α-reductase activity in steroid profiling.
- Potentiates GABA-A receptor signaling (positive allosteric modulation), the same class of inhibitory mechanism that gives allopregnanolone and THDOC their calming, anticonvulsant and sedative properties, though allo-THB is substantially weaker
- Reduces presynaptic calcium influx by inhibiting N-type (Cav2.2) calcium channels, a mechanism associated with lower neurotransmitter release and potential analgesic or neuroprotective effects
- Silences capsaicin-sensitive sensory C-fibers and lowers substance P release by opening BK/Maxi-K potassium channels, of interest for neurogenic airway inflammation, cough and asthma models
- Functions as an endogenous readout of 5α-reductase activity in clinical urinary steroid profiling, helping characterize enzyme deficiencies and drug effects such as finasteride treatment
- Illustrates that 5α-reduction of corticosterone does not abolish glucocorticoid signaling, informing the understanding of tissue-level corticosteroid metabolism
- As a GABA-A positive modulator, high exposure could in theory contribute to sedation, drowsiness or reduced arousal, as seen with the neurosteroid drug class
Overview
The corticosterone-derived, 11β-hydroxylated cousin of THDOC; a modest-potency GABA-A positive modulator with a distinctive multi-channel and glucocorticoid-receptor side profile, better known as a urinary 5α-reductase marker than as a psychoactive neurosteroid.
- Allotetrahydrocorticosterone is to corticosterone what THDOC is to deoxycorticosterone; the two neurosteroids are made by the same 5α-reduction plus 3α-hydroxylation route and differ only by a single 11β-hydroxyl group, which is enough to make allo-THB a much weaker GABA-A potentiator
- It is a rare split-personality steroid: it potentiates GABA-A receptors yet inhibits glycine receptors, with the 3α-hydroxyl group determining which inhibitory chloride channel it helps and which it blocks
- Unlike allopregnanolone and THDOC, allo-THB keeps an intact glucocorticoid pharmacophore and can still switch on the glucocorticoid receptor, so 5α-reduction of corticosterone is not the metabolic dead end it was once assumed to be
- Its 3β-epimer, 3β,5α-tetrahydrocorticosterone, was reported in 2025 to activate the aryl hydrocarbon receptor and suppress neuroblastoma growth while promoting neural differentiation, a surprising anticancer action for a corticosterone metabolite
Mechanism
Biosynthesis: Allotetrahydrocorticosterone is the fully ring-A-reduced product of a two-step metabolic pathway acting on corticosterone. Steroid 5α-reductase (the enzyme isoforms SRD5A1 and SRD5A2 that saturate the steroid A-ring double bond) first converts corticosterone to 5α-dihydrocorticosterone (5α-DHB); 3α-hydroxysteroid dehydrogenase (aldo-keto reductase enzymes of the AKR1C family) then reduces the 3-keto group to a 3α-hydroxyl, producing 3α,5α-tetrahydrocorticosterone. A parallel route through 5β-reductase (AKR1D1) yields the "normal" isomer 3α,5β-tetrahydrocorticosterone; the prefix "allo" denotes the 5α configuration, in which the A and B rings are trans-fused. This exactly mirrors the biosynthesis of THDOC from deoxycorticosterone, the two neurosteroids differing only by the 11β-hydroxyl present in allo-THB.-A receptor: In common with other 3α-hydroxy, 5-reduced pregnane neurosteroids, allo-THB binds the transmembrane neurosteroid-potentiation site of the GABA-A receptor and acts as a positive modulator, prolonging chloride channel open events and strengthening both phasic and tonic inhibition. The 3α-hydroxyl group is the obligatory pharmacophore for this action. Its potency is modest; in cerebellar Purkinje neurons it potentiated GABA-evoked current with an EC50 near 23 micromolar and a maximal potentiation around 420%, roughly one to two orders of magnitude weaker than THDOC or allopregnanolone, a loss attributable to the additional 11β-hydroxyl substituent.
Glycine receptor: In striking contrast to its -A action, allo-THB inhibits strychnine-sensitive glycine receptors, accelerating receptor desensitization with an IC50 near 0.72 micromolar and reducing peak glycine current at higher concentrations. The 3α-hydroxyl configuration favors GABA-A potentiation whereas 3β-hydroxy and 3-oxo congeners favor glycine-receptor block, so allo-THB sits at an unusual crossover point, potentiating one inhibitory chloride channel while inhibiting the other.
Voltage-gated calcium channels: Allo-THB rapidly and reversibly depresses high-voltage-activated calcium current in hippocampal CA1 pyramidal neurons, acting selectively on the ω-conotoxin-sensitive N-type (Cav2.2) component with an IC50 near 0.3 micromolar and a ceiling near 60% inhibition. The effect is membrane-delimited and non-genomic, mediated by a pertussis-toxin-sensitive Gi/o-protein and protein kinase C acting at an extracellular binding site distinct from the classical intramembrane -A neurosteroid site; the consequence is reduced presynaptic calcium entry and transmitter release.
Potassium channels and sensory nerves: In capsaicin-sensitive airway C-fibers, allo-THB opens voltage-gated and large-conductance calcium-activated (BK or Maxi-K) potassium channels through a pertussis-toxin-sensitive G-protein, hyperpolarizing and silencing the nerve terminals and cutting the release of substance P; this underlies its ability to blunt neurogenic bronchoconstriction in guinea-pig airway models.
Glucocorticoid receptor: Because allo-THB retains the 11β,21-dihydroxy-20-one glucocorticoid pharmacophore, it and especially its precursor 5α-dihydrocorticosterone can still engage and activate the nuclear glucocorticoid receptor. 5α-reduction therefore does not fully inactivate corticosterone, and allo-THB is best regarded as a hybrid molecule carrying both membrane (ionotropic) neurosteroid actions and residual genomic corticosteroid activity; the corresponding 5β-reduced metabolites are inactive at the glucocorticoid receptor.
receptor fingerprint
Glycine receptorInhibition (accelerated desensitization, reduced peak current)
-A receptorPositive allosteric modulation (potentiation of chloride current)
N-type calcium channel (Cav2.2)Inhibition via Gi/o-protein and protein kinase C
BK / Maxi-K potassium channelActivation and opening in sensory nerves
Glucocorticoid receptor (NR3C1)Agonist
Glucocorticoid receptorRetained agonism via the 11β,21-diol pharmacophore
Voltage-gated potassium channels (sensory neurons)Facilitation (proposed)
Safetyrisks and cautions, not medical advice
No human safety or tolerability data exist for exogenous allotetrahydrocorticosterone, which is present endogenously at low concentrations and is neither administered clinically nor sold as a supplement. Considerations are therefore mechanistic and class-based: as a positive allosteric modulator of the GABA-A receptor it belongs to a family associated with sedation and, at higher exposures, impaired arousal, yet its own potency at that receptor is low. It also departs from the pure inhibitory neurosteroids in two ways that complicate any safety inference, retaining glucocorticoid-receptor agonism and simultaneously inhibiting glycine receptors, the latter a potentially pro-excitatory action. In the absence of controlled exposure data, allo-THB should be treated as a research metabolite rather than a characterized therapeutic.
History
The reduced metabolites of corticosterone were characterized during the mid-20th-century expansion of steroid biochemistry. Peterson mapped the metabolism of corticosterone in man in 1960, and Di Costanzo and colleagues identified the 3β-epimer of allotetrahydrocorticosterone among the reduced products of radiolabeled corticosterone in 1968.
The compound's neuroactive dimension emerged after the 1986 report by Majewska and coworkers that 3α-reduced ring-A steroid metabolites are barbiturate-like modulators of the GABA-A receptor, which reframed such metabolites as functional neurosteroids. Allo-THB was subsequently examined by ffrench-Mullen and colleagues on neuronal calcium channels (1991 and 1994), by Yoshihara and colleagues on airway sensory nerves (2005 and 2006), and by Solntseva on glycine and GABA-A receptors (2023), while endocrinologists continued to track it as a minor urinary corticosteroid metabolite.
Reputation
Within the neuroactive steroid field, allotetrahydrocorticosterone is a niche and comparatively understudied molecule. It is overshadowed by allopregnanolone and THDOC in the GABA-A literature and is more familiar to clinical endocrinologists as a minor urinary corticosterone metabolite and an index of 5α-reductase activity than as a psychoactive agent. It has no consumer or nootropic following, is not marketed, and attracts scientific interest chiefly for its mechanistic breadth across GABA-A, glycine, calcium, potassium and glucocorticoid targets and for its role in steroid metabolomics.
Subjective profileweighing the evidence above
Not a compound anyone takes. It is an endogenous metabolite with no human dosing data and a GABA-A effect far weaker than allopregnanolone. Its genuine use is as a urinary readout of 5-alpha-reductase activity in clinical steroid profiling, which matters in a lab and not on a shelf.
Resources
This entry is here for reference.
Research
- 1960first citedThe metabolism of corticosterone in man.
- 1990controlled trialC19 and C21 5 beta/5 alpha metabolite ratios in subjects treated with the 5 alpha-reductase inh…
- 2026most recent5α-Reductase Isoenzymes: From Neurosteroid Biosynthesis to Neuropsychiatric Outcomes.
- 1.Corticosteroids as Selective and Effective Modulators of Glycine Receptors.
- 2.Neurosteroids block Ca2+ channel current in freshly isolated hippocampal CA1 neurons.
- 3.Neurosteroids modulate calcium currents in hippocampal CA1 neurons via a pertussis toxin-sensitive G-protein-coupled mechanism.
- 4.A neuroactive steroid, allotetrahydrocorticosterone inhibits sensory nerves activation in guinea-pig airways.
- 5.A neuroactive steroid inhibits guinea pig airway sensory nerves via Maxi-K channel activation.
- 6.The metabolism of corticosterone in man.
- 7.[Identification of 3beta-allotetrahydrocorticosterone following administration of 1,2 3H-corticosterone].
- 8.5alpha-reduced glucocorticoids, novel endogenous activators of the glucocorticoid receptor.
- 9.Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
- 10.Targeting neuroblastoma with 3β,5α-tetrahydrocorticosterone: Activation of aryl hydrocarbon receptor inhibits tumor growth, metastasis, and stemness while promoting neural differentiation.
- 11.Realising the therapeutic potential of neuroactive steroid modulators of the GABA(A) receptor.
- 12.The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy.
32 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is allotetrahydrocorticosterone the same thing as THDOC?
No. Both are 3α,5α-reduced GABA-A-active neurosteroids, but THDOC is made from deoxycorticosterone and has no oxygen at carbon 11, whereas allo-THB is made from corticosterone and carries an 11β-hydroxyl group. That extra hydroxyl makes allo-THB a much weaker GABA-A potentiator, which is the main pharmacological difference between the two.
Is it a strong sedative like allopregnanolone or zuranolone?
No. Its GABA-A potentiating potency is modest, with an EC50 around 23 micromolar in cerebellar Purkinje neurons, roughly one to two orders of magnitude weaker than allopregnanolone or THDOC. It is better described as a weak endogenous modulator than as a sedative in its own right.
Can I buy or take allotetrahydrocorticosterone?
No. It is an endogenous metabolite studied in the laboratory and measured in urinary steroid panels; it is not sold as a supplement or approved as a drug, and there is no established human dose or safety profile for taking it.
What does the allo prefix mean?
Allo marks the 5α-hydrogen configuration, in which the A and B steroid rings are trans-fused. It distinguishes 3α,5α-tetrahydrocorticosterone (allo-THB) from the 5β normal isomer, 3α,5β-tetrahydrocorticosterone.
Does it do anything besides act on GABA-A receptors?
Yes, and this is what makes it unusual. It inhibits glycine receptors, blocks N-type calcium channels through a G-protein and protein kinase C pathway, opens BK/Maxi-K potassium channels in sensory nerves, and can still activate the glucocorticoid receptor.
Limitations of the evidence
- No human safety data exist for administered allotetrahydrocorticosterone; it is an endogenous metabolite, not a marketed drug or supplement
Adverse effects
- As a GABA-A positive modulator, high exposure could in theory contribute to sedation, drowsiness or reduced arousal, as seen with the neurosteroid drug class
Notes and cautions
- Retained glucocorticoid-receptor activity means it is not a pure GABAergic neurosteroid and could exert corticosteroid-like genomic effects
- Its glycine-receptor inhibition is a potentially pro-excitatory action that runs opposite to its GABA-A potentiation, complicating any predicted net effect
- Because it is neither sold nor dosed, all tolerability statements are mechanistic inference rather than observed clinical experience