hpa axis: nootropics and compounds | sci-wiki

DHEA

Dehydroepiandrosterone (DHEA) is an endogenous androstane neurosteroid and the most abundant circulating steroid hormone in humans, secreted chiefly by the adrenal cortex and also synthesized de novo within the central nervous system. It functions primarily as a precursor to androgens and estrogens, yet exerts direct actions on the brain by acting as an agonist at the sigma-1 receptor (an endoplasmic reticulum chaperone protein that shapes calcium and neurotrophic signaling), as a positive modulator of NMDA receptor (the principal excitatory glutamate ion channel involved in learning) signaling, and, chiefly as its sulfate ester DHEAS, as a negative allosteric modulator of the GABA-A receptor (the brain's main inhibitory ion channel). DHEA additionally behaves as a functional anti-glucocorticoid, buffering the neurotoxic effects of cortisol, and shows neuroprotective and mood-related activity in preclinical and clinical studies. Circulating concentrations peak in early adulthood and decline markedly with age, a phenomenon termed adrenopause that has driven its widespread use as an over-the-counter supplement.

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Corticosteroid

Dexamethasone

Dexamethasone is a synthetic fluorinated glucocorticoid, a class of corticosteroid hormone valued for its potent anti-inflammatory and immunosuppressive effects. First introduced in the late 1950s, it is a long-acting relative of cortisol that is many times more potent than the body's natural glucocorticoids while causing little salt and water retention. It is prescribed for a broad range of conditions, including allergic and autoimmune disorders, swelling of the brain, croup, certain cancers, and, since 2020, severe COVID-19. Dexamethasone is a widely available generic medicine and appears on the World Health Organization's list of essential medicines.

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Corticosteroid

Prednisolone

Prednisolone is a synthetic corticosteroid (a glucocorticoid) with strong anti-inflammatory and immune-suppressing effects. It is used across a wide range of conditions, including allergies, asthma, rheumatoid arthritis and other autoimmune and inflammatory diseases, and it is the active form into which the related drug prednisone is converted in the body. Listed by the World Health Organization as an essential medicine, it is widely available as an inexpensive generic in oral, injectable and eye-drop forms.

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Neurosteroid

Androstadienone

Androstadienone (androsta-4,16-dien-3-one) is an endogenous volatile C19 16-androstene steroid found in male axillary sweat, semen, saliva and plasma, and the most intensively studied candidate human chemosignal or "pheromone." It is not a classical ion-channel neurosteroid; its central actions are triggered peripherally through the main olfactory epithelium, where the odorant receptor OR7D4 (a G-protein-coupled receptor) is the principal transducer and its genetic variation explains much of the wide person-to-person difference in whether the compound smells sweaty, urinous, sweet or nothing at all. Controlled exposure has been reported to modulate mood, sustained attention, salivary cortisol, autonomic tone and hypothalamic and frontolimbic activity, often in a sex-dependent and strongly context-dependent way. The evidence base is large but contested; effect sizes are small and several findings have failed to replicate, so the compound remains a putative rather than a proven pheromone.

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Neurosteroid

Deoxycorticosterone

Deoxycorticosterone (11-deoxycorticosterone, 21-hydroxyprogesterone; also called cortexone or desoxycortone) is an endogenous steroid hormone made by the adrenal cortex that functions both as a mineralocorticoid and as the metabolic precursor to a potent neurosteroid. Acting through the mineralocorticoid receptor (a ligand-activated transcription factor that governs sodium and water balance), it promotes renal salt retention with an affinity close to that of aldosterone. Its principal relevance to neuropharmacology is as the parent compound of 3-alpha,5-alpha-tetrahydrodeoxycorticosterone (THDOC), a positive allosteric modulator of the GABA-A receptor (the brain's main inhibitory chloride channel) that is released during stress and shapes seizure threshold, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis activity. Deoxycorticosterone should not be confused with the psychedelic amphetamine also abbreviated DOC (2,5-dimethoxy-4-chloroamphetamine), which is an entirely unrelated compound.

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Nootropic

DHEA Sulfate

DHEA sulfate (DHEAS) is the 3-beta sulfate ester of dehydroepiandrosterone and the most abundant circulating steroid in the human body, present in plasma at concentrations roughly a thousandfold higher than unconjugated DHEA. Synthesized principally in the zona reticularis of the adrenal cortex, it functions as a stable, long-lived reservoir that is interconverted with DHEA and supplies a precursor pool for downstream androgens and estrogens. Within the nervous system it is classified as a neurosteroid (a steroid synthesized in or acting directly upon nervous tissue); it acts as an agonist at the sigma-1 receptor (an intracellular chaperone protein), a positive modulator of the NMDA receptor (a glutamate-gated excitatory ion channel), and a negative allosteric modulator of the GABA-A receptor (the brain's principal inhibitory ion channel), giving it a net excitatory, pro-cognitive neuromodulatory profile. Circulating concentrations fall markedly with age, a decline termed adrenopause that has made DHEAS a widely studied biomarker of adrenal function, cognitive aging, and longevity.

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Anxiolytic

Fasedienol

Fasedienol (developmental code PH94B; international nonproprietary name aloradine) is a synthetic steroidal compound of the "pherine" class, formulated as a low-dose intranasal spray for the acute, as-needed treatment of anxiety. It is chemically the synthetic 4,16-androstadien-3β-ol isomer (molecular formula C19H28O), structurally related to but deliberately distinct from the endogenous putative human pheromone 5,16-androstadienol. Unlike classical neurosteroids such as allopregnanolone, it is not appreciably absorbed into the systemic circulation and does not act by directly modulating central GABA-A receptors (the brain's main inhibitory ion channels); instead it activates peripheral chemosensory neurons in the nasal mucosa, generating afferent signals that reach the olfactory bulb and amygdala (the brain's fear and threat-processing hub). Developed by Pherin Pharmaceuticals and later licensed to VistaGen Therapeutics, it advanced through positive Phase 2 trials in social anxiety disorder but produced mixed results in the pivotal PALISADE Phase 3 program, and it has continued to be investigated for generalized anxiety disorder and post-traumatic stress disorder.

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Antidepressant

Itruvone

Itruvone (development code PH-10, also written PH10) is an investigational synthetic neuroactive steroid of the pherine class being studied as a rapid-acting intranasal treatment for major depressive disorder. Chemically a pregnane steroid (pregn-4-en-20-yn-3-one, an ethynyl-substituted steroid backbone), it is delivered as a low-dose aqueous nasal spray and is proposed to act through a novel chemosensory mechanism, engaging receptors in the nasal lining that signal to limbic (emotion-processing) brain circuits without meaningful systemic absorption. In an early exploratory randomized trial it separated from placebo on standard depression rating scales within the first week of treatment and showed a benign side-effect profile, though its evidence base remains limited to small studies. It is developed by Vistagen and is frequently confused with its sibling pherine fasedienol (PH94B), which targets social anxiety disorder instead.

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Nootropic

MAP4343

MAP4343 (3β-methoxypregnenolone) is a synthetic derivative of the endogenous neurosteroid pregnenolone in which the 3β-hydroxyl group is replaced by a methyl ether, developed by the French steroid pharmacologist Étienne-Émile Baulieu and the biotechnology company Mapreg. Unlike classical neurosteroids that modulate ligand-gated ion channels, MAP4343 acts on microtubule-associated protein 2 (MAP2; a structural protein that governs the assembly and stability of neuronal microtubules), where it promotes tubulin polymerization and restores microtubule dynamics. It has been investigated as a novel, mechanistically distinct antidepressant and anti-addiction candidate, showing rapid and durable antidepressant-like effects in rodent and tree shrew stress models and having advanced into early clinical development. As of the mid-2020s it remains an investigational agent without regulatory approval.

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Neurosteroid

THDOC

THDOC (3-alpha,5-alpha-tetrahydrodeoxycorticosterone) is an endogenous neurosteroid (a steroid that acts rapidly on neuronal membrane receptors rather than on classical nuclear hormone receptors) and the fully reduced 3-alpha,5-alpha metabolite of the adrenal steroid deoxycorticosterone. It is one of the most potent naturally occurring positive allosteric modulators (compounds that amplify a receptor's response to its own transmitter) of the GABA-A receptor, the brain's principal inhibitory chloride ion channel, where it enhances both fast synaptic and sustained extrasynaptic inhibition. Because its synthesis is driven by adrenocorticotropic hormone and by acute stress, THDOC is regarded as a stress-responsive inhibitory neurosteroid that provides negative feedback on the hypothalamic-pituitary-adrenal axis and transiently raises the seizure threshold. Alongside allopregnanolone, it is a prototypical member of the stress-derived GABAergic neurosteroid family.

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