A tier · strong
Full-length ACTH is an endogenous pituitary hormone with a fully characterised human mechanism, and porcine repository corticotropin containing ACTH (1-39) holds FDA approval (Acthar Gel, initial US approval 1952; Purified Cortrophin Gel), which clears the A bar. It falls short of S because there is no multi-thousand-patient phase 3 programme — the approvals largely predate the 1962 efficacy standard and the modern randomised base is a 107-infant trial of the 1-24 analogue plus a 35-patient MS trial.
acth 1-39
ACTH 1-39 is the full-length 39-amino-acid adrenocorticotropic hormone cleaved from pro-opiomelanocortin in the anterior pituitary; it is the physiological driver of adrenal cortisol output and the analyte measured in HPA-axis testing. Porcine-derived repository corticotropin products containing ACTH (1-39) are FDA-approved in the United States for infantile spasms, acute multiple sclerosis exacerbations, nephrotic syndrome and several rheumatic and allergic conditions. The molecule most people encounter clinically in the UK is not ACTH 1-39 but tetracosactide (Synacthen), the synthetic 1-24 fragment, which is a prescription-only medicine licensed chiefly as a diagnostic agent.
the explanation
ACTH is the hormone your pituitary gland releases to tell your adrenal glands to make cortisol. The full 39-amino-acid version is a real, approved medicine in the United States, sold as a gel made from pig pituitary extract, and it is used for a rare infant seizure disorder and for multiple sclerosis flare-ups. In the UK the licensed version is a shorter 24-amino-acid copy called Synacthen, used mainly as a test of adrenal function, and it is prescription-only.
regulatory status
FDA-approved medicine in the US (porcine repository corticotropin); no UK marketing authorisation for full-length ACTH — the UK's licensed corticotropin-class drug is tetracosactide (1-24), a POM
In the United States, repository corticotropin injection is an approved prescription drug: Acthar Gel carries an initial US approval date of 1952 and is indicated as monotherapy for infantile spasms in infants and children under 2 years, for acute exacerbations of multiple sclerosis in adults, and for a list of rheumatic, collagen, dermatologic, allergic, ophthalmic, respiratory and edematous conditions; ANI's Purified Cortrophin Gel is separately approved and its label describes the active as 'porcine derived ACTH (1-39)'. Crucially, neither product is synthetic human ACTH 1-39 — Acthar's label states that 'a major component in the formulated complex mixture is N-25 deamidated porcine ACTH (1-39)'. In the UK there is no full-length corticotropin product listed on the electronic medicines compendium; the licensed corticotropin-class medicines are tetracosactide preparations (Synacthen Ampoules 250 micrograms and Synacthen Depot), both classified as prescription-only medicines (POM), with the 250 microgram ampoules restricted to 'diagnostic test for the investigation of adrenocortical insufficiency' and explicitly 'not to be used for repeated therapeutic administration'. Corticotrophins are prohibited in sport at all times, in and out of competition, under WADA Prohibited List section S2.2.2, which names tetracosactide by example.
how it works · proposed mechanism
ACTH 1-39 is generated by prohormone-convertase cleavage of pro-opiomelanocortin in anterior-pituitary corticotrophs and is the efferent limb of the hypothalamic-pituitary-adrenal axis. Its principal action is on the adrenal cortex, where it drives synthesis and release of cortisol, corticosterone, aldosterone and weakly androgenic steroids. A secondary, far less well-defined arm involves binding at other melanocortin receptors, which is the basis of claims that repository corticotropin does something a synthetic glucocorticoid does not.
Adrenal cortex stimulation via melanocortin signalling
The approved-product labels describe corticotropin as the anterior pituitary hormone that stimulates the functioning adrenal cortex to produce and secrete adrenocortical hormones — cortisol, corticosterone, aldosterone and weakly androgenic substances. This is the canonical MC2 receptor pathway on adrenal zona fasciculata cells, coupled through Gs and cyclic AMP to the steroidogenic enzyme cascade. Because the output is endogenous steroid, the clinical effect profile overlaps heavily with exogenous glucocorticoid therapy.
Activity lives in the 1-24 N-terminus
Biological potency of ACTH is carried by its amino-terminal 1-24 segment; residues 25-39 principally stabilise the molecule. This is precisely why tetracosactide, described in its UK SmPC as 'the first 24 amino acids occurring in the ACTH sequence', reproduces the steroidogenic response well enough to serve as the standard adrenal stimulation agent. It also means tetracosactide is a different chemical entity from ACTH 1-39 and its approvals do not transfer to the full-length peptide.
Claimed steroid-independent melanocortin effects
Acthar Gel's label goes no further than stating the product 'is also reported to bind to melanocortin receptors', which is the entire on-label basis for the idea of direct anti-inflammatory or immunomodulatory action beyond cortisol release. The same label states plainly that 'the mechanism of action of Acthar Gel in the treatment of infantile spasms is unknown'. Any marketing claim that ACTH is mechanistically superior to a corticosteroid therefore runs ahead of what regulators have accepted.
Depot kinetics, not native kinetics
Native ACTH is cleared from plasma within minutes, which is unworkable for therapy. The approved formulations are gelatin repository suspensions: after a single intramuscular dose, median time to peak cortisol was 8 hours with a range of 3 to 12 hours. Pharmacology observed with these depots cannot be read across to unformulated ACTH 1-39 peptide.
what’s reported
evidence shape
7 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
The approval record belongs to porcine pituitary extracts, not to the pure 39-amino-acid human peptide: Acthar Gel's own label describes N-25 deamidated porcine ACTH (1-39) as merely 'a major component in the formulated complex mixture', so batch composition, immunogenicity and potency are not equivalent to synthetic ACTH 1-39. The efficacy foundation is thin for a drug approved since 1952 — most indications predate the 1962 efficacy standard, the largest supporting randomised trial (UKISS, n=107) actually tested tetracosactide or prednisolone rather than full-length ACTH, and the multiple sclerosis randomised evidence rests on a 35-patient study that reported 90% rather than 95% confidence intervals and whose matching ClinicalTrials.gov record (NCT03126760) was terminated for recruitment difficulties and COVID-19 logistics. Other registered Acthar MS trials enrolled 5 to 30 patients and were terminated or withdrawn. The label concedes the mechanism in infantile spasms is unknown, which undercuts the central marketing claim that ACTH does something corticosteroids cannot. And the commercial history is a documented scandal: the US Department of Justice cited a price rise from roughly $50 per vial in 2001 to roughly $40,000, and Mallinckrodt paid $233.7 million in March 2022 to resolve Medicaid rebate and kickback allegations.
key published findings
- ACTH 1-39 is an endogenous POMC-derived pituitary hormone, not a designer research peptide; its sequence (SYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF), formula C207H308N56O58S and mass ~4541 Da are consistently documented.
- FDA-approved products containing ACTH (1-39) exist: Acthar Gel (initial US approval 1952) and ANI's Purified Cortrophin Gel, both porcine-derived repository corticotropin suspensions.
- Acthar Gel's approved indications include monotherapy for infantile spasms in children under 2 years and acute exacerbations of multiple sclerosis in adults, plus rheumatic, collagen, dermatologic, allergic, ophthalmic, respiratory and edematous states.
- Synacthen is tetracosactide, described in its UK SmPC as 'the first 24 amino acids occurring in the ACTH sequence' — a distinct, shorter molecule, and conflating it with ACTH 1-39 or with Acthar Gel is the core error to avoid.
- UK status: no full-length corticotropin product is listed on the UK electronic medicines compendium; tetracosactide (Synacthen, Synacthen Depot) is a prescription-only medicine (POM), with the 250 microgram ampoules licensed for diagnostic use only and explicitly 'not to be used for repeated therapeutic administration'.
- UKISS (Lancet 2004, n=107): spasms had ceased on days 13-14 in 40/55 (73%) of infants assigned hormonal treatment versus 28/52 (54%) assigned vigabatrin.
- A 35-patient randomised, double-blind, placebo-controlled trial in corticosteroid-refractory MS relapse reported day-42 EDSS improvement in 61.1% (90% CI 42.0-77.3) on repository corticotropin versus 11.8% (90% CI 4.0-30.1) on placebo, with no serious adverse events.
- WADA prohibits corticotrophins and their releasing factors at all times, in and out of competition, under S2.2.2, naming corticorelin and tetracosactide as examples.
- Pricing controversy is officially documented: DOJ described a rise from approximately $50 per vial in 2001 to approximately $40,000, and Mallinckrodt agreed in March 2022 to pay $233.7 million ($123.6m federal, $110.1m states) plus a five-year corporate integrity agreement.
limitations of the evidence
- No multi-thousand-patient phase 3 randomised programme exists for full-length ACTH 1-39 in any indication.
- Most Acthar Gel indications rest on approvals granted before the 1962 Kefauver-Harris efficacy requirements rather than on modern controlled trials.
- The label for Acthar Gel states that the mechanism of action in infantile spasms is unknown.
- UKISS randomised infants to prednisolone or tetracosactide (1-24), so its result supports hormonal treatment generally rather than the 39-amino-acid peptide specifically.
- The pivotal MS relapse RCT enrolled only 35 patients and used 90% confidence intervals; the matching trial registration was terminated early for recruitment and COVID-19 reasons.
- Registered ACTH trials in MS repeatedly failed operationally — enrolments of 5, 8, 25, 30 and 35, with several terminated or withdrawn.
- Approved products are porcine pituitary complex mixtures, so animal-sourced variability and immunogenicity risk cannot be equated with synthetic human ACTH 1-39.
- Steroid-independent melanocortin effects remain a hypothesis; no regulator has accepted a non-steroidogenic mechanism claim.
- Published pharmacokinetics describe gelatin depot formulations, not unformulated ACTH 1-39, whose native clearance is on the order of minutes.
documented safety signals
- Increased susceptibility to new infection and increased risk of exacerbation, dissemination or reactivation of latent infection (labelled warning); infections reported in 20-46% of infants treated for infantile spasms.
- Adrenal insufficiency on withdrawal after prolonged administration, reflecting HPA-axis suppression.
- Cushing's syndrome with prolonged use.
- Gastrointestinal perforation and bleeding (labelled warning).
- Hypertension reported in 11-19% and irritability in 7-19% of infants treated for infantile spasms; convulsions 12%, pyrexia 5-8%.
- Behavioural and mood disturbance including psychosis.
- Live vaccines contraindicated during immunosuppressive dosing.
- For the 1-24 analogue tetracosactide, the UK SmPC warns of hypersensitivity reactions that 'tend to be more severe (anaphylactic shock) in patients susceptible to allergies (especially asthma)', usually within 30 minutes, requiring adrenaline and steroids to be prepared in advance.
- Prohibited at all times in competitive sport (WADA S2.2.2).
identity
| full name | Adrenocorticotropic hormone (1-39), corticotropin |
| category | Ancillary & Endocrine |
| modality | peptide |
| formula | C207H308N56O58S |
| molar mass | 4541.1 g/mol |
| cas | 12279-41-3 |
| half-life | Native circulating ACTH is cleared within minutes; the approved products are gelatin 'repository' depots, with median time to peak cortisol of 8 hours (range 3–12) after a single intramuscular dose of repository corticotropin. |
| sequence | SYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF |
laboratory handling
| storage | Lyophilised peptide is stored desiccated at -20 °C and protected from light. Reconstituted solution is unstable and is prepared fresh or aliquoted and frozen. Handling information only; approved corticotropin products are gelatin depot formulations and their storage conditions do not apply to this material. |
| solubility | Soluble in water and dilute aqueous buffer; the 39-residue chain is more prone to oxidation at its methionine residue than the shorter 1-24 analogue. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
7 citedUS FDA / DailyMed · 2024 · official
US FDA / DailyMed · 2023 · official
electronic medicines compendium (emc), MHRA-approved SmPC · 2024 · official
World Anti-Doping Agency · 2025 · official
US Department of Justice, US Attorney's Office, District of Massachusetts · 2022 · official
The Lancet · 2004 · randomized
CNS Neuroscience & Therapeutics · 2022 · randomized
others in Ancillary & Endocrine