Cosyntropin

A synthetic 24-amino-acid peptide identical to the N-terminal segment of adrenocorticotropic hormone, FDA approved since 1970 as Cortrosyn and used worldwide as tetracosactide (Synacthen) as the stimulating agent in the short ACTH test of adrenal cortisol reserve.

Also referenced as: Tetracosactide, Tetracosactrin, Tetracosactide acetate, Cosyntropin acetate, Cortrosyn, Synacthen, ACTH 1-24, ACTH(1-24)

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What is Cosyntropin?

Cosyntropin is a synthetic peptide of 24 amino acids whose sequence is identical to the first 24 residues, counted from the N-terminus, of the 39-residue human adrenocorticotropic hormone (ACTH); the US label names it synthetic beta 1-24 corticotropin and gives the empirical formula C136H210N40O31S and a molecular weight of 2,934 g/mol. Cosyntropin is the United States Adopted Name; the international nonproprietary name is tetracosactide (older British usage: tetracosactrin), and the same molecule is sold as Cortrosyn in the United States and as Synacthen in most other markets. It is a clinic and hospital diagnostic rather than a research-market compound: its approved job is to deliver a standardized, supramaximal ACTH signal to the adrenal cortex so that the cortisol response can be measured in the short ACTH stimulation test, and it has little, if any, presence among research-peptide vendors.

How it works

• Agonist at the adrenal ACTH receptor (MC2R), which depends on an accessory protein. ACTH acts through the melanocortin-2 receptor on the adrenal zona fasciculata, and MC2R cannot reach the cell surface or respond to ACTH without the melanocortin-2 receptor accessory protein (MRAP); loss-of-function MRAP mutations cause familial glucocorticoid deficiency type 2, an inherited ACTH resistance (Metherell et al., Nature Genetics, 2005;37(2):166-170). A 3.3 Å cryo-EM structure of the ACTH-bound MC2R-Gs-MRAP1 complex (PDB 8GY7) shows MRAP1 acting as a “seat belt” that stabilizes ACTH in the receptor pocket, and the ACTH segment modeled in that structure (residues 1 through 18, Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg, including the His-Phe-Arg-Trp core and the Lys-Lys-Arg-Arg basic motif) lies entirely inside the 1-24 sequence that cosyntropin reproduces (Luo et al., Cell Research, 2023;33(1):46-54).
• Gs-coupled stimulation of steroidogenesis. Receptor activation raises cAMP and drives cholesterol delivery to the mitochondrion and the first steps of steroid synthesis, so cortisol secretion rises within minutes of injection. The label states that cosyntropin has the full corticosteroidogenic activity of natural ACTH, that the N-terminal 1-20 sequence is the minimal segment retaining full activity (dropping to 19 residues loses about 70% of potency), and that the standard 0.25 mg dose stimulates the adrenal cortex maximally, to the same extent as 25 units of natural ACTH.
• Why 24 residues rather than 39. According to the label’s pharmacodynamics section, the immunologically active region of ACTH lies in its C-terminal portion, with residues 22-39 carrying the greatest antigenicity; the 1-24 peptide keeps full biologic activity with very little immunologic activity, which was the original rationale for a truncated synthetic analog in place of pituitary-extract ACTH.
• A supramaximal stimulus, with a dose floor far below the labeled strength. In healthy volunteers the 30-minute cortisol response to 1 µg of intravenous ACTH(1-24) was indistinguishable from the response to 250 µg, while the 60-minute response was lower, and the 30-minute response was independent of basal cortisol and time of day (Dickstein et al., Journal of Clinical Endocrinology and Metabolism, 1991;72(4):773-778). That observation is the basis of the “low-dose” variant of the test discussed below.

Research status

Diagnostic use is the established evidence base. The Endocrine Society’s 2016 guideline on primary adrenal insufficiency names the short corticotropin test with 250 µg as the gold-standard diagnostic tool, with a peak cortisol below 500 nmol/L (18 µg/dL), assay dependent, at 30 or 60 minutes indicating adrenal insufficiency, and suggests the 1 µg version only when the substance itself is in short supply (Bornstein et al., Journal of Clinical Endocrinology and Metabolism, 2016;101(2):364-389). The 2024 joint European Society of Endocrinology and Endocrine Society guideline on glucocorticoid-induced adrenal insufficiency places morning cortisol ahead of stimulation testing in that setting and reserves the stimulation test for indeterminate results (Beuschlein et al., Journal of Clinical Endocrinology and Metabolism, 2024;109(7):1657-1683).

Accuracy is better for ruling in than ruling out. A Mayo Clinic systematic review pooling 30 studies of secondary adrenal insufficiency (1,209 adults, 228 children) and 5 studies of primary disease (100 patients) found that the high-dose and low-dose tests performed similarly, with high specificity but low sensitivity: positive likelihood ratios of 9.1 (high dose) and 5.9 (low dose) in adults against negative likelihood ratios of 0.39 and 0.19, and a sensitivity of 92% for the high-dose test in primary adrenal insufficiency; the authors concluded that both tests can rule in but not reliably rule out secondary adrenal insufficiency (Ospina et al., Journal of Clinical Endocrinology and Metabolism, 2016;101(2):427-434). An earlier patient-level meta-analysis of 679 subjects from 13 studies had favored the low-dose test (area under the ROC curve 0.92 versus 0.79 overall, 0.94 versus 0.85 in 254 paired subjects from seven studies) while noting its technical limitations, chiefly the dilution needed to prepare 1 µg from a 0.25 mg vial (Kazlauskaite et al., Journal of Clinical Endocrinology and Metabolism, 2008;93(11):4245-4253).

The cutoff is moving with the assays. The historical 18 µg/dL threshold was derived with older polyclonal immunoassays. In 110 patients tested in parallel on several platforms, the proportion labeled insufficient at 18 µg/dL ranged from 14.5% to 32% depending on the assay, and regression-derived 30-minute cutoffs for the newer monoclonal immunoassays and LC-MS/MS were 14.5 to 14.8 µg/dL (Javorsky et al., Journal of the Endocrine Society, 2021;5(4):bvab022). A prospective study at Montefiore Medical Center re-deriving diagnostic cortisol values after cosyntropin with a highly specific assay in 90 participants is recruiting, with primary completion estimated for December 1, 2027 (NCT05149638, last updated February 19, 2026), and a Sheffield Children’s NHS Foundation Trust program developing a non-invasive version of the test, with nasal tetracosactide and a salivary cortisol readout, is in an adult pharmacokinetic stage comparing two nasal doses against the intravenous 250 µg comparator (NeSST2, NCT03514589, phase 2, recruiting as of its December 3, 2024 update).

Therapeutic use: approved abroad in depot form, unapproved in the United States. Outside the US, a depot suspension (Synacthen Depot) is licensed in some countries for therapeutic indications that vary by jurisdiction; the United Kingdom label covers short-term therapy in conditions where glucocorticoids are indicated, such as ulcerative colitis, Crohn’s disease, and juvenile rheumatoid arthritis, and adjunctive therapy in rheumatoid arthritis and osteoarthrosis. The key trial evidence comes from infantile spasms. The United Kingdom Infantile Spasms Study randomized 107 infants to vigabatrin or hormonal treatment (oral prednisolone or intramuscular tetracosactide depot) and found spasm cessation on days 13 and 14 in 76% (19 of 25) on tetracosactide and 70% (21 of 30) on prednisolone against 54% (28 of 52) on vigabatrin (Lux et al., Lancet, 2004;364(9447):1773-1778), but by 12 to 14 months the proportion free of spasms (75% hormonal versus 76% vigabatrin) and the mean developmental scores no longer differed overall, with a developmental advantage for hormonal treatment confined to infants with no identified underlying etiology (Lux et al., Lancet Neurology, 2005;4(11):712-717). In the United States, a multicenter randomized trial of an investigational cosyntropin injectable suspension, 1 mg/mL, enrolled 37 children with new-onset infantile spasms (34 analyzed): resolution of both hypsarrhythmia and clinical spasms at day 14 occurred in 9 of 12 (75%) on cosyntropin, 1 of 9 (11%) on vigabatrin, and 5 of 13 (38%) on the combination, with the trial acknowledged as underpowered because of incomplete enrollment (Knupp et al., Journal of Child Neurology, 2022;37(3):186-193). The follow-on phase 3 trial, planned for 394 participants and sponsored by the University of Colorado, Denver with the Pediatric Epilepsy Research Foundation and West Therapeutics as collaborators (NCT03347526, started April 19, 2018), is listed as suspended with the explanation that enrollment was placed on hold as a precaution by the pharmaceutical company; its last registry update was posted May 27, 2021, and no US therapeutic approval of a cosyntropin product had followed by November 2026.

Other explored uses are small and unconfirmed. A 28-patient randomized comparison of intravenous cosyntropin with epidural blood patch for post-dural puncture headache found the blood patch superior at day 1 but no significant difference immediately after treatment or at days 3 and 7 (Hanling et al., Pain Medicine, 2016;17(7):1337-1342). Case series and small studies have used synthetic ACTH in nephrotic syndromes; none has produced a controlled, adequately powered trial.

Safety data. The US label lists anaphylactic reaction, bradycardia, tachycardia, hypertension, peripheral edema, and rash as post-marketing adverse reactions and contraindicates the product in anyone with prior hypersensitivity to it. In a retrospective review of 1,480 short Synacthen tests at an Oxford tertiary center from 2017 to 2021, adverse effects were recorded in 1.8% of tests, including one episode of anaphylaxis (Mathara Diddhenipothage et al., Clinical Endocrinology, 2023;99(2):142-151).

Common dosage forms

In the United States, cosyntropin is supplied as Cortrosyn (Amphastar, NDA 016750) and as generic cosyntropin for injection (Sandoz, ANDA 202147): a sterile lyophilized powder in a single-dose vial containing 0.25 mg of cosyntropin with 10 mg of mannitol, labeled for intramuscular or intravenous use and for diagnostic use only. A second US presentation, cosyntropin injection 0.25 mg/mL as a ready-to-use solution for intravenous use (Sandoz, NDA 022028, approved February 21, 2008), is listed in Drugs@FDA as discontinued. Outside the United States the molecule is sold as tetracosactide acetate: Synacthen ampoules of 250 µg in 1 mL as a solution for injection or infusion, and Synacthen Depot as a 1 mg/mL suspension of tetracosactide adsorbed onto zinc phosphate, for intramuscular injection only. The 1 mg/mL cosyntropin injectable suspension used in the US infantile-spasms trials is investigational and not marketed.

Key considerations

• Regulatory status. The FDA Approved status reflects Cortrosyn, NDA 016750, which Drugs@FDA records as originally approved on April 22, 1970. The current Cortrosyn label’s Highlights carry “Initial U.S. Approval: 2008,” a date that tracks the modern labeling lineage rather than the 1970 original; the ready-to-use solution approved under NDA 022028 on February 21, 2008 has since been discontinued, and a generic lyophilized vial (ANDA 202147) remains on the market. The approved US indication is purely diagnostic, as an adjunct to other tests in screening for adrenocortical insufficiency in adults and children; therapeutic indications exist only for depot tetracosactide products licensed abroad.
• Not the same drug as Acthar Gel. Repository corticotropin injection (Acthar Gel, initial US approval 1952) is a naturally sourced porcine pituitary extract whose major component is N-25 deamidated porcine ACTH(1-39) in 16% gelatin, formulated for prolonged release and indicated for infantile spasms, multiple sclerosis exacerbations, and a list of other conditions, with no diagnostic indication on its current label. Cosyntropin is a single, defined, fully synthetic 24-residue peptide with an immediate-release profile and a diagnostic indication. The two are not interchangeable, and the infantile-spasms evidence for one does not transfer to the other.
• The test rules in better than it rules out. The pooled negative likelihood ratios above mean a normal response does not exclude secondary adrenal insufficiency, particularly when pituitary ACTH loss is recent and the adrenal glands have not yet atrophied, and interpretation depends on which cortisol assay was used, since the newer assays read lower than the platform on which the 18 µg/dL threshold was set. Results from different laboratories and eras are not directly comparable without knowing the assay.
• Hypersensitivity is the main safety signal. Anaphylaxis is labeled and was recorded in the Oxford series; the United Kingdom Synacthen label warns that reactions may be more severe, including anaphylactic shock, in people prone to allergies, particularly asthma, and contraindicates the product in patients with allergic disorders such as asthma. The truncated 1-24 sequence was designed to be far less immunogenic than pituitary ACTH, but it is not non-immunogenic.
• Naming. Cosyntropin (US), tetracosactide (INN), tetracosactrin (older British name), ACTH(1-24), and the brands Cortrosyn and Synacthen all denote the same peptide; Synacthen and Synacthen Depot are distinct products despite the shared name. Cosyntropin has essentially no footprint in the research-peptide market, so listings under generic “ACTH” labels should not be assumed to be this molecule.