ACTH (1-34)

What it is

ACTH(1-34) is the biologically active N-terminal 34-amino-acid fragment of the 39-amino-acid full-length adrenocorticotropic hormone (ACTH). Full biological activity of ACTH resides within the first 24 residues (ACTH 1-24 = cosyntropin/tetracosactide), while the C-terminal residues 25-39 contribute to immunogenic and pharmacokinetic properties. ACTH is itself derived from proopiomelanocortin (POMC), a precursor that also gives rise to α-MSH, β-endorphin, and related peptides. The primary mechanism is activation of the melanocortin-2 receptor (MC2R), the adrenal-specific GPCR expressed on adrenocortical zona fasciculata and zona reticularis cells (PMID 23392095, PMID 18713819). MC2R is a Gs-coupled receptor: binding elevates adenylyl cyclase activity, increases intracellular cAMP, and activates PKA, which phosphorylates StAR (steroidogenic acute regulatory protein) and upregulates transcription of steroidogenic enzymes including P450scc (CYP11A1), P450c17 (CYP17A1), 21-hydroxylase (CYP21A2), and 11β-hydroxylase (CYP11B1). This cascade drives de novo cortisol (and to a lesser extent aldosterone) biosynthesis from cholesterol in a dose-dependent manner. Beyond adrenal steroidogenesis, ACTH(1-24) has been shown to stimulate non-insulin-mediated glucose uptake (NIMGU) in skeletal muscle cells via a carrier-mediated mechanism at physiological to supraphysiological concentrations. ACTH binds melanocortin receptors expressed on melanocytes, contributing to melanogenic activity — ACTH(1-24) is a moderate potency melanogenesis stimulator compared to α-MSH. MC2R function requires the accessory protein MRAP (MC2R Accessory Protein) for proper receptor trafficking to the cell membrane. Genetic defects in MC2R, MRAP, or StAR cause familial glucocorticoid deficiency (ACTH resistance syndrome), demonstrating the essentiality of this signaling cascade. Repository corticotropin (full-length ACTH 1-39) and synthetic ACTH(1-24) depot formulations produce different steroidogenic exposure profiles — ACTH(1-24) depot provides substantially higher peak cortisol stimulation than repository corticotropin at therapeutic doses. In clinical diagnostics, the standard 250-µg cosyntropin stimulation test (CST) is the gold standard for adrenal insufficiency diagnosis; post-ACTH cortisol ≥18-18.1 µg/dL at 30–60 minutes indicates intact adrenal reserve (PMID 33122342, PMID 42139516).

Class: Synthetic N-terminal fragment of adrenocorticotropic hormone (ACTH) / melanocortin receptor agonist / adrenal steroidogenesis stimulator

What it's studied for

• Diagnostic assessment of adrenal insufficiency (cosyntropin stimulation test) Human observational
  • Retrospective study (n=393 short synacthen tests, 250 µg synthetic ACTH). Post-ACTH cortisol ≥420 nmol/L at 60 min = normal. Basal morning cortisol ≥354 nmol/L was 100% sensitive predictor of normal reserve — using this threshold could eliminate ~37% of SSTs. Peak cortisol strongly correlated with baseline (R=0.610). S PMID 33122342 Kumar R et al. Postgrad Med J. 2022.
  • Retrospective analysis (n=140, mean age 45.6±19.3 years) undergoing 250-µg cosyntropin stimulation. Revised threshold of 15.6 µg/dL at 60 min reduced false-positive diagnoses by 17.9% vs. traditional 18.0 µg/dL cutoff. Baseline cortisol >13.1 µg/dL predicted normal response; <1.5 µg/dL indicated pathology. High diagnos PMID 41679895 Fernández Velasco P et al. Endocrinol Diabetes Nutr. 2026.
  • Retrospective study (n=298 post-unilateral adrenalectomy patients). Cosyntropin testing post-op day 1: cortisol >10 µg/dL normalised both groups; at <5 µg/dL, abnormal responses in 75% of cortisol-secreting vs. 27% of non-secreting tumours. Supports selective use of CST based on basal cortisol to minimize unnecessary s PMID 42816228 Akkus D et al. Surgery. 2026.
  • Retrospective cohort (n=68 infants <6 months undergoing ACTH stimulation). 43% showed subnormal cortisol; 69% of those lacked identified pathology, with 90% normalizing on repeat testing at median 0.6 years. Small-for-gestational-age infants more frequent among transient cases. Emphasizes need for serial testing in neo PMID 29330170 Tan TSE et al. Arch Dis Child. 2018.
• Adrenocortical steroidogenesis stimulation — mechanistic studies In vitro only
  • HAC15 human adrenocortical carcinoma cells expressing functional MC2R responded to ACTH in dose-dependent manner with increased cortisol and aldosterone production; all steroidogenic enzymes upregulated on qRT-PCR. Model confirmed utility for studying molecular mechanisms of ACTH/MC2R-driven steroidogenesis. PMID 18713819 Parmar J et al. J Clin Endocrinol Metab. 2008.
  • Review: MC2R (ACTH receptor) is adrenal-specific; requires MRAP accessory protein for membrane trafficking. FGD genetic defects in MC2R, MRAP, StAR, MCM4, and NNT genes cause ACTH resistance syndrome. Identifies adrenal cortex as exceptionally vulnerable to replicative and oxidative stress. Confirms cAMP/PKA/StAR casca PMID 23392095 Meimaridou E et al. Endocr Dev. 2013.
• Pharmacological HPA axis stimulation — comparative formulation studies Human observational
  • Phase 1 study in healthy adults: synthetic ACTH(1-24) depot 1 mg twice weekly produced steroidogenic exposure equivalent to ~57 mg/day prednisone; repository corticotropin (full-length) at therapeutic doses equivalent to ~5–16 mg/day prednisone. Demonstrates pharmacological non-equivalence of different ACTH formulation PMID 33369276 Wang X et al. Clin Pharmacol Drug Dev. 2021.
• Adrenal function testing — post-steroid-exposure cortisol recovery Human observational
  • Retrospective cohort (n=115 thyroid eye disease patients) receiving 4.5 g cumulative IV methylprednisolone over 12 weeks; 250-µg ACTH stimulation 7-10 days post-treatment. 93% showed adequate cortisol response at 30 min; 100% at 60 min. All patients with severely depressed baseline cortisol (<5 µg/dL) had intact adrena PMID 42139516 Effraimidis G et al. Eur J Endocrinol. 2026.
• PTSD and trauma — adrenocortical hyperresponsivity studies Human observational
  • Controlled study (n=45 male veterans: 13 PTSD+, 22 PTSD−, 10 non-exposed). Low-dose cosyntropin (1 µg IV): war-exposed groups (both PTSD+ and PTSD−) showed significantly elevated stimulated cortisol vs. non-exposed controls. War-zone exposure itself — independent of PTSD diagnosis — produces persistent adrenocortical h PMID 24485487 Golier JA et al. Psychoneuroendocrinology. 2014.

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

Safety signals

• Standard 250-µg cosyntropin IV/IM is well-established as safe in clinical use; 93–100% of patients tested post-high-dose glucocorticoid therapy showed adequate adrenal response with no adverse events described in abstract. PMID 42139516
• Low-dose 1-µg cosyntropin IV in 45 veterans: no adverse events described; procedure well-tolerated in outpatient setting. PMID 24485487
• Synthetic ACTH(1-24) depot at therapeutic doses produces steroidogenic exposure equivalent to ~57 mg/day prednisone — markedly higher glucocorticoid exposure than repository corticotropin. Risk of glucocorticoid excess with repeated depot administration. PMID 33369276

Contraindications

• Cushing's syndrome and autonomous adrenal cortisol hypersecretion — cosyntropin stimulation testing may not be interpretable in patients with pre-existing hypercortisolism; should only be performed when cortisol excess has been excluded. PMID 42816228
• WADA-prohibited in competitive sport — ACTH and its fragments are listed under S2 Peptide Hormones; use in athletes competing under WADA rules is prohibited regardless of therapeutic intent without TUE. PMID 33369276
• No additional formal contraindications established in reviewed literature beyond standard medical cautions. ACTH should not be used for adrenal insufficiency treatment (as opposed to diagnosis) without physician supervision, given risk of adrenal crisis if pituitary or adrenal function is severely impaired. PMID 23392095