Cosyntropin
What the Research Actually Shows
Human: 2 studies, 10 groups · Animal: 0 · In Vitro: 0
The synthetic first 24 amino acids of ACTH that became the gold-standard diagnostic for adrenal insufficiency—FDA-approved since 1970, used in millions of patients worldwide, prohibited by WADA, and the clinical tool that tests whether your HPA stress axis actually works
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BLUF: Bottom Line Up Front
Cosyntropin is a synthetic version of the first 24 amino acids of ACTH—the hormone your pituitary gland makes to tell your adrenal glands to produce cortisol. A doctor injects 250 micrograms into your arm, draws blood at 30 and 60 minutes, and measures your cortisol response. If cortisol rises above 18 micrograms per deciliter, your adrenal glands work. If it does not rise, something is wrong—either the adrenal glands themselves (Addison's disease) or the pituitary signal that activates them. This test has been the gold standard for diagnosing adrenal insufficiency since 1970 and has been performed millions of times. Outside the US, a depot form is used therapeutically for infantile spasms and multiple sclerosis relapses. WADA prohibits cosyntropin because stimulating cortisol production can enhance performance.
Cosyntropin is the diagnostic face of the HPA axis. Where CRH (also in this cluster) is the brain's signal that starts the stress response, and ACTH is the pituitary signal that relays it to the adrenals, cosyntropin is the synthetic tool that tests whether the adrenal end of this chain is functioning. It is the first 24 amino acids of the 39-amino-acid ACTH molecule—the fragment that retains full biological activity—and its injection provokes cortisol release in anyone with functioning adrenal tissue.
The ACTH stimulation test (cosyntropin stimulation test) is one of the most widely performed endocrine diagnostic procedures in medicine. A single 250 mcg IV or IM injection, blood draws at 30 and 60 minutes, and a cortisol threshold of 18 μg/dL (500 nmol/L) reliably separates normal adrenal function from primary adrenal insufficiency (Addison's disease, where the adrenal glands are destroyed) and secondary adrenal insufficiency (where pituitary ACTH deficiency has caused adrenal atrophy). Sensitivity exceeds 95% for established primary AI (Bornstein et al., 2016; PMID 26760044).
Outside the United States, cosyntropin takes on a therapeutic role. Tetracosactide depot (Synacthen Depot) is an intramuscular formulation with sustained release, approved in the UK and EU for infantile spasms (West syndrome), multiple sclerosis relapses, and certain inflammatory conditions where synthetic corticosteroids have failed. The US has a different history: H.P. Acthar Gel (repository corticotropin), a porcine-derived ACTH preparation, is approved for similar indications at substantially higher cost. This article examines cosyntropin's mechanism, its role in diagnosing stress-axis dysfunction, and its position in the broader landscape of HPA axis pharmacology.
In This Article
Quick Facts: Cosyntropin at a Glance
Type
Synthetic peptide fragment, first 24 amino acids of ACTH (39 amino acids). Retains full biological activity.
Also Known As
Tetracosactide, Synacthen, ACTH 1–24, tetracosactrin, Cortrosyn
Generic Name
Cosyntropin (US), tetracosactide (EU/UK)
Route
IV bolus or IM injection (diagnostic: single 250 mcg dose). IM depot injection (therapeutic: Synacthen Depot, repeated dosing). Not available as oral, nasal, or subcutaneous formulation for self-administration.
Molecular Weight
~2,933 Da (24 amino acids)
Peptide Sequence
Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg-Pro-Val-Lys-Val-Tyr-Pro. ACTH residues 1–24. Residues 25–39 of native ACTH are not required for MC2R activation—cosyntropin has identical adrenal potency to full-length ACTH.
Endogenous Origin
Fragment of ACTH (adrenocorticotropic hormone), which is produced by anterior pituitary corticotrope cells by proteolytic cleavage of proopiomelanocortin (POMC). ACTH release is triggered by CRH (also in this cluster).
Primary Molecular Function
Binds MC2R (melanocortin-2 receptor) on zona fasciculata cells of the adrenal cortex. MC2R is a Gs-coupled receptor: activation → adenylate cyclase → cAMP → protein kinase A → activation of steroidogenic enzymes (StAR protein, CYP11A1, CYP17A1, CYP21A2, CYP11B1) → cortisol synthesis and release. Also stimulates aldosterone (zona glomerulosa) and DHEA (zona reticularis) to lesser degrees.
Active Fragment
ACTH 1–24 (cosyntropin) contains the full pharmacophore. The minimum active sequence for MC2R activation is ACTH 1–17. Residues 25–39 contribute to immunogenicity but not to receptor binding.
Brand Name
Cortrosyn (US, diagnostic), Synacthen Depot (EU/UK, therapeutic depot formulation)
Related Compound Relationship
Fragment of ACTH, which is CRH's downstream effector (CRH → ACTH → cortisol). CRH is also in Cluster J. Full-length ACTH (1–39) also activates MC1R (melanocortin-1, skin pigmentation)—cosyntropin retains weak MC1R activity, which is why chronic ACTH excess causes hyperpigmentation in Addison's disease. ACTH appears in Cluster Q for its melanocortin effects.
Clinical Programs
FDA-approved as Cortrosyn (diagnostic, 1970). Synacthen Depot approved therapeutically in UK/EU for infantile spasms, MS relapses, inflammatory conditions. H.P. Acthar Gel (porcine ACTH, US) approved for similar therapeutic indications. Low-dose (1 mcg) cosyntropin test under ongoing clinical evaluation for mild secondary AI detection.
FDA Status
Approved (1970) as diagnostic agent for adrenal insufficiency. NOT approved therapeutically in the US. Synacthen Depot is available therapeutically in UK/EU.
Community Interest
Minimal. Cosyntropin is a prescription diagnostic agent used in hospital/clinic settings. Not sold by peptide vendors. Discussed in anti-doping circles due to WADA prohibition. No biohacking or self-experimentation protocols exist.
WADA Status
Prohibited at all times. Category S2: Peptide Hormones, Growth Factors, Related Substances and Mimetics. ACTH and all its analogs (including cosyntropin) are prohibited because they stimulate endogenous cortisol production—cortisol has anti-inflammatory and potentially ergogenic effects.
Half-Life
Plasma: ~15 minutes (rapid enzymatic degradation). Adrenal effect duration: cortisol response peaks at 30–60 minutes and returns to baseline within 2–4 hours after a single 250 mcg dose. Depot formulation: sustained release over days.
Evidence Tier
1 Approved Drug
Verdict
Strong Foundation
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Subscribe to Peptidings WeeklyWhat Is Cosyntropin?
Pronunciation: koh-SIN-troh-pin
When a physician suspects your adrenal glands are not working—fatigue, low blood pressure, electrolyte abnormalities, unexplained weight loss—there is a single test that provides the answer in under an hour. The cosyntropin stimulation test. An injection of 250 micrograms of synthetic ACTH, a blood draw at 30 minutes and 60 minutes, and a cortisol measurement. If your cortisol rises above 18 μg/dL, your adrenal glands can respond to stress signals. If it does not, you have adrenal insufficiency—and the pattern of the failure tells the endocrinologist whether the problem is in the adrenal glands themselves or in the pituitary gland that commands them.
Cosyntropin is the first 24 amino acids of ACTH—adrenocorticotropic hormone—the pituitary peptide that sits in the middle of the HPA stress axis between CRH (the brain's stress signal, also in this cluster) and cortisol (the adrenal stress hormone). The full ACTH molecule is 39 amino acids, but the first 24 contain the entire receptor-binding pharmacophore. Amino acids 25–39 contribute to immunogenicity and melanocortin effects but add nothing to adrenal stimulation. By using only the active 24-residue fragment, cosyntropin provides full ACTH-equivalent adrenal stimulation with reduced immunogenicity.
The compound was first synthesized in the 1960s as part of a broader effort to create synthetic analogs of pituitary hormones. FDA approval came in 1970 as Cortrosyn, and the stimulation test rapidly became the global standard for adrenal function assessment. In over five decades of use, the test has been performed on millions of patients—making cosyntropin one of the most widely used peptides in clinical medicine.
PLAIN ENGLISH
Cosyntropin is a synthetic version of the hormone your pituitary makes to tell your adrenal glands to produce cortisol. Doctors inject it and then measure whether your cortisol goes up. If it does, your adrenal glands work. If it does not, you have a problem. This test has been used since 1970 and is one of the most common diagnostic procedures in endocrinology. Cosyntropin is the active core of the natural hormone—the first 24 of 39 amino acids—and it works identically.
Origins and Discovery
The story of cosyntropin is really the story of ACTH—one of the first pituitary hormones isolated and characterized. ACTH was purified from pituitary extracts in the 1940s and 1950s, and its amino acid sequence was determined by the early 1960s. Researchers quickly discovered that the N-terminal portion of ACTH was responsible for adrenocortical stimulation, and that the C-terminal segment (amino acids 25–39) was dispensable for this activity.
Klaus Hofmann's group synthesized ACTH 1–24 (tetracosactide) and demonstrated that it retained full corticotropic activity—identical to the 39-amino-acid parent molecule in its ability to stimulate cortisol production from adrenal cells. The shorter peptide was easier to synthesize, more consistent in purity, and less immunogenic than the full-length hormone. It was a natural candidate for clinical use.
The ACTH stimulation test predates cosyntropin—early versions used crude porcine ACTH extracts. But the availability of synthetic ACTH 1–24 standardized the test. The 250 mcg dose was chosen empirically to provide a supraphysiological ACTH stimulus that maximally stimulates even partially atrophied adrenal glands—ensuring that a normal response reliably excludes adrenal insufficiency. Cortrosyn received FDA approval in 1970.
Outside the US, tetracosactide took a different path. Synacthen Depot—a zinc phosphate complex providing sustained intramuscular release—was developed as a therapeutic agent. Because ACTH stimulates cortisol (and other corticosteroids) from the patient's own adrenal glands, depot tetracosactide produces endogenous steroid production rather than delivering exogenous steroids. This distinction has theoretical advantages (physiological steroid spectrum, intact negative feedback) and is the basis for its therapeutic use in infantile spasms and MS relapses in the UK and EU.
PLAIN ENGLISH
ACTH was one of the first pituitary hormones to be sequenced. Scientists found that only the first 24 amino acids were needed to stimulate cortisol production, so they synthesized just that fragment—cosyntropin. It became the standard diagnostic tool for testing adrenal function in 1970. In Europe, a longer-acting depot version is used as an actual treatment—making the body produce its own cortisol rather than taking synthetic corticosteroids.
Mechanism of Action
MC2R → Steroidogenesis
Cosyntropin's mechanism is straightforward and completely characterized—it is a textbook GPCR signaling cascade:
Step 1 — MC2R binding: Cosyntropin binds MC2R (melanocortin-2 receptor) on the surface of adrenal zona fasciculata cells. MC2R is unique among melanocortin receptors: it requires a co-receptor called MRAP (melanocortin-2 receptor accessory protein) for proper membrane trafficking and signaling. Without MRAP, MC2R remains trapped intracellularly. Mutations in either MC2R or MRAP cause familial glucocorticoid deficiency—genetic resistance to ACTH.
Step 2 — cAMP signaling: MC2R is Gs-coupled. Activation → adenylate cyclase → cAMP increase → protein kinase A (PKA) activation. This is the same signaling pathway used by CRH at the pituitary level and by many other GPCR-mediated systems.
Step 3 — Steroidogenic enzyme activation: PKA activates the steroidogenic acute regulatory protein (StAR), which transports cholesterol from the outer to the inner mitochondrial membrane—the rate-limiting step in cortisol synthesis. Subsequently, a cascade of cytochrome P450 enzymes (CYP11A1 → pregnenolone; CYP17A1 → 17-hydroxypregnenolone; CYP21A2 → 11-deoxycortisol; CYP11B1 → cortisol) converts cholesterol to cortisol over approximately 30–60 minutes.
Step 4 — Cortisol release: Cortisol is not stored—it is synthesized on demand and released directly into adrenal venous blood. The peak cortisol response after a 250 mcg cosyntropin injection occurs at 30–60 minutes and typically exceeds 18 μg/dL (500 nmol/L) in individuals with normal adrenal function.
The Diagnostic Logic
The stimulation test exploits a simple principle: you cannot make cortisol without functioning adrenal tissue and intact steroidogenic machinery. Cosyntropin provides a supraphysiological MC2R stimulus (250 mcg is far more ACTH than the pituitary ever produces). If the adrenal glands respond, they are functional. If they do not respond:
- Primary AI (Addison's): Adrenal tissue is destroyed (autoimmune, infection, hemorrhage). No amount of ACTH can stimulate absent tissue. Cortisol stays flat.
- Secondary AI: Pituitary ACTH deficiency → chronic understimulation → adrenal atrophy. The atrophied adrenals may not respond to a single supraphysiological ACTH dose because the steroidogenic machinery has partially regressed.
- Tertiary AI: Chronic exogenous corticosteroid use → hypothalamic CRH suppression → pituitary ACTH suppression → adrenal atrophy. Same pattern as secondary AI.
Sleep and Stress Context
Cosyntropin itself has no direct sleep effects. Its relevance to Cluster J is as the diagnostic probe for HPA axis integrity. Cortisol follows a strong circadian rhythm—peaking in the early morning (cortisol awakening response) and reaching its nadir around midnight. Disrupted cortisol rhythms are a hallmark of chronic stress, depression, and Cushing's syndrome. The cosyntropin test assesses whether the adrenal end of this rhythm is capable of responding.
PLAIN ENGLISH
Cosyntropin works by plugging into the receptor on your adrenal glands that normally receives ACTH from your pituitary. This triggers a cascade of enzymes that convert cholesterol to cortisol over about 30 to 60 minutes. The diagnostic test gives you a huge dose of this synthetic ACTH—far more than your body ever makes—and measures whether cortisol goes up. If your adrenal glands are healthy, cortisol doubles. If they are damaged or atrophied, nothing happens.
Key Research Areas and Studies
Clinical Practice Guidelines for AI Diagnosis (Bornstein et al., 2016)
Study: Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. PMID: 26760044 Scope: Comprehensive guideline covering the diagnosis and management of adrenal insufficiency. Establishes the 250 mcg cosyntropin stimulation test as the gold standard for AI diagnosis. Key recommendations: Morning cortisol <3 μg/dL strongly suggests AI. Cortisol >18 μg/dL at 30 or 60 minutes after 250 mcg cosyntropin reliably excludes primary AI. Sensitivity >95% for established primary AI. Lower sensitivity for recent-onset or mild secondary AI. Significance: This guideline codifies what has been standard practice since the 1970s. The cosyntropin test is not controversial for established AI—it is the diagnostic standard worldwide.
Low-Dose (1 mcg) Cosyntropin Test (Kazlauskaite et al., 2008)
Study: Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. PMID: 18397988 Design: Meta-analysis of 13 studies comparing standard (250 mcg) and low-dose (1 mcg) cosyntropin stimulation tests. Key findings: The 1 mcg test may be more sensitive than 250 mcg for detecting mild or recent-onset secondary adrenal insufficiency because the supraphysiological 250 mcg dose can stimulate even partially atrophied adrenals that would not respond to physiological ACTH levels. However, the 1 mcg test has technical challenges (dilution inaccuracies, adsorption to plastic syringes, timing sensitivity). Significance: Ongoing debate. The 250 mcg test remains standard in most guidelines, but the low-dose test has advocates for specific clinical scenarios (recent pituitary surgery, subclinical HPA suppression from exogenous steroids).
Synacthen Depot for Infantile Spasms
Depot tetracosactide is a first-line therapy for infantile spasms (West syndrome) in the UK and EU, based on multiple randomized trials demonstrating superiority over vigabatrin for cessation of spasms and improved developmental outcomes. The mechanism involves stimulation of endogenous corticosteroid production plus potential direct neuronal effects of ACTH-related peptides. This therapeutic application is outside the US, where H.P. Acthar Gel (porcine ACTH repository) is used instead—at substantially higher cost.
PLAIN ENGLISH
A major clinical guideline confirmed the cosyntropin test as the global standard for diagnosing adrenal insufficiency—sensitivity over 95% for established disease. There is an ongoing debate about whether a much smaller dose (1 mcg instead of 250 mcg) might catch milder cases that the standard test misses. Outside the US, a long-acting version of cosyntropin is used to treat severe childhood seizures—it makes the body produce its own steroids rather than taking synthetic ones.
Claims vs. Evidence
| Claim | What the Evidence Shows | Verdict |
|---|---|---|
| “Cosyntropin stimulation test diagnoses adrenal insufficiency” | Gold standard diagnostic procedure since 1970. Sensitivity >95% for established primary AI. Endorsed by Endocrine Society guidelines (Bornstein et al., 2016, PMID 26760044). | Supported |
| “250 mcg cosyntropin is the right dose” | Standard dose for decades. Some evidence that 1 mcg may detect mild secondary AI that 250 mcg misses (Kazlauskaite et al., 2008, PMID 18397988). 250 mcg remains guideline-recommended for routine use. | Supported with Caveat |
| “Synacthen Depot treats infantile spasms” | Multiple RCTs demonstrate efficacy for cessation of infantile spasms. First-line therapy in UK/EU guidelines. Well-established therapeutic use. | Supported |
| “Cosyntropin is identical to natural ACTH” | Cosyntropin is the first 24 amino acids of the 39-amino-acid ACTH. It has identical adrenal-stimulating potency but lacks the C-terminal segment that contributes to melanocortin effects and immunogenicity. Functionally equivalent for adrenal stimulation, not structurally identical. | Supported with Caveat |
| “Cosyntropin can enhance athletic performance” | ACTH stimulates cortisol, which has anti-inflammatory and potential ergogenic effects. WADA prohibits cosyntropin for this reason. No published study has tested cosyntropin for performance enhancement. The prohibition is based on pharmacological rationale, not evidence of misuse. | Mixed Evidence |
| “The cosyntropin test can detect all forms of adrenal insufficiency” | It reliably detects established primary AI (>95% sensitivity). It may miss recent-onset or mild secondary AI where the adrenals have not yet fully atrophied. Clinical context and repeat testing are sometimes needed. | Supported with Caveat |
| “Cosyntropin is safer than exogenous corticosteroids” | For therapeutic depot use: cosyntropin stimulates endogenous steroid production (physiological spectrum, intact feedback) rather than delivering synthetic steroids. Theoretically cleaner profile, but chronic ACTH stimulation still produces Cushing's-like effects. | Mixed Evidence |
| “Cosyntropin affects sleep” | No direct sleep effect. Cosyntropin stimulates cortisol, which has a circadian rhythm affecting sleep-wake cycles. A single diagnostic dose does not meaningfully alter sleep. Chronic therapeutic use could affect cortisol rhythm. | Unsupported |
| “H.P. Acthar Gel and cosyntropin are interchangeable” | Both stimulate cortisol via MC2R. H.P. Acthar is porcine-derived, full-length ACTH (39 aa) in a repository gel. Cosyntropin is synthetic ACTH 1–24. They are pharmacologically similar but not identical—regulatory pathways, formulations, and costs differ dramatically. | Mixed Evidence |
| “Cosyntropin self-testing can diagnose adrenal fatigue” | "Adrenal fatigue" is not a recognized medical diagnosis. The cosyntropin test diagnoses adrenal insufficiency—a specific, measurable endocrine disorder. Self-administration of cosyntropin is not practiced or recommended. | Unsupported |
| “Low-dose cosyntropin is better than standard dose” | The 1 mcg test may be more sensitive for mild secondary AI. It is also technically more difficult (dilution issues, timing sensitivity, syringe adsorption). Guidelines recommend 250 mcg as the standard first-line test. | Mixed Evidence |
| “Cosyntropin can treat multiple sclerosis” | Depot tetracosactide (Synacthen Depot) is approved for MS relapses in UK/EU as an alternative to high-dose methylprednisolone. Efficacy is established but it is not first-line. | Supported with Caveat |
The Human Evidence Landscape
Cosyntropin has one of the most extensive human evidence bases of any peptide—not from clinical trials in the traditional sense, but from decades of diagnostic use in millions of patients worldwide. The ACTH stimulation test is one of the most validated diagnostic procedures in endocrinology.
Diagnostic Evidence — Gold Standard
The 250 mcg cosyntropin stimulation test has been the standard diagnostic for adrenal insufficiency for over fifty years. Its performance characteristics are well-established: sensitivity exceeds 95% for primary adrenal insufficiency (where the adrenal glands are destroyed or severely damaged), with specificity similarly high when appropriate cortisol thresholds are used (>18 μg/dL at 30 or 60 minutes). The test is endorsed by the Endocrine Society, the European Society of Endocrinology, and virtually every endocrine guideline worldwide.
The Low-Dose Debate
The 250 mcg dose is supraphysiological—far more ACTH than the pituitary ever produces. This massive stimulus can overcome partial adrenal atrophy, meaning that patients with recent-onset secondary AI (where the adrenals have not yet fully atrophied from ACTH deprivation) may pass the standard test despite having clinically significant HPA axis impairment. The 1 mcg test provides a more physiological stimulus that may detect these milder cases. The Kazlauskaite meta-analysis (2008, PMID 18397988) supported this, but the low-dose test introduces technical variability. Most guidelines recommend 250 mcg as the standard, with the 1 mcg test reserved for specific clinical scenarios.
Therapeutic Evidence — Synacthen Depot
Outside the US, therapeutic depot tetracosactide has a substantial evidence base for infantile spasms (West syndrome), where multiple RCTs demonstrate superiority over vigabatrin for cessation of spasms. For MS relapses, depot tetracosactide is an established alternative to high-dose IV methylprednisolone, with comparable efficacy demonstrated in clinical trials. For other inflammatory conditions (gout, rheumatoid arthritis flares), the evidence is thinner—primarily case series and small trials.
PLAIN ENGLISH
The cosyntropin test is one of the most validated diagnostic procedures in medicine—used millions of times over five decades. It works by giving a huge dose of synthetic ACTH and measuring whether cortisol goes up. There is an ongoing debate about whether a much smaller dose might catch milder cases. Outside the US, a long-acting version is used as an actual treatment for severe childhood seizures and MS flares—making the body produce its own steroids.
Safety, Risks, and Limitations
Diagnostic Use (Single 250 mcg Dose)
The cosyntropin stimulation test is one of the safest diagnostic procedures in endocrinology: - Adverse events are rare: mild flushing, headache, nausea - Anaphylaxis: extremely rare (case reports exist but incidence is vanishingly low) - No cortisol-related side effects from a single dose—the transient cortisol rise is within physiological range and resolves within hours - Safe in pregnancy (Category C, but widely used when indicated)
Therapeutic Depot Use (Chronic)
Chronic depot tetracosactide produces sustained cortisol elevation with predictable consequences: - Cushing's syndrome features: moon face, central obesity, striae, buffalo hump - Hypertension (mineralocorticoid effects) - Hyperglycemia / diabetes precipitation - Osteoporosis with long-term use - Immunosuppression → infection risk - Mood changes, insomnia (cortisol effects on CNS) - Skin hyperpigmentation (MC1R activation by ACTH fragments)
These are the same risks as exogenous corticosteroid therapy because the end product is the same—cortisol. The theoretical advantage of depot tetracosactide (physiological steroid spectrum, intact negative feedback) does not eliminate these risks.
WADA Prohibition
Cosyntropin is prohibited at all times by WADA under Category S2 (Peptide Hormones). The rationale: ACTH stimulates endogenous cortisol production, and cortisol has anti-inflammatory effects that could enhance recovery from training and potentially improve performance. Athletes testing positive for cosyntropin face sanctions. Detection is via mass spectrometry identification of synthetic ACTH fragments in urine.
PLAIN ENGLISH
The diagnostic test is very safe—a single injection with rare minor side effects. The therapeutic depot form used long-term has the same risks as taking cortisol pills: weight gain, high blood sugar, high blood pressure, weakened bones, and increased infection risk. WADA bans cosyntropin because it makes your body produce more cortisol, which could help athletes recover faster.
Legal and Regulatory Status
Cosyntropin (Cortrosyn) is FDA-approved as a diagnostic agent for screening adrenal insufficiency (1970). It is a prescription medication available only through medical facilities.
Tetracosactide depot (Synacthen Depot) is approved therapeutically in the UK, EU, and several other countries for infantile spasms, MS relapses, and certain inflammatory conditions. It is NOT approved for therapeutic use in the US. In the US market, H.P. Acthar Gel (porcine-derived repository corticotropin) is the available therapeutic ACTH product—at substantially higher cost (Acthar has been a subject of pharmaceutical pricing controversies).
Cosyntropin is not sold by consumer peptide vendors and is not available for self-administration.
WADA prohibits ACTH and all analogs, including cosyntropin, at all times (S2: Peptide Hormones). This applies to in-competition and out-of-competition testing.
Research Protocols and Formulation Considerations
Standard ACTH Stimulation Test (250 mcg)
| Parameter | Detail |
|---|---|
| Compound | Cosyntropin 250 mcg (Cortrosyn) |
| Route | IV bolus or IM injection |
| Procedure | Baseline cortisol draw → cosyntropin injection → cortisol draws at 30 and 60 minutes |
| Normal response | Cortisol ≥18 μg/dL (500 nmol/L) at either 30 or 60 minutes |
| Abnormal response | Cortisol fails to rise above threshold → adrenal insufficiency |
| Setting | Outpatient clinic, infusion center, hospital |
| Timing | Best performed in the morning (0800–0900) to align with circadian cortisol peak |
Low-Dose ACTH Stimulation Test (1 mcg)
| Parameter | Detail |
|---|---|
| Compound | Cosyntropin 1 mcg (diluted from standard vial) |
| Route | IV bolus only (IM unreliable at low dose) |
| Procedure | Same as standard test |
| Threshold | Same cortisol cutoff (≥18 μg/dL) |
| Technical challenges | Dilution errors, adsorption to plastic IV tubing, precise timing critical |
| Use case | Suspected mild/recent-onset secondary AI where 250 mcg may be falsely normal |
Synacthen Depot (Therapeutic)
| Parameter | Detail |
|---|---|
| Compound | Tetracosactide depot (zinc phosphate complex) |
| Route | IM injection |
| Dose | 0.25–1.0 mg every 1–3 days (condition-dependent) |
| Duration | Sustained cortisol stimulation over 24–72 hours per injection |
Dosing in Published Research
The following table summarizes dosing protocols for Cosyntropin as reported in published clinical and preclinical research. These reflect study designs, not treatment recommendations.
Published Clinical Dosing
| Use | Route | Dose | Frequency |
|---|---|---|---|
| Diagnostic (standard) | IV/IM | 250 mcg | Single dose |
| Diagnostic (low-dose) | IV | 1 mcg | Single dose |
| Infantile spasms (UK/EU) | IM depot | 0.25–0.5 mg | Every 2 days × 2 weeks, then taper |
| MS relapse (UK/EU) | IM depot | 1 mg | Daily × 5 days |
Dosing in Self-Experimentation Communities
WHY NO COMMUNITY DOSING SECTION?
Cosyntropin is an FDA-approved prescription medication. Dosing is established by clinical guidelines and managed by prescribing physicians. Community “dosing protocols” for prescription medications can be dangerous and are not appropriate to present here. Consult your healthcare provider for dosing information.
Why This Section Is Nearly Empty
Cosyntropin is a prescription diagnostic/therapeutic agent used in medical settings. It is not sold by peptide vendors, not discussed in biohacking forums for self-use, and has no self-experimentation protocol. The only non-medical discussions of cosyntropin involve WADA prohibition—athletes need to know that cosyntropin is banned and detectable. Self-injection of cosyntropin would stimulate cortisol production with no clinical benefit outside of a diagnostic context—and chronic use would produce Cushing's syndrome.
Combination Stacks
COMMUNITY-SOURCED INFORMATION
The dosing information below is drawn from community reports, forums, and anecdotal sources — not clinical trials. It reflects what people report using, not what has been validated by research. This is not medical advice.
Research into Cosyntropin combination protocols is limited. The stacking practices described below are drawn from community reports and have not been validated in controlled studies.
If you are considering combining Cosyntropin with other compounds, consult a qualified healthcare provider. Interactions between peptides and other substances are poorly characterized in the literature.
Related Compounds: How Cosyntropin Compares
Cosyntropin belongs to a broader family of compounds being investigated for similar applications. The table below compares key characteristics across related compounds in the Sleep, Stress & Recovery cluster.
Mechanistic overlap does not imply equivalent evidence. Each compound has a distinct research profile, regulatory status, and level of clinical validation.
| Compound | Type | Evidence Tier | Verdict | Primary Mechanism | Primary Application | Human Data | FDA Status | WADA Status | Key Limitation |
|---|---|---|---|---|---|---|---|---|---|
| Neuropeptide Y | Neuropeptide (36 aa) | Tier 2 — Clinical Trials | Eyes Open | Y1 receptor anxiolysis, CRH antagonism, HPA axis modulation | Stress resilience, PTSD, anxiety | Phase Ib RCT (intranasal, PTSD) + RCT (MDD) — ~54 patients total | Not approved | Not prohibited | Small early-phase trials; intranasal BBB penetration uncertain |
| Desmopressin | Synthetic vasopressin analog (9 aa, cyclic) | Tier 1 — Approved Drug | Strong Foundation | V2 receptor agonism → antidiuresis → reduced nocturnal urine volume | Nocturnal enuresis, nocturia, central DI | Cochrane review (47 RCTs, N=3,448) + Phase III nocturia (N=757) | Approved (multiple formulations, 1978+) | Not prohibited | Hyponatremia risk; nasal spray withdrawn for enuresis (2007) |
| Corticotropin-Releasing Hormone | Neuropeptide (41 aa) | Tier 4 — Preclinical (therapeutic) | Eyes Open | HPA axis master switch — CRH-R1 activation → ACTH → cortisol | Understanding stress biology; CRH-R1 antagonists for depression (failed) | Biomarker studies (elevated CSF CRH in depression); CRH-R1 antagonist trials failed | Diagnostic only (Acthrel for Cushing's differentiation) | Not prohibited | CRH-R1 antagonists failed in depression trials despite strong mechanistic rationale |
| Orexin | Neuropeptide pair (OxA 33 aa + OxB 28 aa) | Tier 1 — Approved Drug | Strong Foundation | OX1R/OX2R wake promotion; loss → narcolepsy | Insomnia (via DORAs); narcolepsy diagnosis/treatment | 3 Phase III DORA trials (N=4,945 total); CSF orexin diagnostic for narcolepsy | 3 DORAs approved (suvorexant 2014, lemborexant 2019, daridorexant 2022) | Not prohibited (DORAs may be relevant) | DORAs are small molecules not peptides; orexin agonists for narcolepsy still in development |
| Cortistatin | Neuropeptide (14–17 aa, somatostatin-related) | Tier 4 — Preclinical Only | Eyes Open | Cortical activity depression → slow-wave sleep induction; ACh antagonism | Deep sleep promotion (theoretical) | None | Not approved | Not prohibited | No human data; single research group; somatostatin receptor cross-reactivity |
| Galanin | Neuropeptide (29 aa) | Tier 3 — Limited Human Data | Eyes Open | VLPO sleep-switch activation; LC noradrenergic inhibition | Sleep initiation; potential antidepressant | 1 IV study in healthy men: increased REM, preliminary antidepressant signal | Not approved | Not prohibited | Single small human study; 3 receptor subtypes with opposing effects complicate targeting |
| PACAP | Neuropeptide (27–38 aa, VIP family) | Tier 2 — Clinical Trials | Eyes Open | PAC1/VPAC receptor activation → stress amplification + migraine | Migraine prevention (via anti-PAC1 antibody); PTSD genetics | Phase 2 anti-PAC1 antibody (migraine, positive); PTSD genetic association | Not approved (anti-PAC1 Lu AG09222 Phase 2b ongoing) | Not prohibited | Therapeutic = blocking PACAP not administering it; stress/sleep applications undeveloped |
| Melanin-Concentrating Hormone | Neuropeptide (19 aa) | Tier 4 — Preclinical Only | Eyes Open | MCH neuron activation → selective REM sleep promotion | REM sleep regulation; narcolepsy (MCHR1 antagonism) | None clinical | Not approved; HBS-102 IND stage (narcolepsy) | Not prohibited | No human clinical data; obesity MCHR1 programs failed; narcolepsy IND not advanced |
| Cosyntropin | Synthetic ACTH fragment (24 aa) | Tier 1 — Approved Drug | Strong Foundation | MC2R activation → adrenal cortisol production | Adrenal insufficiency diagnosis (ACTH stimulation test) | Millions of diagnostic tests performed worldwide since 1970 | Approved diagnostic (Cortrosyn, 1970). Synacthen Depot therapeutic (EU/UK). | Prohibited (S2 — ACTH analogs) | US diagnostic only; therapeutic use primarily outside US |
Frequently Asked Questions
What is cosyntropin?
Cosyntropin is a synthetic version of the first 24 amino acids of ACTH—the pituitary hormone that tells your adrenal glands to make cortisol. It is used as a diagnostic test for adrenal insufficiency (Addison's disease and related conditions). A single injection followed by blood draws at 30 and 60 minutes measures whether your adrenal glands can respond to stress signals.
How does the cosyntropin stimulation test work?
A nurse or doctor injects 250 micrograms of cosyntropin into your arm (IV or IM). Blood is drawn at baseline, 30 minutes, and 60 minutes. If your cortisol rises above 18 μg/dL, your adrenal glands are functioning normally. If cortisol fails to rise, you may have adrenal insufficiency—further testing determines whether the problem is in the adrenal glands or in the pituitary.
Is the cosyntropin test accurate?
For established primary adrenal insufficiency, sensitivity exceeds 95%. It is the global diagnostic standard endorsed by every major endocrine society. It is less sensitive for mild or recent-onset secondary AI, where the low-dose (1 mcg) version may be better but is technically more challenging.
Is cosyntropin the same as ACTH?
It is the active fragment. Natural ACTH has 39 amino acids. Cosyntropin is the first 24—the portion that contains the full MC2R binding site. It stimulates cortisol production identically to full-length ACTH. The missing C-terminal amino acids (25–39) contribute to melanocortin effects and immunogenicity but not to adrenal function.
Why is cosyntropin banned by WADA?
ACTH and all analogs are prohibited (S2: Peptide Hormones) because they stimulate endogenous cortisol production. Cortisol has anti-inflammatory effects that could enhance recovery from exercise-induced inflammation and potentially improve performance. Detection uses mass spectrometry to identify synthetic ACTH fragments in urine.
What is Synacthen Depot?
Synacthen Depot is a sustained-release formulation of tetracosactide (cosyntropin equivalent) approved in the UK and EU as a therapeutic agent. It is used for infantile spasms, MS relapses, and certain inflammatory conditions. It works by stimulating the patient's own adrenal glands to produce cortisol rather than delivering synthetic steroids.
Is cosyntropin the same as Acthar Gel?
They are pharmacologically similar but not identical. Cosyntropin is synthetic ACTH 1–24. H.P. Acthar Gel is porcine-derived full-length ACTH (1–39) in a repository gel formulation. Both stimulate cortisol production via MC2R. Acthar Gel has been controversial due to its very high price in the US market.
Does cosyntropin affect sleep?
Not directly. A single diagnostic dose produces a transient cortisol rise that resolves within hours and does not meaningfully affect sleep. Cosyntropin's relevance to Cluster J is as the diagnostic tool for HPA axis function—the system that connects stress and cortisol to sleep regulation.
Can cosyntropin diagnose \u0022adrenal fatigue\u0022?
\u0022Adrenal fatigue\u0022 is not a recognized medical diagnosis—it is a term used in alternative medicine that does not correspond to a measurable endocrine disorder. The cosyntropin test diagnoses adrenal insufficiency, which is a specific, measurable condition where the adrenal glands cannot produce adequate cortisol. These are different concepts.
How does cosyntropin relate to CRH?
CRH (also in this cluster) is the brain signal that starts the stress response. CRH triggers ACTH release from the pituitary. ACTH (or cosyntropin, its synthetic fragment) triggers cortisol release from the adrenals. Cosyntropin tests the adrenal end of this chain—whether the glands can respond when stimulated. CRH testing (Acthrel) tests the pituitary response to the brain signal.
Is the cosyntropin test painful?
It involves an injection (IV or IM) and two or three blood draws over 60 minutes. The injection itself is brief. Some patients experience mild flushing or warmth after injection. The test is typically completed in an outpatient setting in under 90 minutes.
Can children have the cosyntropin test?
Yes. The standard 250 mcg dose is used in children of all ages for suspected adrenal insufficiency. Weight-adjusted dosing (15 mcg/kg) has been proposed for neonates and infants but the standard 250 mcg dose is most commonly used in pediatric endocrinology.
Summary of Key Findings
Cosyntropin is the clinical tool that tests whether the HPA stress axis can deliver its final product—cortisol. As a synthetic fragment of ACTH retaining full adrenal-stimulating activity, it has been the gold-standard diagnostic for adrenal insufficiency since 1970. The evidence base is not measured in clinical trials but in decades of global clinical practice—millions of patients, sensitivity exceeding 95% for established primary AI, and endorsement by every major endocrine guideline.
Its position in Cluster J is structural rather than therapeutic. Cosyntropin does not promote sleep, modulate stress perception, or aid recovery. But it is the diagnostic probe for the system that connects all of those functions: the HPA axis, initiated by CRH, relayed by ACTH, and executed by cortisol. When a patient presents with fatigue, hypotension, and electrolyte abnormalities—symptoms that overlap with stress-related and sleep-related complaints—the cosyntropin test determines whether the problem is an endocrine emergency (adrenal insufficiency) or something else entirely.
Outside the US, the therapeutic depot formulation adds a treatment dimension—stimulating the body's own cortisol production for infantile spasms and MS relapses rather than delivering synthetic steroids. WADA prohibits cosyntropin because stimulating endogenous cortisol production has anti-inflammatory and potentially ergogenic effects.
Verdict Recapitulation
Evidence Tier 1 — Approved Drug. FDA-approved diagnostic since 1970. Synacthen Depot approved therapeutically in UK/EU. Gold standard for adrenal function assessment worldwide.
Verdict: Strong Foundation. The cosyntropin stimulation test is as established as any diagnostic procedure in endocrinology. The mechanism is completely characterized, the clinical utility is undisputed, and the evidence base spans five decades of global use. This is a peptide whose value was proven before most compounds on this site were discovered.
For readers considering Cosyntropin, the evidence above represents the current state of knowledge. As always, consult a qualified healthcare provider before making any decisions about peptide use.
Where to Source Cosyntropin
Further Reading and Resources
If you want to go deeper on Cosyntropin, the evidence landscape for sleep, stress & recovery peptides, or the methodology behind how we evaluate this research, these are the places worth your time.
ON PEPTIDINGS
- Sleep, Stress & Recovery Research Hub — Overview of all compounds in this cluster
- Reconstitution Guide — How to properly prepare injectable peptides
- Storage and Handling Guide — Proper storage to maintain peptide stability
- About Peptidings — Our editorial methodology and evidence framework
EXTERNAL RESOURCES
- PubMed: Cosyntropin — All indexed publications
- ClinicalTrials.gov — Active and completed trials
Selected References and Key Studies
- Bornstein SR, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364–389 PubMed
- Kazlauskaite R, et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab. 2008;93(11):4245–4253 PubMed
- Lerman P, Prahalad P. Repository corticotropin injection: a review of cosyntropin and its clinical and financial implications. Clin Ther. 2009. PMC2697107
- Hofmann K, et al. Studies on polypeptides: the synthesis of tetracosactide (ACTH 1–24). J Am Chem Soc. 1963;85(6):833–834
- Langer M, et al. Synacthen Depot versus vigabatrin in infantile spasms (ICISS): a multicentre, randomised, open-label trial. Lancet Neurol. 2017;16(1):33–42 PubMed
- Husebye ES, et al. Adrenal insufficiency. Lancet. 2021;397(10274):613–629 PubMed
DISCLAIMER
Cosyntropin is an FDA-approved prescription medication. The information presented in this article is for educational purposes only. Off-label uses discussed here may not be supported by the same level of evidence as the approved indications. Always follow the guidance of your prescribing physician.
Consult a qualified healthcare provider before making any decisions about peptide use. Report adverse events to the FDA via MedWatch.
For the full Peptidings editorial methodology and evidence framework, visit our About page and Evidence Framework pages.
Article last reviewed: April 09, 2026. Next scheduled review: October 06, 2026.