Macimorelin
Orally active ghrelin receptor agonist, FDA-approved in 2017 as a single-dose diagnostic for adult growth hormone deficiency — not a treatment.
What is Macimorelin?
Macimorelin is a small peptidomimetic — a tripeptide-based ghrelin (GHSR-1a) receptor agonist re-engineered for oral bioavailability and metabolic stability. It is sold under the brand name Macrilen and is the first and so far only oral growth-hormone secretagogue approved by the FDA (December 2017) and EMA (2019) as a diagnostic test for adult growth hormone deficiency (AGHD). The test is a single-use procedure: a patient fasts overnight, dissolves a 0.5 mg/kg dose of macimorelin granules in roughly 120 mL of water, drinks it within 30 seconds, and serum growth hormone is sampled at 30, 45, 60, and 90 minutes. A peak GH below the FDA-cleared cutoff of 2.8 ng/mL diagnoses AGHD with high concordance against the historic gold-standard insulin tolerance test. Crucially, macimorelin is not a therapy — it is administered exactly once as a stimulation challenge, then the patient is referred for treatment decisions about somatropin replacement on the basis of the GH response.
What Macimorelin Is Investigated For
Macimorelin's role is narrow but unique: it is the first FDA-approved oral GH-secretagogue diagnostic, designed to replace the dangerous insulin tolerance test (ITT) and the now-defunct GHRH-arginine test in evaluating adult growth hormone deficiency. The pivotal head-to-head trial (Garcia 2018) showed 95.4% negative and 74.3% positive agreement with the ITT at the label's 2.8 ng/mL cutoff — strong at confirming a normal axis, weaker at catching every ITT-positive case — with markedly better tolerability and zero hypoglycaemic risk. Outside this single diagnostic indication, macimorelin has no approved therapeutic use — it is a one-dose challenge agent, not a peptide therapy. Pediatric studies are ongoing.
History & Discovery
Macimorelin's lineage traces back to the European peptide-medicinal-chemistry programmes of the late 1990s, when groups led by Romano Deghenghi and Jean Martinez set out to design orally bioavailable ghrelin-receptor agonists from a tripeptide scaffold. The compound first appeared in the literature as EP-1572 (Broglio 2002, Journal of Endocrinological Investigation), a peptidomimetic with potent and selective GH-releasing activity in human subjects. Aeterna Zentaris licensed the asset and re-developed it as AEZS-130, repositioning the molecule away from a chronic-therapy ambition (which had stalled commercially in the wake of MK-677 and other secretagogues) toward a single-use diagnostic indication where competition was thin and unmet need was clear: the insulin tolerance test was dangerous, the GHRH-arginine test depended on GHRH that was disappearing from the US market, and clinicians needed a safer modality. Phase 2 validation (Garcia 2013, JCEM) confirmed the test's pharmacological profile, and the pivotal Phase 3 head-to-head against the ITT (Garcia 2018, JCEM) provided the FDA evidence base. Macimorelin was approved by the FDA in December 2017 under the brand name Macrilen and subsequently by the EMA in January 2019, where it is marketed as Ghryvelin rather than Macrilen. Strongbridge Biopharma (now part of Xeris Biopharma) acquired the US rights, and Novo Nordisk entered into a 2020 licensing agreement covering paediatric development — making macimorelin one of the few peptidomimetic diagnostics to reach commercial scale. The GH Research Society's 2025 Delphi consensus (Arlien-Søborg et al., Pituitary) subsequently endorsed macimorelin alongside the insulin tolerance test and the glucagon stimulation test as an acceptable first-line diagnostic option for adult GHD, formalizing what had already become common practice.
How It Works
Macimorelin binds the ghrelin receptor on the pituitary the same way the natural hunger hormone ghrelin does, telling the gland to release a burst of growth hormone. A healthy pituitary responds strongly; a damaged one cannot.
Macimorelin is a peptidomimetic agonist of the growth hormone secretagogue receptor type 1a (GHSR-1a), the same G-protein-coupled receptor activated by endogenous ghrelin. It is structurally derived from a tripeptide scaffold (a modified D-Trp/Ala/D-2-methyl-Trp backbone) optimised in the Aeterna Zentaris/Europeptides programme (originally as EP-1572) for high oral bioavailability and resistance to peptidase cleavage. On binding GHSR-1a expressed on pituitary somatotrophs, macimorelin activates Gαq/11, mobilising intracellular calcium via phospholipase-C/IP3 signalling and stimulating pulsatile GH release. There is also a hypothalamic component: GHSR-1a is expressed on GHRH neurons in the arcuate nucleus, where ghrelin-receptor activation enhances GHRH tone and suppresses somatostatin output, amplifying the somatotroph signal. The net effect is a brisk, dose-dependent rise in serum GH peaking 30–60 minutes after oral dosing — a response that requires both intact somatotroph reserve and a functional hypothalamic-pituitary axis. AGHD patients, with depleted somatotroph mass or disrupted hypothalamic input, fail to generate a normal peak. A 2025 cryo-EM and molecular-dynamics study (Wang et al., Acta Pharmacol Sin) resolved the structural basis of macimorelin's engagement with GHSR-1a, clarifying how the tripeptide-scaffold pharmacophore occupies the ghrelin-binding pocket and rationalizing the oral bioavailability and receptor selectivity that were engineered into the molecule.
Evidence Snapshot
Human Clinical Evidence
Strong. The pivotal Garcia 2018 JCEM trial established agreement with the ITT and underpins the December 2017 FDA approval. Both the FDA and EMA labels still use a 2.8 ng/mL cutoff, but the evidence has moved against it: the Garcia 2021 post hoc reanalysis (Endocr Connect) found 5.1 ng/mL gave maximal specificity at 96% with 92% sensitivity, and the first real-world series (Yadav 2026, Pituitary) found the 5.1 cutoff classified 54.0% of patients as deficient against 40.5% at 2.8 — an absolute difference in diagnostic yield of 13.5%, with the discordant low-probability cases clustering above a BMI of 35. The test itself is well validated; the cutoff is the live controversy.
Animal / Preclinical
Moderate. Mechanistic studies in rodents and primates established GHSR-1a agonism, oral bioavailability, and dose-dependent GH release; Osterstock 2010 (PLoS One) confirmed direct ghrelin-receptor stimulation of arcuate GHRH neurons.
Mechanistic Rationale
Strong. GHSR-1a agonism as a probe of somatotroph reserve has decades of physiological grounding from native ghrelin and earlier secretagogues like GHRP-6 and ipamorelin.
Research Gaps & Open Questions
What the current literature has not yet settled about Macimorelin:
- 01Performance in obesity: BMI is a well-known modifier of GH response; whether the 2.8 ng/mL cutoff needs adjustment in patients with BMI >35 remains debated.
- 02Paediatric GHD diagnosis: dose-escalation safety data exist (Csákváry 2021), but a definitive paediatric cutoff and regulatory approval are still pending in the US and EU.
- 03Use after traumatic brain injury, where somatotroph recovery may evolve for years and a single-time-point diagnostic may misclassify patients. Comparative work is currently being carried by the glucagon stimulation test (Snyder et al., Endocrinol Diabetes Metab 2026 established GST safety in adults with chronic moderate-to-severe TBI) rather than macimorelin, and prospective macimorelin data in this population remain sparse.
- 04Re-testing childhood-onset GHD at the paediatric-to-adult transition — comparative data against insulin, arginine, and glucagon-based tests are limited. Fava et al. (JCEM 2026) reported that BMI plays a minimal role in the GH response to glucagon during transition once etiology is accounted for, an insight that has not yet been replicated in a macimorelin transition cohort.
- 05Cost-effectiveness vs. the glucagon stimulation test, which is cheaper and widely available but takes 3–4 hours and has its own confounders.
- 06Whether macimorelin response correlates with downstream therapy benefit (i.e. predicts who responds best to somatropin replacement) — currently the test predicts diagnosis, not treatment response.
Forms & Administration
Macimorelin is supplied as Macrilen — single-use sachets of granules to be reconstituted in 120 mL of cold water immediately before dosing, which yields a 0.5 mg/mL solution from which only the weight-based dose volume is actually given — the number of millilitres to drink equals the patient's weight in kilograms, so a 70 kg patient drinks 70 mL and discards the rest, within 30 minutes of preparation. The patient fasts at least 8 hours, drinks the solution within 30 seconds, and remains seated. Blood for serum GH is drawn at 30, 45, 60, and 90 minutes after dosing. Each test consumes one sachet at a weight-based dose of 0.5 mg/kg. There is no chronic, multi-dose, injectable, or compounded formulation: macimorelin exists only as a single-use oral diagnostic product distributed through specialty pharmacies on prescription. Patients should not take it outside a medically supervised endocrinology testing setting; the value of the test depends entirely on standardised conditions (fasting state, no interfering medications, accurate timing of the GH samples).
Common Questions
What is macimorelin used for?
Macimorelin is used as a single-dose oral stimulation test to diagnose adult growth hormone deficiency (AGHD). It is the first FDA-approved oral GH secretagogue and is administered once, not as ongoing therapy. After dosing, blood is drawn at four timepoints over 90 minutes to measure peak GH; values below 2.8 ng/mL are consistent with AGHD.
How does the macimorelin test work?
The patient fasts overnight, then dissolves 0.5 mg/kg of macimorelin granules in about 120 mL of water and drinks the solution within 30 seconds. Serum GH is measured at 30, 45, 60, and 90 minutes. Macimorelin binds the ghrelin receptor (GHSR-1a) on pituitary somatotrophs, triggering GH release — a normal pituitary mounts a strong response, while a damaged or insufficient one cannot. The peak GH value is compared against a 2.8 ng/mL diagnostic cutoff.
How does macimorelin compare to the insulin tolerance test?
The pivotal Garcia 2018 trial in JCEM compared macimorelin head-to-head with the ITT. At the label cutoffs — 2.8 ng/mL for macimorelin, 5.1 ng/mL for the ITT — negative agreement was 95.4% and positive agreement 74.3%. In plain terms, macimorelin rarely labels an intact pituitary as deficient, but it misses roughly a quarter of the cases the ITT calls positive. It is also far more likely to produce a usable result: 99% of macimorelin tests were evaluable against 82% of insulin tolerance tests, because adequate hypoglycaemia simply could not be induced in a sizeable minority of ITTs. Macimorelin is far better tolerated: there is no hypoglycaemia, no IV access required, no continuous physician monitoring for neuroglycopenia, and the test takes 90 minutes instead of 2+ hours. The ITT remains the historical gold standard but is contraindicated in patients with seizure disorders, ischaemic heart disease, or advanced age — exactly the populations macimorelin can serve safely.
Is macimorelin a treatment or just a test?
It is purely a diagnostic — administered once. There is no approved therapeutic indication, no chronic dosing protocol, and no body of clinical-trial evidence supporting macimorelin as a GH-replacement strategy. Patients diagnosed with AGHD via macimorelin are typically referred for treatment with recombinant human GH (somatropin), not repeat doses of macimorelin.
Who should not take the macimorelin test?
The most important contraindication is concurrent use of strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort, phenytoin), which lower macimorelin exposure and produce false-positive AGHD results. The label also carries a warning about QT-interval prolongation: drugs that prolong QT should be discontinued before testing where feasible, and macimorelin is avoided in patients with congenital long QT or significant electrolyte disturbances. Recent (within 30 days) high-dose glucocorticoid use, untreated hypothyroidism, and acromegaly are also reasons to defer or avoid the test.
Can macimorelin be used in children?
Macimorelin is not yet FDA-approved for paediatric GHD diagnosis, although the Csákváry 2021 dose-escalation trial in Hormone Research in Paediatrics established safety, pharmacokinetics, and a candidate paediatric protocol. Approval applications for paediatric GHD have been pursued by the manufacturer; until those land, paediatric use is investigational and most centres still rely on clonidine, arginine, glucagon, or insulin-based stimulation tests in children.
Who Macimorelin Is NOT For
- •The US Macrilen label lists no contraindications at all — section 4 reads simply “None” — and the EU label lists only hypersensitivity to macimorelin or its excipients. Everything below is a reason to defer, reschedule, or specially supervise the test rather than a labeled contraindication.
- •Patients with congenital long QT syndrome or known significant QT prolongation, given macimorelin's modest QT-prolonging effect.
- •Patients on strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's wort, enzalutamide) — these reduce macimorelin exposure and can produce false-positive AGHD diagnoses.
- •Patients who have received high-dose glucocorticoids within roughly 30–60 days, which suppresses the somatotroph response and confounds interpretation.
- •Patients with untreated primary hypothyroidism — thyroid replacement should be optimised before testing.
- •Acromegaly or active GH-secreting pituitary tumours, where stimulation testing is not clinically meaningful and may be hazardous.
- •Pregnancy and lactation — there are no adequate human data and the diagnostic benefit rarely outweighs unknown fetal exposure.
Drug & Supplement Interactions
The most clinically important interaction is with strong CYP3A4 inducers — rifampin, carbamazepine, phenytoin, St. John's wort, enzalutamide, and similar agents lower macimorelin plasma exposure and have been documented to produce false-positive AGHD test results; these drugs should be discontinued for an appropriate washout period before testing where feasible. CYP3A4 inhibitors (clarithromycin, ketoconazole, ritonavir) raise exposure but have less clear effect on test interpretation. QT-prolonging drugs — including macrolides like clarithromycin, certain antiarrhythmics (sotalol, amiodarone), some antipsychotics, and methadone — can be additive with macimorelin's small QT effect and should be paused where it is safe to do so. Recent glucocorticoid exposure (particularly oral or injected high-dose steroids) blunts the GH response independent of any pharmacokinetic interaction. Levothyroxine should be at steady-state and TSH within range. Of note, opioids and somatostatin analogues (octreotide, lanreotide) can also dampen the response and ideally are held before the test.
Safety Profile
Common Side Effects
Cautions
- • QT-interval prolongation: macimorelin produces a small but measurable QT increase; concurrent QT-prolonging drugs should be paused where clinically reasonable.
- • Strong CYP3A4 inducers reduce macimorelin exposure and can yield false-positive AGHD diagnoses — they must be stopped before testing.
- • Recent (within ~2 months) high-dose glucocorticoid exposure can blunt the GH response and impair test accuracy.
- • Untreated hypothyroidism should be corrected before testing; thyroid hormone is permissive for the somatotroph response.
- • Test is single-use; not intended as a therapeutic agent at any dose or frequency.
What We Don't Know
Long-term safety data are essentially unavailable because macimorelin is administered exactly once. Open questions include performance in obese patients (BMI is known to blunt GH responses across all stimulation tests), optimal cutoffs in childhood-onset GHD transitioning to adulthood, and the test's behaviour in patients with partial pituitary dysfunction or following traumatic brain injury where somatotroph recovery may evolve over years.
Legal Status
United States
FDA-approved December 2017 (Macrilen) as a diagnostic for adult growth hormone deficiency. Prescription only, supplied as a single-use sachet through specialty pharmacies. Not a controlled substance.
International
Approved in the European Union on 11 January 2019 — but under a different brand name: the EU product is Ghryvelin, not Macrilen, and it is indicated for the diagnosis of growth hormone deficiency in adults. It remains authorised across the EU and is subject to additional monitoring. Available in the EU, US, and Canada via prescription. Not approved in most Asian or Latin-American markets as of 2026.
Sports & Competition
Prohibited at all times under Section S2 of the WADA Prohibited List (Peptide Hormones, Growth Factors, Related Substances and Mimetics). Macimorelin is not merely caught by a class clause — it is named outright in the 2027 List, in the S2.2 entry for “growth hormone secretagogues (GHS) and their mimetics,” alongside anamorelin, capromorelin, ibutamoren (MK-677), ipamorelin, lenomorelin (ghrelin) and tabimorelin. A diagnostic single dose used under medical supervision can be declared via a Therapeutic Use Exemption, but unsupervised use in athletes would constitute an anti-doping violation.
Regulatory status changes over time. Verify current local rules with a qualified professional.
Myths & Misconceptions
Myth
Macimorelin is a growth-hormone-boosting peptide you can take chronically.
Reality
It is a single-use diagnostic. There is no approved therapeutic protocol, and the regulatory record contains no chronic-dosing safety data. Anyone selling 'macimorelin cycles' is misrepresenting the drug.
Myth
Because it raises GH, macimorelin works like MK-677 or ipamorelin for muscle and recovery.
Reality
All three hit the same GHSR-1a receptor, but macimorelin is dosed once at 0.5 mg/kg as a stimulation challenge — a fundamentally different exposure than nightly chronic agonism. Effects on body composition or sleep at therapeutic frequencies have never been studied.
Myth
Macimorelin replaced the insulin tolerance test entirely.
Reality
It is now the preferred first-line test in many endocrinology practices, but the ITT remains the historical gold standard and is still used at expert centres, particularly when adrenal axis testing is also needed. AACE 2019 guidelines list both as acceptable options.
Myth
A normal macimorelin test rules out all pituitary disease.
Reality
It only assesses the GH axis. Patients with normal GH responses can still have ACTH, TSH, gonadotrophin, or prolactin abnormalities that require separate workup.
Myth
Oral peptides don't work, so macimorelin can't really stimulate GH.
Reality
Macimorelin is technically a peptidomimetic — a small molecule built on a tripeptide scaffold and engineered specifically to survive gastric and intestinal proteolysis. Bioavailability and pharmacodynamic effect are well-documented in dose-ranging studies; it is one of the clearest counterexamples to the 'no oral peptides' generalisation.
Published Research
16 studiesA Prospective Evaluation of Glucagon Stimulation Test Safety in Adults With Chronic Moderate-to-Severe Traumatic Brain Injury
Real-world diagnostic performance of the macimorelin stimulation test in the diagnosis of adult growth hormone deficiency
GH Response to Glucagon in Transition: Role of Body Mass Index and Etiology in Childhood-onset GH Deficiency
Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor
Wang et al., Acta Pharmacol Sin 2025. Structural characterization of how macimorelin and anamorelin engage the growth hormone secretagogue receptor (GHSR-1a) using cryo-EM and molecular-dynamics simulations. Provides the modern structural anchor for macimorelin's peptidomimetic engineering — resolving the tripeptide scaffold in the ligand-binding pocket that supported its oral bioavailability and receptor selectivity.
Consensus and controversies about diagnosing GH deficiency: a Delphi survey by the GH research society
Once upon a time: the glucagon stimulation test in diagnosing adult GH deficiency
Diagnosis and testing for growth hormone deficiency across the ages: a global view of the accuracy, caveats, and cut-offs for diagnosis
Macimorelin Acetate for the Diagnosis of Childhood-onset Growth Hormone Deficiency
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Macimorelin in Children with Suspected Growth Hormone Deficiency: An Open-Label, Group Comparison, Dose-Escalation Trial
Sensitivity and specificity of the macimorelin test for diagnosis of AGHD
Garcia et al., Endocrine Connections 2021 — the post hoc reanalysis that started the argument over macimorelin's cutoff. Re-examining the phase 3 data across GH cutpoints of 2.8, 4.0, 5.1 and 6.5 ng/mL, the authors found macimorelin's performance was not meaningfully affected by age, BMI or sex, with ROC areas under the curve above 0.99 — but that of the four cutpoints tested, 5.1 ng/mL gave maximal specificity (96%) with high sensitivity (92%) and the best overall agreement with the ITT at the same cutpoint (87%). Both the FDA and EMA labels still specify 2.8 ng/mL, so the approved threshold and the best-performing threshold have now diverged in the published literature for several years.
AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF GROWTH HORMONE DEFICIENCY IN ADULTS AND PATIENTS TRANSITIONING FROM PEDIATRIC TO ADULT CARE
Macimorelin as a Diagnostic Test for Adult GH Deficiency
Garcia et al., JCEM 2018 — the FDA-pivotal, open-label, randomized two-way crossover trial against the insulin tolerance test. At the pre-specified cutoffs (2.8 ng/mL for macimorelin, 5.1 ng/mL for the ITT) negative agreement was 95.4% and positive agreement 74.3%, with 87% sensitivity and 96% specificity — strong at confirming an intact axis, weaker at catching every ITT-positive case. Reproducibility on retesting was 97%. The practical advantage was reliability as much as accuracy: 99% of macimorelin tests were evaluable against 82% of ITTs. A post hoc analysis applying 5.1 ng/mL to both tests gave 94% negative and 82% positive agreement with 92% sensitivity, and the authors argued 5.1 is the better cutoff — a disagreement with the approved label that is still unresolved. No serious adverse events were reported. This is the trial that anchored the December 2017 FDA approval.
The macimorelin-stimulated growth hormone test for adult growth hormone deficiency diagnosis
Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency
Garcia et al., JCEM 2013 — the Phase 2 validation trial that first demonstrated macimorelin (then AEZS-130) produced a robust, reproducible oral GH response in healthy controls and a blunted response in AGHD patients, defining the cutoff range that the 2018 pivotal trial later refined.
Targeting the ghrelin receptor: orally active GHS and cortistatin analogs
EP1572: a novel peptido-mimetic GH secretagogue with potent and selective GH-releasing activity in man
Quick Facts
- Class
- Ghrelin Receptor Agonist (Diagnostic)
- Tier
- B
- Evidence
- Strong
- Safety
- Well-Studied
- Updated
- Oct 2026
- Citations
- 16PubMed
Also known as
Tags
Peptide Families
Evidence Score
Clinical Trials
View Clinical TrialsLinks to ClinicalTrials.gov for reference. Listing does not imply endorsement.