Ipamorelin (NNC 26-0161)

A pentapeptide built by subtraction

Ipamorelin is five residues long: Aib-His-D-2-Nal-D-Phe-Lys-NH2. It carries the Novo Nordisk development code NNC 26-0161 and was described in 1998 by Raun and colleagues, who identified it within a series of compounds that removed the central Ala-Trp dipeptide from growth hormone-releasing peptide-1. PubChem record CID 9831659 gives CAS 170851-70-4, formula C38H49N9O5, molecular weight 711.9 g/mol, UNII Y9M3S784Z6 and ChEMBL58547. FDA's 2024 review lists the same UNII, CAS and formula, but its identity table footnotes DrugBank and supplier catalogue pages, so the two records are not independent confirmations of one another. They also disagree on one figure: FDA's narrative text gives the molecular weight as 711.85 g/mol while its own Table 1 and PubChem give 711.9.

Three of the five positions are not ordinary amino acids. Position one is 2-aminoisobutyric acid, position three is D-2-naphthylalanine, position four is D-phenylalanine, and the C-terminus is an amide rather than a free acid. FDA's chemistry assessment treated that as a characterisation problem rather than a curiosity: less is established about the purification behaviour of unnatural amino acids and their derivatives, and about what they do to a peptide's tendency to aggregate. The nominated product is a 2000 microg/mL lyophilised powder for subcutaneous injection. FDA recorded the free base as slightly soluble in water at 0.0032 mg/mL and stated in its chemistry section that it is impossible to formulate the proposed injectable dosage form at 2 mg/mL; the conclusions section of the same document softens that to unclear how it would be possible. The acetate is recorded as soluble at 5 mg/mL.

Ipamorelin free base and ipamorelin acetate are distinct bulk drug substances, and the public identifiers do not cover them equally. The acetate has no UNII, no listed molecular weight, and a CAS number, 1258196-85-8, that FDA sourced from a supplier catalogue page while noting the same number is used for ipamorelin itself in some references. Both compounding nominations FDA reviewed named one substance in the title of the certificate of analysis and a different one in the molecular weight and formula on the same document. The identity block on this page describes the free base.

The storage figures in circulation split along the same line. FDA recorded, from a peptide supplier's product page, that lyophilised free base is reported stable at room temperature for 3 weeks and, once reconstituted, for 2 to 3 weeks at 4 degrees C and 3 to 4 months at minus 20 degrees C, with desiccated storage below minus 18 degrees C recommended. From the nominator's certificate of analysis and a catalogue page it recorded that the acetate is reported stable up to 4 years at minus 20 degrees C. Those are reported storage conditions carried from commercial pages into a regulatory review. No stability time-course was located.

The selectivity finding, and the species it was measured in

Raun and colleagues measured potency across three systems. In primary rat pituitary cell culture, ipamorelin released growth hormone with an EC50 of 1.3 plus or minus 0.4 nmol/l and an Emax of 85 plus or minus 5 per cent, against 2.2 plus or minus 0.3 nmol/l and 100 per cent for GHRP-6. In pentobarbital-anaesthetised rats the ED50 was 80 plus or minus 42 nmol/kg. In conscious swine it was 2.3 plus or minus 0.03 nmol/kg, with an Emax of 65 plus or minus 0.2 ng GH/ml plasma. Profiling with GHRP and GHRH antagonists placed the action at a GHRP-like receptor.

Specificity was tested in swine, and in swine only. None of the secretagogues examined altered plasma FSH, LH, prolactin or TSH. GHRP-6 and GHRP-2 raised ACTH and cortisol. Ipamorelin did not, at levels significantly different from those following GHRH stimulation, and the authors reported that this held even at doses more than 200-fold above the ED50 for growth hormone release. They called the result surprising. A PubMed search pairing ipamorelin with cortisol or prolactin returned three records, none of them a human measurement; the selectivity finding on this page therefore rests on that swine experiment (PMID 9849822).

The three records that search returns are the 1998 swine paper, a pharmacological characterisation of a different compound, and a 2026 narrative review that discusses the class rather than measuring it. None of the published human administrations of ipamorelin assayed those hormones: the 1999 pharmacokinetic study measured ipamorelin and growth hormone concentrations only, the 2014 ileus trial measured neither, and the 2015 nasal doping-control study measured urinary metabolites. Extending the selectivity finding from pigs to people is an extrapolation. No human study measuring ACTH, cortisol or prolactin after ipamorelin was located for this page.

The human pharmacokinetics exist, in one study

Gobburu and colleagues published the human pharmacokinetic and pharmacodynamic characterisation in 1999. The design escalated 15-minute intravenous infusions across five rates: 4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg. Pharmacokinetics were dose-proportional, with a terminal half-life of about 2 hours, clearance of 0.078 L/h/kg and a steady-state volume of distribution of 0.22 L/kg. Growth hormone rose as a single episode peaking at 0.67 hours and declined exponentially to negligible concentrations at every dose. The concentration producing half-maximal stimulation was 214 nmol/L and the maximal growth hormone production rate 694 mIU/L/h. Variability between individuals was larger for the pharmacodynamic parameters than the pharmacokinetic ones.

The sample size does not agree between two accounts of the same trial. The published abstract describes eight healthy male subjects at each of five dose levels. FDA's 2024 review describes 48 subjects enrolled, with five groups of six receiving ipamorelin and two per group receiving placebo, and the lowest dose group and the placebo subjects excluded from the modelling because growth hormone levels were negligible. Both statements are about the same randomised, placebo-controlled dose-escalation study. They are recorded here as each source reports them rather than averaged into a single figure.

Route matters more here than usual. FDA searched in 2024 and identified no pharmacokinetic or pharmacodynamic information for the proposed subcutaneous route of administration of either form, and separately recorded that it identified no nonclinical study assessing the pharmacokinetic profile by that route. Subcutaneous is the route the compounding nominations proposed and the route the marketing describes. The intravenous human data are the only pharmacokinetic data in people, and they come from the single 1999 study.

The rat pharmacokinetics reach this page through the same review. FDA describes adult male rats given an intravenous injection of ipamorelin acetate at a dose of 1 mg/kg with respect to free base, plasma peaking within a minute and a half-life of approximately 27 minutes, attributing the study to Johansen 1998. The Xenobiotica abstract reports neither figure. What it does report is systemic plasma clearance 5-fold lower than GHRP-6, mainly urinary excretion, 60 to 80 per cent of the administered dose recovered as intact peptide for ipamorelin and two related NNC peptides collectively, and intranasal bioavailability near 20 per cent against roughly 50 per cent for three comparator peptides. The only human nasal administration located was a 2015 doping-control study in which each compound went to a single volunteer and urine was collected for two days. It measured metabolites, not growth hormone.

Postoperative ileus, the indication it was actually developed for

The clinical programme was gastrointestinal, not endocrine. Venkova and colleagues worked in fasted male rats after laparotomy and intestinal manipulation: a single intravenous dose of 1 mg/kg shortened the time to first bowel movement but changed nothing about cumulative faecal output, food intake or body weight at 48 hours, while repetitive dosing at 0.1 or 1 mg/kg increased all three. Greenwood-Van Meerveld and colleagues measured gastric emptying in the same model and reported 78 plus or minus 5 per cent of the meal remaining in vehicle controls against 52 plus or minus 11 per cent after 0.014 micromol/kg intravenously, with non-surgical controls at 44 plus or minus 6 per cent.

Beck and colleagues ran the phase 2 proof-of-concept trial, registered as NCT00672074. One hundred and seventeen adults undergoing small or large bowel resection were enrolled and 114 formed the modified intent-to-treat population, receiving 0.03 mg/kg intravenously twice daily from postoperative day 1 until day 7 or discharge. Median time from first dose to tolerance of a standardised solid meal was 25.3 hours with ipamorelin and 32.6 hours with placebo, a difference of 7.3 hours that did not reach statistical significance at p equals 0.15. Secondary endpoints covering upper and lower gastrointestinal recovery and length of stay showed no differences.

FDA's review of the same trial records detail the abstract omits. Hypokalaemia occurred in 12.5 per cent of the ipamorelin group against 3.4 per cent on placebo, insomnia in 10.7 against 5.2 per cent, and hyperglycaemia at discharge in 14.3 against 8.6 per cent. Serious adverse events were reported in 10 ipamorelin subjects and 9 placebo subjects. Two subjects in the ipamorelin group had fatal serious adverse events; both had undergone bowel resection for colon cancer and developed the postoperative complication of anastomotic leak, and FDA records the primary causes of death as hyperkalaemia in a subject with aortic clots, sepsis, perforated ulcer, and renal failure and sepsis in a subject with pneumonia. FDA stated it was unclear whether the deaths were related to the drug, and cited them among its reasons for concern.

A second and larger trial reported nothing. NCT01280344 was a phase 2 double-blind dose-finding study in patients following small or large bowel resection with primary anastomosis, with three ipamorelin arms against saline placebo and an enrolment of 320. It began in April 2011, its primary completion date is recorded as June 2013, and the study completed in May 2014. No results have been posted, and no publication reporting it was located in PubMed or Europe PMC.

The rodent bone and body-composition record

Johansen and colleagues injected adult female rats subcutaneously three times daily for 15 days at 0, 18, 90 and 450 microg/day and measured longitudinal bone growth by tetracycline labelling in the proximal tibial metaphysis. The rate rose from 42 microm/day on vehicle to 44, 50 and 52 microm/day across the treatment groups, at p below 0.0001, with a dose-dependent effect on body weight gain. Total IGF-I, the IGF binding proteins and serum markers of bone formation and resorption were unchanged, as was pituitary growth hormone content. The growth hormone response to a provocative intravenous dose was marginally reduced, at p below 0.03; the response to GHRH was not.

Svensson and colleagues ran a longer study and reached a narrower conclusion than the one usually quoted from it. Thirteen-week-old female Sprague-Dawley rats received ipamorelin at 0.5 mg/kg per day, n equals 7, GHRP-6 at the same rate, n equals 8, growth hormone at 3.5 mg/kg per day, n equals 7, or vehicle, by continuous subcutaneous minipump for 12 weeks. Bone mineral content by DXA increased with every treatment; corrected for the accompanying body weight increase, it did not. Tibial areal bone mineral density, meaning bone mineral content divided by projected area, was increased, while total and vertebral areal densities were unchanged. Peripheral quantitative computed tomography attributed the cortical gain to increased cross-sectional bone area; volumetric bone mineral density was unchanged by both pQCT and Archimedes' principle.

Lall and colleagues compared ipamorelin against growth hormone in GH-deficient lit/lit mice and GH-intact littermates, dosing twice daily subcutaneously. Ipamorelin produced roughly a 15 per cent body weight increase by two weeks that was not further augmented by nine weeks, and increased fat pad weights relative to body weight in both lit/lit and +/lit animals. Two weeks of secretagogue treatment increased relative body fat by DEXA in GH-intact mice, and raised serum leptin and food intake. Growth hormone did the opposite, decreasing relative fat mass in lit/lit mice. The authors concluded that secretagogues increase body fat by mechanisms independent of growth hormone, possibly including increased feeding.

Two catabolism models point the other way. Andersen and colleagues gave 8-month-old female rats subcutaneous methylprednisolone at 9 mg/kg per day, ipamorelin at 100 microg/kg three times daily, or both for three months, and found periosteal bone formation rate four-fold higher and maximum tetanic tension of the calf muscles significantly increased in the combination group relative to glucocorticoid alone. Aagaard and colleagues, in prednisolone-treated rats, found ipamorelin at 0.5 mg/kg per day reduced hepatic urea-N synthesis capacity by 20 per cent and neutralised nitrogen balance, against a 33 per cent reduction and a 2.5-fold improvement in nitrogen balance for growth hormone itself. Their summary was that the secretagogue worked in the same direction as growth hormone, less efficiently, at the doses given.

The regulatory record

FDA evaluated ipamorelin free base and ipamorelin acetate for the 503A bulk drug substances list and brought both to the Pharmacy Compounding Advisory Committee on 29 October 2024. The uses reviewed were growth hormone deficiency, which the compounding nominations proposed, and postoperative ileus, which FDA added on its own initiative. Neither substance has a United States Pharmacopeia or National Formulary monograph, and neither is a component of an FDA-approved drug. The committee voted 0 in favour, 12 against and 1 abstention on placing the free base on the list, and by the same margin on the acetate, on the stated grounds of insufficient safety and effectiveness information for both uses.

The review also documents a long list of absences. FDA searched the published literature and identified no acute toxicity study, no repeat-dose study, no genotoxicity study, no developmental or reproductive toxicity study and no carcinogenicity study for either form, in any species, and no study of immunogenicity or aggregation. Part of the nonclinical file it did assemble is not peer-reviewed literature at all: a conference abstract and a patent application supplied some of the gastric-motility findings. A search of the FDA adverse event reporting system through 30 September 2023 retrieved two non-serious reports, both involving compounded products. A separate search of national medical registries, the European Medicines Agency website and the European, Chinese, Indian and Japanese pharmacopoeias returned no monograph listing for either form.

Reviewers turned to class-level risks where compound-specific data were absent. They noted that ghrelin receptors are expressed in reward-processing regions including the ventral tegmental area, that ghrelin increases dopamine release there in rats, and that a ghrelin receptor agonist could therefore carry reinforcing properties, while stating the nonclinical studies were insufficient to determine whether ipamorelin does. Luque and colleagues, in female Albino Swiss mice given subcutaneous synthetic ghrelin at 2 or 4 nmol per animal per day or the ghrelin receptor antagonist D-Lys3-GHRP6 at 6 nmol per animal per day, reported that the antagonist alone reduced the fertilisation rate, while both the antagonist and the higher ghrelin dose increased the percentage of atrophied fetuses, and both compounds delayed embryo development. Ipamorelin was not administered in that study. Under the World Anti-Doping Agency 2026 Prohibited List, ipamorelin is named at section S2.2.4, prohibited at all times.

What has been found in the vials, and what is claimed for them

Forensic chemistry has looked at the material in circulation twice, and both times found something adjacent to the molecule in the papers. Gajda and colleagues analysed preparations seized by Danish customs and identified analogues of GHRP-2, GHRP-6, ipamorelin and modified GRF (1-29); in every case the modification was an extra glycine at the N-terminus, and they recommended that detection methods be updated to catch it. Krug and colleagues had characterised the same modification in black-market growth-promoting products, confirming Gly-ipamorelin by custom synthesis. A hexapeptide with an added glycine is not the pentapeptide any of the studies on this page administered.

The claims attached to that material are broader still, and FDA catalogued them as part of its historical-use assessment. Compounding pharmacy and clinic websites the agency reviewed asserted uses including weight management, hormone replacement, vitality and mental clarity, cardiovascular and immune support, sex drive, recovery and repair from injury, nerve tissue regeneration, cognition and memory, lean muscle, skin laxity, sleep and bone density, in injectable, nasal and oral forms. One site quoted by the review claimed a specific multiple of growth hormone release for ipamorelin combined with another secretagogue; FDA attached no measurement to that figure, and it is recorded in the unsourced section below with the searches that failed to find one. Not one of those uses has been the subject of a published trial of this compound.

What is not known

No study has administered ipamorelin subcutaneously to a human being, in any registered trial or published paper, which is the route in which it is nominated for compounding and the route the marketing describes; FDA searched in 2024 and identified no pharmacokinetic or pharmacodynamic information for that route for either form, and separately recorded no nonclinical study assessing the pharmacokinetic profile by that route. There is no published toxicology of any kind for either the free base or the acetate: no acute toxicity study, no repeat-dose study, no genotoxicity, no developmental or reproductive toxicity, no carcinogenicity, and no assessment of immunogenicity or aggregation, all of which FDA searched for and recorded as absent. No trial has measured body composition, bone density, sleep, cognition, injury recovery or any of the other outcomes the compound is marketed for, in any species for most of them and in no human for any of them. The largest study ever run, a 320-patient phase 2 dose-finding trial in bowel resection patients, completed in May 2014 and has posted no results and produced no publication, so what it found is not in the public record. Effect on ACTH, cortisol and prolactin has been measured in swine and never in people. Impurity, aggregate and endotoxin profiles for either substance are absent from the public literature, no stability time-course was located for either, and the material seized from the supply chain has twice been found to carry an undeclared extra glycine residue.

Questions