Ipamorelin

Ipamorelin is a pentapeptide growth hormone secretagogue developed through systematic medicinal chemistry optimization of the GHRP-1 scaffold, specifically by removing the central Ala-Trp dipeptide while maintaining GH-releasing potency and efficacy.² The compound was designed to address limitations of earlier GHRPs (GHRP-2, GHRP-6, hexarelin) which, while effective at stimulating GH release, also elevated ACTH, cortisol, and prolactin—potentially limiting therapeutic utility and causing unwanted side effects.²

The structural modifications in ipamorelin result in a compound that displays high GH-releasing potency (EC₅₀ = 1.3±0.4 nmol/L in vitro) comparable to GHRP-6, but with dramatically improved selectivity.² ³ Pharmacological profiling using GHRP and GHRH antagonists confirmed that ipamorelin stimulates GH release via the GHRP-like receptor (now known as the ghrelin receptor or GHS-R1a), not through the GHRH receptor pathway.²

The hallmark feature distinguishing ipamorelin from other GHRPs is its selectivity for GH release without affecting other pituitary hormones.² In swine studies, while both GHRP-6 and GHRP-2 significantly increased plasma ACTH and cortisol levels, ipamorelin did not release ACTH or cortisol at levels different from GHRH stimulation—even at doses more than 200-fold higher than the ED₅₀ for GH release.² Similarly, ipamorelin, GHRP-6, and GHRH all failed to affect FSH, LH, prolactin, or TSH plasma levels.² This unique selectivity profile suggested ipamorelin might offer the benefits of GH stimulation without the adverse effects associated with elevated stress hormones.²

Pharmacokinetic studies in humans revealed a terminal elimination half-life of approximately 2 hours following IV administration, with a brief GH release window consistent with this short half-life.⁵ Unlike modified GHRH analogs with extended durations (CJC-1295 with DAC), ipamorelin requires multiple daily administrations to maintain elevated GH secretory capacity.⁵

Despite promising preclinical characterization and theoretical advantages, clinical development of ipamorelin has been extremely limited. A comprehensive 2020 systematic review conducted by the University of Maryland for the FDA—searching all major databases through November 2019—identified only one human clinical trial meeting inclusion criteria.¹ This single trial (Beck et al., 2014) examined ipamorelin for postoperative ileus rather than GH deficiency or body composition applications, finding the compound well-tolerated but without significant efficacy for the tested indication.¹ ⁴

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How It Works

 

Mechanism of Action

Ipamorelin operates through the ghrelin receptor (GHS-R1a) signaling pathway to stimulate pituitary GH release:² ³

Ghrelin Receptor Activation: Ipamorelin binds to and activates GHS-R1a receptors expressed on somatotroph cells in the anterior pituitary.² ³ GHS-R1a is a G-protein coupled receptor that, upon ligand binding, activates Gq proteins leading to phospholipase C (PLC) activation, inositol trisphosphate (IP₃) production, and intracellular calcium mobilization.³ The calcium flux triggers immediate GH secretion from stored granules while also activating protein kinase C (PKC) and other signaling cascades that enhance GH gene transcription.³

Selective GH Release: The defining characteristic of ipamorelin is its remarkable selectivity for GH secretion without affecting other pituitary hormones.² In preclinical studies across multiple species (rats, swine), ipamorelin released GH with potency and efficacy comparable to GHRP-6:²

• In vitro (rat pituitary cells): EC₅₀ = 1.3±0.4 nmol/L, Emax = 85±5%
• In vivo (anesthetized rats): ED₅₀ = 80±42 nmol/kg, Emax = 1545±250 ng GH/mL

Unlike GHRP-6 and GHRP-2, which significantly elevated ACTH and cortisol (stress hormones) in swine at doses 45-85-fold higher than the ED₅₀ for GH release, ipamorelin showed no effect on ACTH or cortisol even at doses exceeding 200-fold the GH-releasing ED₅₀.² This suggests ipamorelin does not activate hypothalamic neurons regulating the stress axis, avoiding a major limitation of earlier GHRPs.²

Complementary Mechanism with GHRH: While ipamorelin acts through the ghrelin receptor (GHS-R) pathway, GHRH analogs act through the GHRH receptor (GHRH-R) pathway.² ³ These pathways are complementary rather than redundant—GHRH primarily enhances GH pulse amplitude and stimulates GH synthesis, while GHRPs like ipamorelin suppress somatostatin inhibition and enhance pulse frequency.³ When coadministered, GHRH analogs and GHRPs produce synergistic GH release substantially exceeding either compound alone.³ This synergy explains the popularity of ipamorelin + CJC-1295 combination protocols in clinical practice, though no human trials have systematically validated this combination.¹ ³

Pharmacokinetics: Following intravenous administration in humans, ipamorelin displays a terminal elimination half-life of approximately 2 hours with rapid distribution and clearance.⁵ Peak GH responses occur 30-60 minutes post-administration, returning toward baseline within 3-4 hours.⁵ This short duration necessitates 2-3 daily administrations if sustained GH elevation is desired, typically timed before meals or exercise to maximize physiological synergy with endogenous GH pulses.³ ⁵

Gastrointestinal Prokinetic Effects: Beyond GH stimulation, ghrelin receptor agonism produces gastrointestinal prokinetic effects—enhancing gastric emptying and intestinal transit through direct effects on enteric neurons and smooth muscle.⁴ ⁶ This dual mechanism (GH release + GI motility) led to clinical investigation of ipamorelin for postoperative ileus, a temporary impairment of GI motility following abdominal surgery.¹ ⁴ However, the 2014 Beck trial found no significant benefit for this indication despite acceptable safety.¹ ⁴

Physiological Effects

The downstream effects of GH elevation include:² ³

• Body Composition: Increased lean body mass and reduced fat mass through enhanced protein synthesis and lipolysis
• Bone Metabolism: Increased bone turnover and potential improvements in bone mineral density
• Metabolic Effects: Complex effects on glucose and lipid metabolism mediated by GH and IGF-I
• Collagen Synthesis: Enhanced connective tissue health and wound healing
• GI Motility: Prokinetic effects through direct ghrelin receptor activation in the GI tract⁴

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Research Evidence

 

Comprehensive Systematic Review

University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), 2020 – Ipamorelin acetate: Summary Report for FDA 503B Bulks List Evaluation

*Comprehensive scoping review examining clinical use of ipamorelin to assist FDA in evaluating inclusion on the 503B Bulks List for compounding by outsourcing facilities.*¹

**Systematic Literature Review Methodology:**¹

• Comprehensive search of Ovid MEDLINE and Embase databases through November 30, 2019
• PRISMA-compliant systematic review process
• Inclusion criteria: Studies using ipamorelin in nominated dosage form, ROA, or combination to diagnose, prevent, or treat any condition
• Two independent reviewers screened 96 titles/abstracts; 3 full-text articles reviewed
• Quality assessment using standardized tools

**Results:**¹

• Total studies included: 1 (Beck et al., 2014)
• Reason for exclusions: Wrong study design (1 study); ipamorelin not used clinically (1 study)
• Total patients: 117 adults undergoing small or large bowel resection
• Treatment: Ipamorelin 0.03 mg/kg IV twice daily vs. placebo
• Duration: Postoperative day 1 through day 7 or hospital discharge
• Primary outcome: Time to tolerance of standardized solid meal

Key Finding: “Ipamorelin was well tolerated, but there was no significant difference between ipamorelin and placebo” for recovery of GI function.¹ ⁴

**Subject Matter Expert Interviews (N=8 SMEs):**¹

• Postoperative ileus context: SMEs confirmed postoperative ileus is common after abdominal surgery but typically resolves with time; management focuses on bowel regimen medications, opioid antagonists (alvimopan, methylnaltrexone), or neostigmine
• Ipamorelin awareness: “In general, the SMEs said that they were not familiar with the use of ipamorelin acetate for postoperative ileus in any patient population”¹
• Alternative uses mentioned: Several urologist SMEs discussed off-label use of ipamorelin for growth hormone deficiency, often combined with CJC-1295 in a “trending synergistic combination”¹
• Compounding status: “Ipamorelin acetate was previously compounded in a 503B facility, but one SME said that it is no longer produced due to changes based on regulations and updates”¹

**Survey Results:**¹

• Professional medical associations: Zero respondents
• Ambulatory Surgery Center Association: 230 respondents total; only 1 respondent (0.34% of 290 responses) reported obtaining ipamorelin from a 503B outsourcing facility

**Conclusion:**¹
“Ghrelin agonists that have been evaluated for postoperative ileus have not been shown to improve postoperative ileus management… The SMEs were not familiar with the use of ipamorelin acetate for postoperative ileus, but several said that they could see the potential, despite not practicing surgeries that are at risk for ileus. In addition, several SMEs mentioned using ipamorelin acetate in combination with CJC-1295 for patients with growth hormone deficiency.”

Significance: This FDA-commissioned systematic review represents the most comprehensive assessment of ipamorelin’s clinical use to date. The finding of only one qualifying human trial—conducted for an indication (postoperative ileus) different from primary interest (GH deficiency, body composition)—highlights the vast disconnect between widespread use in anti-aging/performance communities and published clinical evidence.¹

Primary Clinical Study

Beck DE et al., 2014 – Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients

Design: Multicenter, double-blind, placebo-controlled Phase 2 trial (ClinicalTrials.gov NCT00672074) examining ipamorelin for postoperative ileus following abdominal surgery.⁴

**Study Population:**⁴

• 117 adult inpatients after small or large bowel resection via open or laparoscopic surgery
• Mean age range: 21-84 years
• 54% male
• Ipamorelin group: N=56
• Placebo group: N=61

**Intervention:**⁴

• Dose: 0.03 mg/kg (0.06 mg/kg/day total) ipamorelin IV vs. placebo
• Frequency: Twice daily
• Duration: Postoperative day 1 through day 7 or hospital discharge, whichever occurred first
• Route: Intravenous infusion

Primary Outcome: Time to first tolerated standardized solid meal⁴

*Results:*⁴

• Efficacy: Median time to first tolerated meal was 25.3 hours (ipamorelin) vs. 32.6 hours (placebo); difference not statistically significant (p=0.15)
• Safety: Overall incidence of treatment-emergent adverse events was 87.5% in ipamorelin group vs. 94.8% in placebo group
• Adverse events: Most common were consistent with recent bowel surgery (nausea, vomiting, dyspepsia) and may not be treatment-related
• Serious adverse events: No drug-related serious adverse events reported

*Limitations:*⁴

• Small sample size (N=117) limits statistical power
• Single dose level tested (0.03 mg/kg twice daily); dose-ranging not explored
• Postoperative ileus indication differs from primary interest (GH deficiency, body composition)
• No assessment of GH, IGF-I, or body composition outcomes
• Unclear if compounded formulation was used

Significance: This represents the only published randomized controlled trial of ipamorelin in humans identified by the comprehensive FDA-commissioned systematic review.¹ ⁴ While the compound was well-tolerated, lack of efficacy for the tested indication “dampened enthusiasm to develop this class of compounds” for postoperative ileus.⁶ The study provides safety data supporting tolerability but offers no evidence for ipamorelin’s effects on GH secretion, body composition, or other outcomes of primary interest in anti-aging and performance applications.¹ ⁴

Foundational Preclinical Study

Raun K et al., 1998 – Ipamorelin, the first selective growth hormone secretagogue

*Comprehensive preclinical characterization establishing ipamorelin’s unique selectivity profile.*²

**Key Findings:**²

• In vitro potency: EC₅₀ = 1.3±0.4 nmol/L in rat pituitary cells; comparable to GHRP-6
• In vivo efficacy: ED₅₀ = 80±42 nmol/kg in anesthetized rats; Emax comparable to GHRP-6
• Receptor selectivity: Acts via GHRP-like receptor (GHS-R), not GHRH receptor
• Hormonal selectivity: No effects on FSH, LH, prolactin, or TSH at any dose
• Unique ACTH/cortisol profile: Unlike GHRP-6 and GHRP-2, ipamorelin did not significantly elevate ACTH or cortisol even at doses >200-fold higher than ED₅₀ for GH release²
• Duration of action: Single IV injection produced GH elevation lasting longer than the plasma half-life of the peptide

Significance: This foundational study established ipamorelin as “the first GHRP-receptor agonist with a selectivity for GH release similar to that displayed by GHRH,” suggesting superior therapeutic potential compared to earlier, less selective GHRPs.² The preclinical promise has not yet translated to human clinical trials demonstrating functional benefits.¹

Broader GH Secretagogue Context

Sigalos JT & Pastuszak AW, 2017 – The Safety and Efficacy of Growth Hormone Secretagogues

*Systematic review of GH secretagogues including context for ipamorelin within the broader class.*³

**Key Points Relevant to Ipamorelin:**³

• GH secretagogues offer theoretical advantages over exogenous GH: preserved pulsatile secretion, maintained negative feedback, lower risk of supratherapeutic levels
• GHRPs and GHRH analogs produce synergistic GH release when coadministered
• Evidence for functional benefits (body composition, strength, quality of life) remains limited across the GH secretagogue class
• Most studies focus on biomarker elevation (GH, IGF-I) rather than clinically meaningful outcomes

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Current Status & Considerations

 

Research Status

As of January 2026, ipamorelin is not FDA-approved for any medical indication.¹ ³ The compound is available through research chemical suppliers and compounding pharmacies, though the University of Maryland review noted that 503B outsourcing facilities have largely stopped producing ipamorelin due to regulatory changes.¹

The FDA-commissioned systematic review’s finding of only one human clinical trial—conducted for postoperative ileus rather than GH deficiency or body composition—represents a striking disconnect between widespread use in anti-aging, wellness, and athletic communities and published clinical evidence.¹ Zero survey respondents from professional medical associations reported using ipamorelin, and only 1 of 230 ambulatory surgery center respondents obtained the compound from a 503B facility.¹

The preclinical promise of ipamorelin—selective GH stimulation without unwanted hormonal side effects—has not translated to robust human clinical development.¹ ² A follow-up Phase 2 dose-finding study (NCT01280344) examining various ipamorelin doses for postoperative ileus had no posted results at the time of the University of Maryland review.¹

Potential Research Applications

Growth Hormone Deficiency: Ipamorelin’s selective GH-releasing properties theoretically position it for GH deficiency treatment, particularly in individuals with intact pituitary responsiveness but diminished ghrelin signaling.² ³ However, no human trials have examined ipamorelin for this indication.¹ The lack of ACTH/cortisol stimulation distinguishes ipamorelin from earlier GHRPs that complicated HPA axis evaluation in GH deficiency diagnosis.²

Body Composition Optimization: Preclinical studies demonstrated GH-mediated effects on body composition, and SME interviews noted off-label use for this purpose.¹ ² However, the University of Maryland review identified zero clinical trials examining body composition outcomes with ipamorelin.¹ Broader GH secretagogue literature shows modest effects on lean mass (1-3 kg gains over 2-12 months), but ipamorelin-specific human data is absent.³

Combination with GHRH Analogs: SME interviews revealed “trending” use of ipamorelin + CJC-1295 combinations, exploiting synergistic GH release from dual pathway activation.¹ ³ However, no human trials have systematically evaluated this combination despite widespread clinical use.¹ The theoretical advantage—”stepping on the gas [GHRH] and releasing the brake [somatostatin inhibition via ghrelin]”—lacks empirical validation.¹

Postoperative Ileus: The Beck 2014 trial found ipamorelin well-tolerated but ineffective for postoperative ileus.⁴ A 2017 review concluded that ghrelin agonists evaluated for postoperative ileus “have not been shown to improve postoperative ileus management,” dampening enthusiasm for this class in GI motility disorders.⁶ This application appears to be a dead end for ipamorelin development.¹ ⁴ ⁶

Diagnostic Testing: While not systematically studied, ipamorelin’s selective GH stimulation without ACTH elevation could theoretically benefit GH deficiency diagnostic testing by avoiding confounding HPA axis activation.² However, recombinant ghrelin or approved diagnostic agents serve this role, and ipamorelin offers no clear advantage.

Safety Profile Summary

Based on the Beck 2014 trial (N=117, up to 7 days IV ipamorelin 0.03 mg/kg twice daily):⁴

• Well-tolerated: 87.5% of ipamorelin patients experienced treatment-emergent adverse events vs. 94.8% placebo, suggesting similar or better tolerability
• No serious drug-related adverse events
• Common adverse events: Nausea, vomiting, dyspepsia—consistent with postoperative status rather than drug-related
• Short-term safety: Acceptable safety profile over 7-day exposure period

**Critical Limitations:**¹ ⁴

• Single small trial: N=117 insufficient to detect rare adverse events
• Short duration: Maximum 7 days provides no long-term safety data
• Specific population: Postoperative bowel surgery patients may not represent general ipamorelin users
• No GH/IGF-I monitoring: Study did not assess hormonal effects or potential consequences of sustained GH elevation
• No body composition assessment: Safety of chronic use for anti-aging/performance applications unstudied

Preclinical studies suggested lack of ACTH/cortisol stimulation reduces HPA axis disruption risk compared to earlier GHRPs.² Whether this translates to superior long-term human safety remains speculative without chronic exposure trials.¹

Important Considerations

Profound Evidence Gap: The University of Maryland FDA review represents the most comprehensive assessment of ipamorelin clinical use, and identified only one human trial—for an indication (postoperative ileus) different from primary interest (GH deficiency, body composition).¹ This is perhaps the starkest evidence-practice disconnect in the peptide field. Zero human data support efficacy for applications driving current use.¹

Preclinical Promise ≠ Clinical Reality: Ipamorelin’s impressive preclinical profile—selective GH stimulation without unwanted hormonal effects—generated enthusiasm but has not translated to clinical development.¹ ² Over two decades after the foundational 1998 publication, clinical evidence remains limited to a single small negative trial for a niche indication.¹ ² ⁴ This suggests either commercial development challenges, patent issues, or disappointing unpublished results.

Combination Use Lacks Evidence: SME interviews revealed widespread use of ipamorelin + CJC-1295 combinations, with claims of synergistic benefits.¹ However, the University of Maryland review found zero human trials validating this combination despite its popularity.¹ All combination rationale derives from mechanistic reasoning and preclinical data, not human efficacy studies.¹ ³

Not Approved, Minimally Studied: Ipamorelin is not FDA-approved for any indication and is available only as a research chemical or through compounding.¹ ³ Regulatory uncertainty affects product quality, purity, and consistency. The University of Maryland review noted that 503B outsourcing facilities have largely stopped producing ipamorelin due to regulatory changes, further complicating access.¹

Unknown Long-Term Safety: The single human trial involved only 7 days of exposure.⁴ Long-term safety (months to years) of chronic GH elevation via ipamorelin is completely unknown.¹ Theoretical concerns about IGF-I elevation and cancer risk apply to all GH-elevating interventions but remain uninvestigated for ipamorelin.¹ ³

Dose and Schedule Optimization Absent: The Beck trial used 0.03 mg/kg IV twice daily; no dose-ranging or schedule optimization studies exist.⁴ Community-used protocols (often subcutaneous, varying doses 100-300 µg 2-3× daily) lack empirical validation.¹ Optimal dosing for GH stimulation vs. other effects remains speculative.

Pharmacokinetic Challenges: The ~2-hour half-life necessitates multiple daily administrations for sustained GH elevation.⁵ This creates compliance challenges and complexity compared to once-weekly alternatives (CJC-1295 with DAC).³ ⁵ Whether frequent pulsatile stimulation offers advantages over sustained elevation remains untested in humans.

Regulatory and Legal Status: Ipamorelin is not FDA-approved, is prohibited by WADA for competitive athletes, and exists in regulatory gray areas for clinical use.¹ ³ Prescribing and use carry potential legal and professional consequences depending on jurisdiction and context.

Alternative Approaches Exist: For documented GH deficiency, FDA-approved recombinant GH remains the evidence-based standard of care.³ For enhancement purposes, no peptide-based approach has sufficient evidence to recommend over lifestyle interventions (exercise, nutrition, sleep optimization) with established safety and efficacy.³

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Footnotes

 

1. University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI). Ipamorelin acetate: Summary Report prepared for Food and Drug Administration. December 2020.
2. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology. 1998;139(5):552-561.
3. Sigalos JT, Pastuszak AW. The Safety and Efficacy of Growth Hormone Secretagogues. Sexual Medicine Reviews. 2018;6(1):45-53.
4. Beck DE, Sweeney WB, McCarter MD, Ipamorelin 201 Study Group. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. International Journal of Colorectal Disease. 2014;29(12):1527-1534.
5. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research. 1999;16(9):1412-1416.
6. Stakenborg N, Gomez-Pinilla PJ, Boeckxstaens GE. Postoperative ileus: Pathophysiology, current therapeutic approaches. Handbook of Experimental Pharmacology. 2017;239:39-57.

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References

 

Comprehensive Systematic Review

University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI). Ipamorelin acetate: Summary Report prepared for Food and Drug Administration, Clinical use of bulk drug substances nominated for inclusion on the 503B Bulks List. Grant number: 5U01FD005946. December 2020.

Primary Clinical Study

Beck DE, Sweeney WB, McCarter MD, Ipamorelin 201 Study Group. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. International Journal of Colorectal Disease. 2014;29(12):1527-1534. doi:10.1007/s00384-014-2030-8. PMID: 25331030.

Foundational Preclinical Study

Raun K, Hansen BS, Johansen NL, Thøgersen H, Ankersen M, Andersen PH, Rasmussen JS. Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology. 1998;139(5):552-561. doi:10.1530/eje.0.1390552. PMID: 9849822.

Comprehensive GH Secretagogue Reviews

Sigalos JT, Pastuszak AW. The Safety and Efficacy of Growth Hormone Secretagogues. Sexual Medicine Reviews. 2018;6(1):45-53. doi:10.1016/j.sxmr.2017.02.004. PMID: 28400207.

Stakenborg N, Gomez-Pinilla PJ, Boeckxstaens GE. Postoperative ileus: Pathophysiology, current therapeutic approaches. Handbook of Experimental Pharmacology. 2017;239:39-57. doi:10.1007/164_2016_108.

Additional Pharmacokinetic Study

Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research. 1999;16(9):1412-1416.

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Disclaimer

 

This content is for educational and research purposes only and does not constitute medical advice. Ipamorelin is not FDA-approved for any medical indication. A comprehensive FDA-commissioned systematic review identified only one human clinical trial, which found the compound well-tolerated but without significant efficacy for the tested indication. Current evidence does not support efficacy for growth hormone deficiency, body composition, or other applications driving widespread use. All products are intended strictly for laboratory research and development purposes only.