Product description
What is AOD-9604?
AOD-9604 (Anti-Obesity Drug 9604) is a synthetic peptide consisting of 16 amino acids, a modified fragment of the C-terminal domain of human growth hormone (hGH), encompassing amino acids 177-191 with an additional tyrosine at the N-terminus. The compound was developed in the 1990s by Metabolic Pharmaceuticals Ltd. in Australia as a potential anti-obesity drug intended to harness the lipolytic properties of growth hormone without its broader metabolic and anabolic effects.
The chemical structure of AOD-9604 contains two cysteine residues forming a disulfide bond, which stabilizes the peptide conformation. The molecular formula is C₇₈H₁₂₃N₂₃O₂₃S₂, and the molecular weight is approximately 1815 Da. The N-terminal tyrosine modification was introduced to increase the compound's metabolic stability.
The concept behind the development of AOD-9604 arose from the observation that full-length growth hormone, despite its strong lipolytic action and reduction of adipose tissue, causes numerous adverse effects, including insulin resistance, joint pain, and fluid retention. Scientists identified the C-terminal region of hGH as the area responsible for lipolytic activity and attempted to isolate this function in a smaller peptide fragment.
AOD-9604 was designed to stimulate lipolysis (fat breakdown) and inhibit lipogenesis (formation of new fat) without affecting levels of insulin-like growth factor 1 (IGF-1), glucose homeostasis, or muscle growth. Unlike full growth hormone, the peptide does not bind to the classic GH receptor, acting through independent mechanisms.
Mechanism of action
Activation of β3-adrenergic receptors - Studies in animal models have shown that AOD-9604 may mimic the way hGH stimulates β3-adrenergic receptors on adipocytes. Activation of these receptors promotes breakdown of stored fat. The peptide increases β3-AR receptor mRNA expression in obese mice to levels comparable to those observed in lean individuals.
Stimulation of lipolysis - AOD-9604 induces the release of fatty acids from adipose tissue through activation of hormone-sensitive lipase (HSL) and modulation of acetyl-CoA carboxylase activity. The released fatty acids can then be used as an energy source by muscles and other organs.
Inhibition of lipogenesis - The peptide reduces the formation of new fat cells and lipid accumulation in existing adipocytes. This mechanism involves decreased activity of lipogenic enzymes without affecting protein synthesis or carbohydrate metabolism.
Increased fat oxidation - In studies on obese ob/ob mice, AOD-9604 was shown to increase the rate of fat oxidation without affecting glucose oxidation. The peptide may also slightly increase energy expenditure.
No interaction with the GH receptor - In in vitro experiments using BaF-BO3 cells transfected with the growth hormone receptor, it was confirmed that AOD-9604 does not bind to the GH receptor and does not induce cell proliferation in a receptor-dependent manner. This distinguishes the peptide from full-length hGH.
Scientific research directions
Research on AOD-9604 has focused mainly on its potential use in reducing obesity, although other areas were also explored, including cartilage regeneration.
Preclinical obesity studies
In pharmacological studies on adult obese Zucker rats treated with AOD-9604 (500 μg/kg/day orally) for 21 days, approximately 50% less body-weight gain was observed compared with the control group, along with significantly higher lipolytic activity in adipose tissue. Unlike hGH, AOD-9604 did not affect insulin sensitivity. Similar results were obtained in obese ob/ob mice after 14 days of intraperitoneal treatment.
Phase II clinical studies
Between 2001 and 2007, Metabolic Pharmaceuticals conducted several human clinical trials. In a 12-week phase IIa study involving 300 participants, a moderate reduction in body weight (2.6 kg vs 0.8 kg in the placebo group) was observed. However, a subsequent 24-week phase IIb study involving 536 people found no statistically significant difference in weight loss between AOD-9604 and placebo, which led to the termination of the clinical development program in 2007.
Safety profile in clinical studies
Despite the lack of clinical efficacy, AOD-9604 demonstrated an excellent safety profile in controlled studies involving more than 900 participants. The peptide was well tolerated and did not produce effects typical of full growth hormone, such as increased IGF-1, effects on glucose levels, or insulin.
Cartilage regeneration studies
In early studies on chondrocytes, AOD-9604 demonstrated the ability to modulate proteoglycan synthesis, suggesting potential applications in cartilage regeneration. However, this evidence is limited to in vitro and animal-model studies.
Scientific context
AOD-9604 is an example of a “peptide drug candidate” that showed promising biological activity in preclinical studies but did not confirm efficacy in large human clinical trials. The history of its development illustrates the challenges of translating results from animal models into clinical therapy.
Compared with other approaches to obesity treatment, AOD-9604 offered the theoretical advantage of selective action on adipose tissue without affecting muscle growth, glucose homeostasis, or IGF-1 levels. However, this selectivity did not translate into meaningful clinical efficacy.
Today, AOD-9604 remains of interest in the biohacker community and among fitness enthusiasts, despite the lack of clinical evidence supporting its use. The peptide is promoted as a “fat-burning fragment”, although the available scientific data do not support such claims.
Since 2007, when clinical development ended, AOD-9604 has not received approval from any major regulator (FDA, EMA, TGA). In December 2024, the FDA decided that AOD-9604 (both in free-base form and as the acetate) should not be included on the list of substances allowed for pharmacy compounding under Section 503A, citing concerns about limited long-term safety data, peptide impurities, and potential immunogenicity.
Safety profile in studies
Tolerability in clinical studies - In six controlled clinical studies involving more than 900 participants, AOD-9604 demonstrated a very good safety profile. The frequency of adverse events was comparable to the placebo group.
Lack of hormonal effects - Unlike full growth hormone, AOD-9604 did not cause increased IGF-1 levels, did not affect blood glucose concentrations, and did not induce insulin resistance. No effects on insulin or cortisol levels were observed either.
Potential adverse effects - Sporadically observed symptoms included injection-site reactions, mild headaches, and nausea. The frequency of these symptoms did not differ significantly from the placebo group.
Regulatory concerns - The FDA expressed concerns regarding: the lack of long-term safety data, potential impurities in peptide synthesis, and possible immunogenicity (antibody formation). The peptide is not approved for clinical use.
WADA status - AOD-9604 is on the list of prohibited substances of the World Anti-Doping Agency (WADA) as a growth hormone mimetic.
Bibliography – latest scientific studies
- FDA. Evaluation of AOD-9604 for the 503A Bulks List. FDA Drug Evaluation. 2024. FDA
- Heffernan MA et al. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice. Endocrinology. 2001;142(12):5182-5189. PubMed
- Heffernan MA et al. Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. Int J Obes Relat Metab Disord. 2001;25(10):1442-1449. PubMed
- Ng FM et al. Metabolic effects of a growth hormone releasing peptide (AOD9604) in obese Zucker rats. Mol Cell Endocrinol. 2000;159(1-2):107-115. PubMed
- Stier H et al. Safety and tolerability of the hexadecapeptide AOD9604 in humans. Growth Horm IGF Res. 2005;15(6):suppl A. [Abstract]
- Thompson JL et al. AOD-9604: a novel lipolytic peptide with potential therapeutic applications in obesity. Drug Dev Res. 2004;62(2):165-172. Wiley
- Sackmann-Sala L et al. Heterogeneity in signal transduction, gene expression profiles and metabolic effects of growth hormone. J Mol Endocrinol. 2012;48(1):R1-10. PubMed
- Obesity pharmacotherapy: Current perspectives and future directions. Metabolism. 2013;62(3):395-404. PMC
- Yuen KCJ et al. Growth hormone/insulin-like growth factor I axis in health and disease states. Front Endocrinol. 2024;15:1456195. PubMed
- Spengler J et al. Synthesis of AOD-9604 using N-methylbenzimidazolinone linker. J Pept Sci. 2018;24(S1):e3062. PubMed
