Seeking an in-depth analysis of AOD-9604 vs. ipamorelin in terms of their respective research applications, benefits, and side effects?
Our extensive comparison explores published research on the benefits of both ipamorelin and AOD-9604, which include:
- Increased muscle mass and strength and
- Reduced body fat
- Increased bone density
Additionally, we'll provide insights into the compound’s underlying mechanisms, recommended dosages, and possible adverse effects.
We’ll also share details on our top-recommended supplier for acquiring research-grade AOD-9604 and ipamorelin for your studies.
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What is AOD-9604?
AOD-9604, or Anti-Obesity Drug 9604, is a modified version of the C-terminal fragment of the human growth hormone (hGH) molecule. This peptide fragment was developed in the late 1990s by Australian firm Metabolic Pharmaceuticals .
The C-terminal fragment of hGH, which contains its last 15 amino acids, is referred to as hGH 177-191 (aka AOD-9401), and is known to mediate the hormone’s fat-burning effects .
As mentioned, AOD-9604 is a modified version of the hGH 177-191 fragment, with the only modification being the addition of the amino acid tyrosine at the N-terminus .
The rest of the structure is identical to the 177-191 amino acid sequence of hGH, including the disulfide bridge between the two cysteine amino acids (Cys182 and Cys189), which in the case of AOD-9604 are at the 7th and 14th positions .
The presence of a disulfide bridge, combined with the addition of tyrosine at the N-terminus, significantly enhances the peptide’s stability, making it orally active .
AOD-9604 has been researched for various potential uses:
- It has been studied primarily as a weight loss medication that can be administered as an oral tablet . However, the development of AOD-9604 as an anti-obesity pill was terminated in 2007 for lack of effectiveness in trials .
- AOD-9604 has been administered intraarticularly to manage osteoarthritis in laboratory animal models .
- The peptide was investigated by Australian pharmaceutical company Lateral Pharma as a potential management of migraines and neuropathic pain, but the results were similar to placebo [10, 11].
The peptide is not approved by the United States Food and Drug Administration (FDA) in any form, meaning it is not commercially available for patients. Qualified experts can purchase it legally for research purposes.
What is Ipamorelin?
Ipamorelin (NNC 26-0161) is a pentapeptide derived from a growth hormone secretagogue (GHS) called growth hormone-releasing peptide-1 (GHRP-1). GHRP-1 is a met-enkephalin analog without any affinity for the opioid receptor.
GHRP-1 and ipamorelin are both GH secretagogues that target the ghrelin receptor in the pituitary gland to stimulate growth hormone synthesis.
Ipamorelin stands out as more selective compared to other member compounds of the GHS class, as it stimulates growth hormone release without affecting the synthesis of other pituitary hormones, such as ACTH or prolactin .
Ipamorelin was originally formulated and patented by Novo Nordisk alongside Helsinn Therapeutics in 1994. It was developed to mimic ghrelin's function in the digestive tract, amplifying peristalsis .
The peptide underwent testing for its potential advantages in patients suffering from post-surgical ileus, a condition related to lack of peristalsis manifesting after gastrointestinal surgery.
Although phase-2 studies indicated some positive outcomes of ipamorelin for this condition, the benefits observed over 7-10 days were not considered substantial, leading to the discontinuation of clinical development [14, 15].
Nevertheless, laboratory studies suggest that when administered subcutaneously or intravenously, ipamorelin may offer benefits linked to its effect of increasing both GH and insulin-like growth factor-1 (IGF-1). These may include :
- Increased muscle and whole-body mass
- Increased muscle strength
- Increased bone mineral density and mineralization
At present, the FDA has not authorized the marketing of ipamorelin to the public, and like AOD-9604, it is available for research use.
AOD-9604 vs. Ipamorelin | Comprehensive Comparison
Ipamorelin works by upregulating the production of growth hormone while AOD-9604 mimics some of hGH’s effects. Thus, the two compounds have varying mechanisms and effects.
In terms of their respective mechanisms:
- Ipamorelin stimulates the GHS-R1a in the pituitary and causes an increase in hGH levels within 40 minutes when applied to healthy adults. The peptide has a half-life of two hours, and its effects on hGH synthesis last up to three hours. Doses higher than 60mcg/kg of body weight can lead to hGH peaks reaching up to 26.6ng/ml (80mIU/l) .
- In comparison, AOD-9604 does not influence hGH or IGF-1 synthesis in the body. Instead, it appears to increase lipolysis in the body via mechanisms that are not fully elucidated. Preliminary research suggests that these mechanisms may be similar to those observed with exogenous hGH therapy, including the activation of the adrenergic receptors and increased lipolysis in adipocytes .
In terms of respective effects:
- Ipamorelin therapy increases serum GH, appetite, and body weight. Preclinical studies of ipamorelin report significant appetite increase and weight increase related to muscle and fat gain. Some animal experiments also showcase a 54% increase in IGF-I and reduced loss of muscle strength loss in drug-induced catabolic conditions [18, 19].
- In comparison, AOD-9604 appears to result in weight loss, primarily related to fat loss. It has demonstrated significant weight loss in test animals. In one experiment, obese Zucker rats lost around 50% of their weight in 19 days, with the researchers noting 23% increased lipolytic activity, measured as glycerol release from the fatty tissue of the treated animals .
In brief, it appears that ipamorelin can cause weight and muscle gain, while AOD-9604 may be a weight loss agent.
Benefits of AOD-9604
Several clinical studies investigated the potential effects of AOD-9604 for weight loss, as well as other for cartilage recovery, neuropathic pain, and migraines.
Below, we outline some of the most notable preclinical and clinical studies related to AOD-9604's effects:
- In a 12-week clinical trial, participants administered 1mg/daily AOD-9604 experienced an average weight loss of 5.72lb, while the placebo group shed only 1.76lb. Interestingly, the weight loss effects were not dose-dependent, as a higher dose of 10mg/daily AOD-9604 did not correspond to greater weight reduction .
- There is some evidence that AOD-9604 may be less effective for weight loss than exogenous hGH. A murine study involving 250 mg/kg/daily AOD9604 and 1mg/kg/day HGH for 14 days reported that obese mice lost 28% and 40% of their body weight, respectively .
- Researchers investigating a collagenase-induced knee osteoarthritis model reported that AOD9604 boosted the regeneration of damaged cartilage compared to placebo (saline). The study further revealed that the combination of AOD9604 and hyaluronic acid injections surpassed the effectiveness of either hyaluronic acid or AOD9604 alone .
Overall, AOD-9604 appears to possess fat-burning effects similar to that of hGH. The peptide may also have some of the recovery-promoting effects of the growth hormone, but more research is necessary to confirm this.
Benefits of Ipamorelin
Clinical research on ipamorelin is scarce, with most studies spanning one week or less. Such brief investigations do not provide ample evidence to fully understand the ramifications of increased GH levels via ipamorelin therapy, despite the peptide's evident potency.
On the other hand, preclinical investigations have explored ipamorelin’s impact on muscle mass, appetite, body weight, and bone density. Some of the standout findings include:
- A murine study showed that ipamorelin can reduce muscle strength loss in catabolic conditions induced by corticosteroids. This hints at the peptide's potential to combat muscle atrophy under specific circumstances. The peptide also enhanced bone mineralization in the test animals treated with ipamorelin and corticosteroids, compared to those treated with corticosteroids only .
- Research in female rats indicates that ipamorelin administration may boost bone mineral content, which results in improved bone density and reduced frailty .
- A study in healthy mice documented a 16.9% rise in body weight over a two-week treatment period. This gain was believed to stem from the hunger-inducing effect of ghrelin receptor stimulation .
Thus, ipamorelin appears to exert anabolic and appetite-stimulating effects, which may result in improved muscle and weight gain, as well as increased muscle and bone strength.
AOD-9604 Side Effects and Complications
Currently, only two studies (METAOD005 and METAOD006) have investigated the long-term safety of AOD-9604. Both employed an oral AOD-9604 formulation .
The larger of the two studies (METAOD006), which included over 500 subjects at up to 1mg/daily AOD-9604, reported the following side effects:
- Any adverse event: 78.7% vs. 83.2% for placebo.
- Infections and infestations (mainly nasopharyngitis): 46.8% vs. 17.5% prior to treatment.
- Nervous system disorders (mainly headache): 30.1% vs placebo: 25.9%.
- Musculoskeletal and connective tissue disorders (mainly back pain): 25.5% vs. placebo: 8.2%.
- Gastrointestinal disorders (mainly diarrhea): 22.9% vs. placebo: 7.8%.
None of the side effects were deemed definitively related to the treatment.
Both studies also reported relative safety and no side effects that may otherwise occur with exogenous hGH use :
- No statistically significant differences in IGF-1 levels were observed among the treatment and placebo groups throughout the study.
- No significant changes or trends were observed in any treatment group with the Oral Glucose Tolerance Test (OGTT). The overall change in pre-load glucose after 24 weeks of treatment was not statistically significant among the treatment groups.
- Further, there were no significant changes in laboratory parameters, vital signs, or ECGs during the study in any treatment group, including placebo. No anti-AOD9604 antibodies were detected in the subset of patients selected for antibody assay.
Overall, AOD-9604 appears safe, with a profile similar to a placebo. The peptide does not appear to significantly alter IGF-1 levels, pose a risk for cancer progression, or induce insulin resistance.
Yet, researchers should note that the peptide has not been researched regarding its safety following subcutaneous administration.
Ipamorelin Side Effects and Complications
Long-term trial data on ipamorelin's potential side effects in test subjects are limited. Studies spanning one week have indicated that this peptide might lead to minor gastrointestinal disturbances, including nausea .
Laboratory animal studies suggest that extended use of ipamorelin might elevate appetite . This could result in weight gain, aligning with anecdotal observations made by some researchers.
Ipamorelin is administered subcutaneously, which can lead to reactions at the injection site, such as induration, pain, or redness.
Further, given its potential proliferative effects, ipamorelin is not advised for subjects with cancerous conditions, as it might intensify disease progression.
Dosage Calculator | AOD-9604 and Ipamorelin
Below are reference dosing guidelines for AOD-9604 and ipamorelin, derived from clinical studies and anecdotal reports.
Reference AOD-9604 Dosing Protocol
In addition to its pill form, AOD-9604 is available for research as a lyophilized powder that should be reconstituted with bacteriostatic water and administered subcutaneously.
Studies involving intravenous AOD-9604 use in humans report a half-life of 3min. Unfortunately, there is a lack of data regarding the peptide’s half-life when administered subcutaneously . Nevertheless, researchers may consider administering the peptide twice daily instead of once daily, considering the short half-life after an infusion.
Available data on oral AOD-9604 suggest significant weight loss at daily doses of 1mg taken for 12 weeks . Considering the superior bioavailability but also the lack of research regarding subcutaneous AOD-9604, experts recommend more conservative dosing protocols involving 0.2-0.5mg/daily for up to four weeks.
Here is a sample dosing protocol based on these considerations:
- Daily AOD-9604 Dosage: 200-500mcg
- Administration Frequency: 1-2 times daily as subcutaneous injections
- Study Duration: Four weeks
- Notes: Alternate injection sites after each use. Cycle the subject off for at least two weeks before repeating the therapy
Reference Ipamorelin Dosing Protocol
There are no clinical studies on the prolonged use of ipamorelin. The only clinical data originate from a week-long trial where participants received approximately 0.03mg of ipamorelin per kilogram of body weight twice daily. This equates to 2.4mg for each dose, up to 4.8mg daily .
Longer trials are needed for researchers targeting alterations in body composition or other GH-associated advantages in their subjects. Anecdotal reports suggest administering reduced dosages over cycles lasting 8-12 weeks.
Based on the foregoing, the suggested experimental ipamorelin dosage for longer studies is as follows:
- Daily Ipamorelin Dosage: 200-300mcg
- Frequency of Administration: 2-3 subcutaneous injections of 100mcg
- Study Duration: 8-12 weeks
- Notes: Rotate injection locations with each application
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Ipamorelin vs. AOD-9604 | Overall
Ipamorelin and AOD-9604 have notable differences in their mechanisms, effects, and safety profiles.
Ipamorelin is a GHS that stimulates growth hormone synthesis and elevates IGF-1 levels. As a ghrelin receptor agonist, it also increases hunger. These effects potentially spur muscle gain, weight gain, and overall strength.
AOD-9604 is a modified fragment of growth hormone’s C-terminal region, which mediates its fat burning effects. Preliminary studies suggest that it may be an effective weight loss agent.