AOD-9604

AOD-9604 stands for Anti-Obesity Drug 9604. It is a synthetic peptide consisting of 16 amino acids derived from the C-terminal end of human growth hormone, specifically positions 176-191. A tyrosine residue replaces phenylalanine at the N-terminus for enhanced stability, and a disulfide bridge connects Cys7 and Cys14, creating a cyclic structure. This molecular architecture was designed to isolate the fat-burning properties of growth hormone while avoiding its broader metabolic effects.

Professor Frank Ng and his team at Monash University in Australia developed AOD-9604 during the 1990s. Over $50 million was invested in research and development through Metabolic Pharmaceuticals Ltd. The goal was ambitious: create an anti-obesity compound that could harness the lipolytic activity of HGH without triggering muscle growth, affecting blood sugar, or elevating IGF-1 levels. Early research proved promising enough that six clinical trials involving approximately 900 human participants were conducted between 2001 and 2007.

What Makes AOD-9604 Different From Regular Growth Hormone

Full-length human growth hormone contains 191 amino acids and affects the body in numerous ways. The N-terminal region has insulin-potentiating action, while amino acids 108-129 elicit high mitogenic (cell growth) responses. AOD-9604 specifically avoids these regions, containing only the C-terminal fragment responsible for fat metabolism.

This selectivity has real consequences. Studies confirmed that AOD-9604 does not meaningfully raise IGF-1 levels, does not affect glucose tolerance, and does not stimulate tissue growth. It cannot bind strongly to growth hormone receptors because the binding site 2 of HGH is completely missing. In BaF3 cell proliferation tests, AOD-9604 did not induce cell growth even at very high dosages. Radiography studies showed distribution to pancreas, pineal body, thyroid, liver, and kidney cortex, but notably not the central nervous system.

The Development Journey and Why It Was Discontinued

After showing promise in early trials, AOD-9604 progressed to Phase IIb testing. A 12-week trial in 300 obese subjects demonstrated that 1mg daily produced average weight loss of 2.8kg versus 0.8kg for placebo. The rate of weight loss was maintained throughout treatment, with small improvements in cholesterol profiles and reduced incidence of impaired glucose tolerance.

However, the larger 24-week trial with 536 subjects failed to achieve statistical significance when both groups followed intensive diet and exercise programs. This led to development termination in 2007. Professor Gary Wittert, who led five of the six human trials, has publicly explained that the beta-3 adrenergic receptor AOD-9604 depends on differs between mice and humans. In his words: "It's not surprising that AOD-9604 doesn't work in humans because the receptor on which it appears to be dependent is not the same in mice and humans."

Despite this, AOD-9604 received FDA GRAS (Generally Recognized As Safe) status in 2014 for use in foods and supplements. The original manufacturer no longer produces it, with current supplies coming from compounding pharmacies or research chemical suppliers, often manufactured in China. Australia classifies it as Schedule 4 prescription-only, while WADA has banned it for competitive athletes under the S0 category of non-approved substances.

Beyond Weight Loss: Emerging Applications

Research has expanded beyond the original anti-obesity purpose. A 2015 study in 32 rabbits with induced osteoarthritis showed that AOD-9604 combined with hyaluronic acid produced the least cartilage degeneration compared to either treatment alone. In vitro studies suggest the peptide may enhance differentiation of adipose-derived mesenchymal stem cells into bone-forming cells, and stimulates chondrocytes to produce proteoglycans and collagen.

An intriguing 2022 study explored cancer applications. Researchers loaded chitosan nanoparticles with both doxorubicin and AOD-9604, finding enhanced anti-proliferative activity against MCF-7 breast cancer cells compared to doxorubicin alone. The connection to non-alcoholic fatty liver disease (NAFLD) has also drawn attention, given that 95% of Type 2 diabetics also have NAFLD and AOD-9604's effects on liver fat metabolism.

Understanding how AOD-9604 produces its effects requires looking at fat metabolism at the cellular level. The peptide influences adipose tissue through multiple interconnected pathways, though the primary mechanism centers on beta-3 adrenergic receptor upregulation.

Beta-3 Adrenergic Receptor Upregulation

AOD-9604 does not directly activate beta-3 receptors to trigger lipolysis. Instead, it increases the expression of these receptors in adipose tissue. Research in obese subjects showed the peptide restores suppressed beta-3 receptor levels to those typically seen in lean individuals. This makes fat cells more responsive to naturally occurring lipolytic signals. Stored triglycerides begin breaking down into glycerol and free fatty acids that enter the bloodstream for use by muscles and other tissues.

Studies in obese mice demonstrated that AOD-9604 treatment increased beta-3 receptor RNA expression in fat cells. To confirm this mechanism, researchers tested the peptide in mice with genetically knocked-out beta-3 receptors. These animals showed no weight change, proving the receptor is essential for the primary fat-loss effect. However, some studies noted residual effects even without the receptor, suggesting secondary mechanisms exist.

Lipogenesis Inhibition Through Enzyme Suppression

AOD-9604 does more than break down existing fat. It also inhibits acetyl-CoA carboxylase activity in both adipocytes and hepatocytes. This enzyme is essential for lipogenesis, the process of creating new fat from dietary sources. By suppressing it in both fat cells and liver cells, the peptide reduces new fat formation while simultaneously enhancing fat breakdown.

Studies in Zucker rats, a genetic model of obesity, demonstrated this dual effect clearly. After 19 days of daily administration at 500mcg/kg body weight, treated animals showed over 50% reduction in weight gain (15.8g versus 35.6g in controls). Adipose tissue analysis revealed both increased lipolytic activity and reduced lipogenic markers. Crucially, euglycemic clamp testing confirmed no disruption to insulin sensitivity, distinguishing AOD-9604 from full-length growth hormone which commonly impairs glucose tolerance.

Independence From Growth Hormone Pathways

What sets AOD-9604 apart is its independence from typical HGH signaling. The peptide lacks binding site 2 of growth hormone, making it unable to dimerize the GH receptor. In competition binding assays, AOD-9604 cannot compete with HGH for receptor binding. Clinical trials confirmed that administration had no meaningful impact on circulating IGF-1 levels.

This independence has practical implications. Users do not experience water retention common with HGH therapy. There is no stimulation of tissue or organ growth. Glucose metabolism remains stable. The peptide achieves weight reduction without altering caloric intake or appetite, unlike GLP-1 agonists which work primarily through satiety signaling. This makes AOD-9604 mechanistically different from most other weight loss interventions.

Rapid Degradation and Metabolite Activity

One unique characteristic is the extremely short plasma half-life of approximately 4 minutes. The peptide degrades through amino-terminal truncation in a cascade fashion, with -2aa and -3aa fragments being the principal metabolites. Interestingly, these truncated fragments retain some (reduced) anti-lipogenic activity, which may explain why metabolic effects persist despite rapid clearance.

Pharmacokinetic studies in pigs showed IV administration at 0.4mg/kg reached maximum plasma concentration of 1,945ng/mL after just 2 minutes, followed by rapid decline. Oral administration showed 8.5 times higher area under curve (AUC) than IV injection, suggesting prolonged absorption that extends the effective window despite the short half-life. This may explain why once-daily dosing produces sustained effects.

Energy Expenditure and Fat Oxidation

Research in beta-3 receptor knockout mice revealed that AOD-9604 produces some effects through heightened energy expenditure and enhanced fat oxidation independent of receptor activation. The peptide appears to increase basal metabolic rate, promoting more efficient calorie burning at rest. Users often report increased energy levels, particularly during initial weeks of use, without the jittery stimulant sensation associated with other fat burners.

The increase in fat oxidation means your body becomes better at using fat as fuel rather than relying primarily on glucose. This metabolic flexibility benefits body composition and may contribute to the muscle-sparing effects users frequently report. When efficiently burning fat for energy, there is less pressure to break down muscle protein during caloric deficits. Notably, AOD-9604 triggers fat release from obese fat cells more than from lean ones, suggesting preferential targeting of excess fat stores.

The research base for AOD-9604 spans multiple decades and includes both animal studies and human clinical trials conducted primarily in Australia and the UK. While the peptide did not achieve FDA approval as a drug, the accumulated evidence provides valuable insights into its effects, limitations, and potential applications.

Foundational Animal Studies

The earliest research occurred in animal models during the 1990s and early 2000s. A landmark 2001 study published in Endocrinology examined AOD-9604's effects in obese mice over 14 days. Treated animals showed significant reductions in body weight and adipose tissue accumulation. Researchers observed increased levels of beta-3 adrenergic receptor RNA in fat cells, suggesting enhanced sensitivity of lipolytic pathways.

The beta-3 receptor knockout mouse experiments proved particularly important. These animals showed no weight change with AOD-9604 treatment, confirming the receptor's essential role. However, some residual effects through energy expenditure pathways suggested secondary mechanisms. This finding later became relevant when Professor Wittert explained that beta-3 receptors differ between mice and humans, potentially limiting translation of animal results.

A 2000 study in obese Zucker rats provided the most impressive weight loss data. Daily oral administration at 500mcg/kg for 19 consecutive days reduced weight gain by over 50% (15.8g versus 35.6g in controls). Adipose tissue analysis revealed markedly increased lipolytic activity. Euglycemic clamp techniques confirmed no disruption to insulin sensitivity, distinguishing AOD-9604 from full-length growth hormone which commonly impairs glucose tolerance with chronic use.

Human Clinical Trial Data

Six randomized, double-blind, placebo-controlled trials evaluated AOD-9604 in humans between 2001 and 2007:

• METAOD001: Phase I IV dose escalation in 15 healthy males with BMI 24-30. Doses 25-400mcg/kg were well tolerated with 29 adverse events reported, mostly headache.
• METAOD002: Phase IIa IV study in 23 obese males with BMI 35+. Notable finding: 5 of 23 subjects (21.7%) reported mild euphoria during active treatment but not placebo.
• METAOD003: Phase IIa oral study in 17 obese males testing 9, 27, and 54mg doses. Two serious adverse events occurred: diarrhea (possibly related) and bronchial pneumonia (unrelated).
• METAOD004: Phase IIa 7-day oral study in 36 obese males. The 54mg group showed more headaches, diarrhea, and flatulence than lower doses.
• METAOD005: Phase IIb 12-week oral study in 300 obese adults (54% male, 46% female). The 1mg group lost average 2.6kg versus 0.8kg placebo, representing 3.25 times greater weight loss.
• METAOD006: Phase IIb 24-week oral study in 502 obese adults. Safety profile was indistinguishable from placebo, but weight loss did not reach statistical significance.

The safety findings proved consistently reassuring across all trials. No effect on serum IGF-1 levels was detected. Oral glucose tolerance tests showed no negative impact on carbohydrate metabolism. No anti-AOD-9604 antibodies were found in any tested patients, indicating the peptide does not trigger immune responses. Side effects were essentially indistinguishable from placebo, with no withdrawals or serious adverse events attributed to AOD-9604.

Why the Phase IIb Trial Failed

The critical question most articles avoid: why did development stop? The 24-week trial with 536 subjects included intensive diet and exercise programs for both active and placebo groups. When lifestyle intervention was optimized, the additional benefit of AOD-9604 became statistically insignificant. This "floor effect" happens when the control group loses substantial weight through behavior change, making it harder to demonstrate drug benefit.

Professor Gary Wittert provided a mechanistic explanation. The beta-3 adrenergic receptor that mediates AOD-9604's effects in mice differs in humans. This receptor mismatch may explain why dramatic animal results did not fully translate. His public statements reflect genuine scientific skepticism: "There's so much misinformation out there" and "I cannot understand why athletes are taking it."

Cartilage and Joint Health Research

More recent research has explored applications beyond fat metabolism. A 2015 study published in Annals of Clinical and Laboratory Science examined AOD-9604 in a rabbit osteoarthritis model. Thirty-two white rabbits were divided into four groups of eight receiving placebo, AOD-9604 alone, hyaluronic acid alone, or the combination. After 4-7 weeks, morphological and histopathological evaluation showed that rabbits receiving both AOD-9604 and hyaluronic acid exhibited the least cartilage degeneration.

In vitro studies suggest AOD-9604 may enhance differentiation of adipose-derived mesenchymal stem cells into bone-forming osteogenic lineages. When researchers applied the peptide to isolated bovine chondrocytes, they observed increased production of proteoglycans and collagen, fundamental components of healthy cartilage. The peptide also appears to stimulate differentiation of myoblasts into mature muscle cells, suggesting broader regenerative potential.

Cancer Research and Future Applications

An intriguing 2022 study explored AOD-9604's potential in cancer therapy. Researchers loaded chitosan nanoparticles with both doxorubicin (a chemotherapy agent) and AOD-9604. Results showed that dual-loaded nanoparticles demonstrated greater anti-proliferative activity against MCF-7 breast cancer cells compared to doxorubicin-loaded nanoparticles alone. The mechanism appears to involve enhanced drug binding to multiple protein targets within cancer cells.

Connections to metabolic disease treatment continue emerging. Given that 95% of Type 2 diabetics also have non-alcoholic fatty liver disease (NAFLD), and AOD-9604's effects on liver fat metabolism, researchers have proposed investigating this application. The peptide's favorable impact on cholesterol profiles and glucose tolerance observed in trials supports this direction. Alternative delivery systems including transdermal and optimized oral formulations are also under investigation.

Genotoxicity and Long-Term Safety Studies

Extensive toxicology testing was conducted during development. AOD-9604 showed no genotoxicity in Ames tests, chromosome aberration assays, or bone micronucleus assays. A 4-week IV rat study found females receiving 1.0 and 10.0mg/kg/day showed significantly reduced body mass gain with no adverse effects. The 6-month rat chronic toxicology study established a NOAEL (No Observable Adverse Effect Level) at 100mg/kg/day. A 9-month cynomolgus monkey study confirmed NOAEL at 50mg/kg/day. These safety margins are substantially higher than human doses, supporting the favorable tolerability profile observed in clinical trials.

Important Notice: AOD-9604 is not FDA-approved for any therapeutic use. The information below reflects protocols from clinical research and practitioner experience. Always consult with a qualified healthcare provider before starting any peptide therapy.

Clinical Trial Dosing Data

Clinical trials tested AOD-9604 across a wide range: from 25mcg/kg IV up to 54mg oral daily. The surprising finding was that higher doses did not produce better results. In the 12-week Phase IIb trial testing 1mg, 5mg, 10mg, 20mg, and 30mg daily, the 1mg group achieved results comparable to all higher dose groups. This ceiling effect means more is not better with AOD-9604.

The 1mg daily dose showed average weight loss of 2.8kg over 12 weeks, more than triple the 0.8kg placebo result. This translates to roughly 300mcg three times daily or 500mcg twice daily in practical terms. Higher doses only increased side effects (particularly GI symptoms at 54mg) without improving efficacy.

Practical Dosing Protocols

Most practitioners use subcutaneous injection despite AOD-9604 showing approximately 40% oral bioavailability in rat studies, unusually high for a peptide. Injectable administration provides more consistent absorption and results.

• Beginner protocol (weeks 1-4): 300mcg subcutaneous injection, morning, 30 minutes before first meal, once daily
• Standard protocol (weeks 5-12): 400mcg subcutaneous injection, morning, fasted state, once daily
• Advanced protocol (weeks 5-16): 500mcg total split into 250mcg morning and 250mcg late afternoon (6 hours apart)

Weight-based adjustments from clinical experience suggest: under 160 lbs use 300mcg daily, 160-200 lbs use 400mcg, 200-250 lbs use 500mcg, and over 250 lbs may require extended cycling at 500mcg. Higher individuals often need more due to increased adipose tissue mass and altered peptide distribution.

Administration Method

Subcutaneous injection places the peptide into the fatty layer beneath the skin. Preferred injection sites include the lower abdomen (2-3 inches from navel), outer thighs (upper quadrant), or posterior upper arms. Rotate sites to prevent localized irritation or lipodystrophy from repeated injections in the same location.

Use insulin syringes with 30-31 gauge needles, 0.5-1ml capacity, 12.7mm (1/2 inch) needle length. Pinch a fold of skin, insert at 45-90 degree angle, inject slowly, hold for a few seconds, then release. Clean the injection site with alcohol before and apply gentle pressure after. Most users report minimal discomfort with proper technique.

Reconstitution and Storage

AOD-9604 comes as lyophilized (freeze-dried) powder requiring reconstitution:

• Add 2ml bacteriostatic water to a 5mg vial (resulting concentration: 2.5mg/ml or 250mcg per 0.1ml)
• Direct water stream down the side of vial, not directly onto powder
• Let sit 1-2 minutes, then gently swirl until fully dissolved (never shake vigorously)
• Store reconstituted solution refrigerated at 2-8°C (36-46°F)
• Use within 28 days of reconstitution for optimal potency
• Can freeze reconstituted solution at -20°C for 3-4 months if needed
• Unreconstituted powder stable at room temperature for weeks, or frozen long-term
• Avoid repeated freeze-thaw cycles

Timing Considerations

Morning administration on an empty stomach, 30-60 minutes before eating, appears to maximize fat oxidation effects. The fasted state allows the peptide to work on fat mobilization before dietary nutrients become available. Some users inject before fasted cardio for potentially enhanced results, taking their dose 45-60 minutes before exercise.

Avoid eating immediately after injection. Wait at least 30 minutes, preferably 45-60 minutes. Carbohydrates in particular may blunt lipolytic effects if consumed too soon. For those using split dosing, the second injection should occur in late afternoon (around 4-6pm), also away from meals. Some protocols suggest before-bed dosing, but morning remains most common.

Cycling and Duration

Standard cycling involves 8-12 weeks of active use followed by 4-6 weeks off. This helps maintain receptor sensitivity and prevents potential desensitization. Alternative protocols include:

• Standard cycle: 12 weeks on, 4 weeks off
• Extended cycle: 16 weeks on, 6 weeks off
• Intensive cycle: 8 weeks on, 2 weeks off (for rapid results)
• Long-term: 20 weeks on, 10-day break

Early research suggests no receptor desensitization occurs with AOD-9604, which would make it different from many other peptides. However, cycling remains common practice among practitioners. During off periods, maintain the dietary and exercise habits established during active use. Many users find improved metabolic function persists somewhat beyond the active cycle when healthy habits continue. Results typically become noticeable by weeks 4-6, with peak effects around weeks 8-12.

Medical Disclaimer: AOD-9604 is an investigational compound without FDA drug approval. While clinical trial data supports a favorable safety profile, long-term effects beyond study periods are not fully established. Do not use without consulting a qualified healthcare provider.

Clinical Trial Safety Data

Six randomized, placebo-controlled trials involving approximately 900 participants provide the most reliable safety information. These studies consistently showed AOD-9604's side effect profile was essentially indistinguishable from placebo. No serious adverse events were attributed to the peptide. No participants withdrew from studies due to AOD-9604-related issues.

Specific safety assessments confirmed several important points:

• IGF-1 levels remained stable, eliminating concerns about growth-related effects
• Oral glucose tolerance tests showed no negative impact on carbohydrate metabolism
• No anti-AOD-9604 antibodies were detected in any tested patients, indicating no immune response
• No effect on blood pressure observed in short-term studies
• No effect on cholesterol levels (minor improvements actually noted)
• Genotoxicity testing (Ames test, chromosome aberration, micronucleus assay) all negative

Commonly Reported Side Effects

While clinical trials showed minimal side effects, practical use sometimes produces mild temporary reactions:

• Injection site reactions: Redness, swelling, tenderness, itching, mild pain. Rotating sites and proper technique minimize this.
• Headaches: The most commonly reported effect across trials, occurring in up to 42.6% of subjects in one study but also high in placebo groups. Usually resolve within first week.
• Mild euphoria: Notably, 5/23 subjects (21.7%) in the METAOD002 trial reported mild euphoric feelings during active treatment but not placebo phases.
• GI symptoms: Upset stomach, nausea, diarrhea, flatulence. More common at higher doses (54mg showed significantly more GI events).
• Fatigue or tiredness: Occasionally reported as body adjusts to enhanced fat mobilization.
• Tingling sensations: Transient, typically early in treatment.

What AOD-9604 Does NOT Cause

Understanding what AOD-9604 avoids is as important as knowing potential effects:

• No water retention or edema (unlike full HGH)
• No carpal tunnel syndrome
• No joint pain or swelling
• No organ or tissue overgrowth
• No insulin resistance or glucose intolerance
• No hormonal shutdown or suppression requiring PCT
• No appetite stimulation (unlike some GH secretagogues)
• No CNS effects (does not cross blood-brain barrier per radiography)

Who Should Avoid AOD-9604

Certain individuals should not use AOD-9604:

• Pregnant or breastfeeding women (no safety data in these populations)
• Active cancer diagnosis (effects on tumor cells not fully understood)
• Severe cardiovascular disease
• Uncontrolled diabetes (monitor blood sugar closely if diabetic)
• Children and adolescents under 18
• History of hormone-sensitive disorders
• Known hypersensitivity to peptide compounds

Anyone taking medications affecting metabolism, insulin, or growth hormone pathways should consult their healthcare provider before starting. Potential interactions with diabetes medications, thyroid medications, stimulant-based weight loss drugs, and other growth hormone therapies should be evaluated.

Quality and Sourcing Concerns

Perhaps the greatest safety concern relates to product quality rather than the peptide itself. The original manufacturer (Metabolic Pharmaceuticals) no longer produces AOD-9604. Current supplies come from compounding pharmacies or research chemical suppliers, often manufactured in China. Quality varies enormously.

Health Canada has seized unauthorized AOD-9604 products from fitness stores, highlighting real risks from unregulated sources. When sourcing, look for:

• Third-party purity testing with certificates of analysis
• Purity above 98% confirmed by HPLC
• Proper lyophilization and packaging
• GMP manufacturing standards
• Appropriate storage and shipping (temperature-controlled)

Avoid suspiciously cheap products. Quality peptide manufacturing is expensive. Poorly manufactured peptides may contain impurities, incorrect concentrations, or degraded material that reduces effectiveness while potentially introducing safety risks.

Regulatory and Legal Status

AOD-9604 occupies a complex regulatory position:

• FDA: GRAS status for foods/supplements (2014), but NOT approved as a drug. Some reports indicate placement on FDA List 2, making it unavailable through certain clinics.
• Australia: Schedule 4 prescription-only medication
• Canada: Listed as unauthorized by Health Canada
• European Union: No medical approval
• WADA: Prohibited substance under S0 category (non-approved substances). Athletes risk anti-doping violations regardless of performance-enhancing effects. Drug testing can detect AOD-9604 and metabolites in urine.