AOD-9604: The Anti-Obesity Peptide

Jay Campbell

By Jay Campbell

January 20th, 2022

 

Obesity continues to drive the world into a slow, gradual yet eventual extinction.

It destroys both individual and global health… and in many ways:

  • 1.6 billion adults worldwide are overweight, 400 million are clinically obese
  • Leading contributor to chronic diseases (cancers, heart diseases, diabetes)
  • 300,000 Americans die each year due to obesity-related causes

So it only makes sense to use the best tools possible to rapidly reverse course.

One promising therapeutic peptide in our toolbox appears to be AOD-9604, which I talked about in my last article as an incredible fat burner.

It works like magic with Semaglutide, but how does it stand on its own?

Today’s article will answer that question.

What Is AOD-9604?

AOD-9604 - Anti-Obesity Peptide

Short for “Advanced Obesity Drug”, AOD-9604 is a modified form of the amino acids #177-191 located at the C-terminus of human growth hormone (HGH).

Where it differs structurally as a synthetic peptide is the addition of the amino acid tyrosine at the N-terminus to provide additional stability to the peptide (hence a longer half-life), seen on the top-right corner of the picture below:

(Source)

Hence why you’ll also see it labeled as “Tyr-hGH Frag 176-191”.

But why focus on less-than-10% of HGH, and why this particular area?

If you recall what I’ve previously said about HGH, one of its main benefits is fat loss — but it does come with its fair share of nasty side effects (insulin resistance, compromised natural HGH production, negatively pituitary gland function, etc.).

And even though we have peptides such as CJC-1295 and Ipamorelin that can increase production and release of HGH without the side effects, why not just isolate the part of HGH that accelerates fat metabolism?

It would be a medical breakthrough for the treatment of obesity!

That was the idea devised by Australian biochemist Frank Ng his colleagues of Monash University in the 90’s.

Two pivotal studies published by this group in 1993 and 1994 confirmed the following about amino acids #177-191:

  • Adipose (fat) tissue mass was reduced
  • Body weight gain was reduced
  • Demonstration of anti-lipogenic activity seen in HGH (i.e. reducing the conversion of substrates such as carbohydrates into triglycerides and fatty acids, thereby decreasing formation of body fat)

It was soon discovered that AOD-9604 was more potent than HGH itself when it came to the third effect mentioned above!

Plus, AOD-9604 was also found to be more potent than amino acids #177-191 (a.k.a. AOD-9401) at lowering lipogenesis, while also increasing lipolysis (i.e. fat breakdown)!

More information about the history of AOD-9604’s development can be found here, and Dave Palumbo has a good 5-minute summary of the peptide’s effects:

So how does all of this work in the human body?

AOD-9604’s Mechanism Of Action

Let’s quickly recap what AOD-9604 does for fat loss:

  1. Stimulates lipolysis, which increases the rate of fat destruction
  2. Inhibits lipogenesis, which decreases the rate of fat formation from substrates that are not fat
  3. Hence, boosts fat metabolism just as HGH does and thereby increases caloric burn

It was originally believed that both HGH and AOD-9604 exhibit their fat-destroying properties by interacting with the beta-3-adrenergic receptors in your body.

Yet this wasn’t the case when the hypothesis was tested in mice who did not have said receptors:

“The importance of beta(3)-AR was verified when long-term treatment with hGH and AOD9604 in beta(3)-AR knock-out mice failed to produce the change in body weight and increase in lipolysis that was observed in wild-type control mice.

However, in an acute experiment, AOD9604 was capable of increasing energy expenditure and fat oxidation in the beta(3)-AR knock-out mice.

… the lipolytic actions of both hGH and AOD9604 are not mediated directly through the beta(3)-AR although both compounds increase beta(3)-AR expression, which may subsequently contribute to enhanced lipolytic sensitivity.”

But that’s where the similarities end — take a look at the picture below:

 

(Source)

This may seem confusing, but peptide physician Dr. William Seeds explains what is happening in his book Peptide Protocols Volume 1:

“[AOD-9604] is unable to induce dimerization and thereby activation of the receptor (no competition with HGH)

This fragment holds the fat-reducing and tissue repair sequence and mimics the effect of HGH on lipid metabolism, without having growth-promoting or pro-diabetic effects

[AOD-9604] inhibits lipoprotein lipase activity in adipose tissue, stimulating lipolysis in adipocytes”

Since AOD-9604 does not interact with growth hormone receptors, it means the peptide has the following advantages over HGH:

Since beta-3-adrenergic receptor activation appears to be a secondary mechanism of AOD-9604, its primary and complete mechanism for fat mobilization and/or fat cell death within adipose tissue is not currently known.

Top 2 Health Benefits Of AOD-9604

As you’ve probably deduced from everything I’ve shared thus far, AOD-9604 is meant for the singular purpose of shredding fat at a faster rate than normal.

It took me a lot of searching beyond PubMed to find all the information available about this peptide, and the best I could find was one additional use requiring further investigation.

Nevertheless, here are the two primary health benefits of the peptide AOD-9604…

AOD-9604 Is Extremely Promising For Fat Loss

Despite seeing great results with AOD-9604 myself, I wanted to see what other biohackers had to say about the peptide.

Unfortunately, testimonials are rather scarce and I was only able to dig up two of them.

The first one comes from a TRT user who wrote an extremely detailed review with before-and-after pictures.

He used HGH Frag 176-191, which is extremely similar to AOD-9604, but his results were phenomenal:

“Ran Frag 176-191 for 3.5 weeks, upping the dose each week. AM/PM doses with fasting periods before/after doses. Zero sides effects, zero “feeling it working”, felt the same except weight kept dropping and dropping.

Lost 7lbs in 3 weeks after upping my cals and slacking on diet, how much of that was fat and how much was water/glycogen stores dropping from coming off cycle I have no idea, you be the judge.

Best use case IMO is when you are already very lean and need something to break through a sticking point. Results are subtle so you will not notice anything if you are not already low BF%. Best analogy I can think of is NOS in a race car, you don’t blast the NOS when your at 80mph to get to 100mph quicker, you blast it when your at 150mph and need to hit 160mph that would otherwise be a slow crawl or impossible to reach without NOS.”

The second testimonial is much shorter and provides support to AOD-9604 speeding up the rate of fat loss, even if you are in a caloric deficit:

“I threw in AOD, and all progress began to speed up (not instantly of course). Despite following the aforementioned protocol above, I began to lose weight faster (i.e, instead of losing around 1 pound a week, I would lose it in 5 days). Add those extra 2 days up throughout the cycle, and we have our evidence. (it’s also worth mentioning, that I wasn’t blasting this shit, and that it was more of an experiment).”

But what does the science have to say about this?

Even if we factor in the animal experiments I quoted earlier, there are still others consistently showing AOD-9604’s fat-melting properties.

Such as this 2000 study done in obese rats:

“Daily treatment with an oral dose of AOD9604 of 500 µg/kg body weight for 19 days reduced over 50% (15.8 ± 0.6 vs. 35.6 ± 0.8 g) body weight gain of the animals in comparison with the control. The adipose tissues of the AOD9604–treated animals were found to have an increase in lipolytic activity. In contrast to chronic treatment with intact hGH, chronic treatment with AOD9604 showed no adverse effect on insulin sensitivity of the animals, as demonstrated with euglycemic clamp techniques”

Another study published in 2001 found the same thing, yet the results were very different for lean rats versus obese rats:

“Both hGH and AOD significantly reduced body weight gain in obese mice. This was associated with increased in vivo fat oxidation and increased plasma glycerol levels (an index of lipolysis).

Unlike hGH, however, AOD9604 did not induce hyperglycaemia or reduce insulin secretion. AOD9604 does not compete for the hGH receptor and nor does it induce cell proliferation, unlike hGH.

Both hGH and its C-terminal fragment reduce body weight gain, increase fat oxidation, and stimulate lipolysis in obese mice, yet AOD9604 does not interact with the hGH receptor”

Unfortunately, the human clinical trials didn’t show the same level of promise.

There were a total of six double-blind placebo-controlled human clinical trials done spanning a total of ~900 clinically obese subjects between 2001 and 2006.

METAOD001: A Phase I (double-blind, placebo-controlled, dose escalation) safety study with doses (ranging from 25 to 400 µg/kg AOD9604) administered intravenously to 15 healthy adult male volunteers presenting with a BMI between 24 and 30 kg/m2. A single dose of recombinant hGH (0.12 international units/kg) was administered intravenously as positive control.

METAOD002: A Phase IIa (double-blind, placebo-controlled 4 × 4 Latin Square design) safety study with single doses (25, 50 and 100 µg/kg AOD9604) administered intravenously to 23 healthy clinically obese males presenting with a BMI ≥ 35 kg/m2.

METAOD003: A Phase IIa (double-blind, placebo-controlled 4 × 4 Latin Square design) safety study with single doses (9, 27 and 54 mg AOD9604) administered orally (capsules) to 17 healthy, clinically obese males presenting with a BMI ≥ 35 kg/m2.

METAOD004: A Phase IIa (double-blind, placebo-controlled, dose escalation) safety study with multiple daily doses (9, 27 or 54 mg AOD9604) administered orally (capsules) for seven days in 36 healthy clinically obese males presenting with a BMI ≥ 30 kg/m2. 5).

METAOD005: A Phase IIb (randomized, double-blind, placebo-controlled) study to assess the efficacy (reduction in body weight), safety and tolerability of 12 weeks treatment with daily doses (1, 5, 10, 20 or 30 mg AOD9604) administered orally (capsules) in 300 healthy, clinically obese males, and females of non-child bearing potential, with a BMI ≥ 35 kg/m2.

METAOD006: A Phase IIb, randomized, double-blind, placebo-controlled study to assess the efficacy (reduction in body weight), safety and tolerability of 24 weeks treatment with different doses of AOD9604 tablets (0.25 mg, 0.5 mg, 1 mg, or placebo) in 502 obese adults.

Two studies involved intravenous injection, and four studies involved an oral tablet.

Without writing a book and explaining every single trial in detail, I’ll share the key takeaway points:

Trials #1-4 demonstrated an excellent safety profile in which AOD-9604 was well-tolerated and safe, with next to no difference compared to a placebo

Trial #5 saw patients taking AOD-9604 lose 2.8 kg on a dose of 1 mg, compared to the placebo group losing 0.8 kg over the same time period. Fewer patients had impaired glucose tolerance and saw their cholesterol profiles improve

Trial #6 was the nail in the coffin: The group taking AOD-9604 and the group taking the placebo were also following a strict diet and exercise routine over the entire 24-week period… yet the weight loss induced in the AOD-9604 group was not statistically significant (at least not compared to HGH).

Metabolic Pharmaceuticals, a subsidiary of Calzada Ltd., had no choice but to terminate all further efforts and funding related to AOD-9604:

“In 2007, the company that owns Metabolic Pharmaceuticals, Calzada, reported to their shareholders that AOD-9604 showed no promise, and was being abandoned as a weight loss drug.

The peptide was shelved, until the company heard that athletes were using it based on the early work in obese mice. They found that there was a growing market for their patented product. So rather than try to sue the Chinese companies that were illegally copying their patented peptide, they decided to get their own version onto the market.

…The doses used in trials were around 500ug/kg, which means a 100kg person was receiving 50mg of the peptide daily.”

$50 million in research and development down the drain for a promising product that was no longer a viable pharmaceutical product.

To make matters worse, University of Adelaide professor Gary Wittert, who was the principal investigator for 5 out of the 6 trials, had this to say:

“[The clinical trials] showed quite clearly there was no effect on weight. It was never going to be an anti-obesity drug.”

“In mouse studies, AOD-9604 was shown to break down fat and prevent weight gain, but it was also shown that this effect over the longer term was dependent on a specific receptor… When you give AOD-9604 to mice that are deficient in this receptor the weight-losing effect is lost.”

“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.”

For anybody who knows anything about peptides used for fat-burning, the problem should have been obvious from the get-go.

Even Avecho Biotechnology (formerly Phosphagenics), a company who wanted to repurposed AOD-9604 as a transdermal formulation, knew why the clinical trials failed:

“AOD9604’s delivery could have been the key issue. [Our] basic thinking on AOD9604 is that the drug failed because it was made orally available, which likely reduced bioavailability and also potentially resulted in protein denaturisation in the gastrointestinal tract, which would have reduced the drug’s activity.

The molecule was too unwieldy to be a pill – At a molecular weight of 1,815 daltons, AOD9604 is a large drug, around five or six times the size of a typical small molecule. Drugs much smaller have low oral bioavailability due to difficulty in getting through the gut wall… Even if AOD9604 was only a small peptide, it would still be susceptible to enzymatic degradation in the gut, being derived as it is from a naturally occurring protein12.

Some drug, but probably not enough, got through – For AOD9604, large molecule size wouldn’t have reduced bioavailability to zero, and the use of polyethylene glycol as an excipient may have increased bioavailability slightly13, however there is the distinct possibility that not enough of the drug got through the gastrointestinal tract to make a therapeutic difference.”

In summation: Given the stark contrast between the biohackers and the institutional scientists, we have the selective release of fats from the fat cells in obese or lean individuals (depending on who you ask).

AOD-9604 May Be A Useful Therapeutic Agent For Osteoarthritis And Cartilage Repair

When I was reading Dr. Williams Seeds’ book Peptide Protocols Volume 1 for more information on AOD-9604, I was surprised to see a mention of AOD-9604’s potential regenerative properties.

Specifically, he outlined four potential mechanisms through which AOD-9604 could be applied to osteoarthritis and cartilage/bone repair:

  • Stimulates bone differentiation and mineralization in adipose-derived mesenchymal stem cells (MSC)
  • Promotes myoblast differentiation
  • Promotes chondrocyte production of collagen and proteoglycan
  • Stimulates stem cell differentiation toward bone, muscle, and cartilage repair

One peptide physician on Reddit shared his results with doing so and reported positive results:

“This is exactly what I use in practice. I have amazing results with my patients. Granted, I do a lot more than this to my patients up for success. But I have had amazing results with joints and using this combination. You need to find a practitioner that can acquire these and will use them.

I cannot say I have done x-rays or MRI’s following injections since this is typically not covered and the patient doesn’t care if they have no pain. Though, my last patient told me he no longer feels grinding in his knees, which would lead me to believe that new cartilage has been formed.”

In simpler terms, AOD-9604 may be able to strengthen bone density and improve the speed of cartilage repair. Even if osteogenesis (i.e. bone formation) isn’t a feasible mechanism, at the very least it can be useful for the prevention/reduction of bone degradation. 

And three Master’s Degree theses published by students attending the University of Toronto in 1977, 1980, and 2009 suggest these two physicians aren’t proposing something out of the extraordinary.

Calzada Ltd was aggressively pursuing this treatment route in the early 2010s, reporting in 2012 that AOD-9604 “might promote cartilage creation and repair [in vitro]” (Source).

This was followed up one year later with positive results from an experiment involving rabbits with collagenase-induced knee osteoarthritis… except the combination of AOD-9604 AND hyaluronic acid were more effective in cartilage regeneration than either compound alone!

The results were publicly published in 2015 in the journal Annals of Clinical and Laboratory Science.

(NOTE: The only human dosing protocol I saw for this combination was 0.5-0.75 mL of a 10 mg/mL hyaluronic acid + 1000 mcg/mL AOD-9604 solution injected intra-articularly (i.e. directly in the joint) weekly for 4 months and then monthly for 5 months… still in the works)

For the more adventurous biohackers, you could even consider the combination of AOD-9604 with BPC-157!

The BEST Dose Of AOD-9604 For Faster Fat Loss

Although there is insufficient data to recommend an optimal AOD-9604 dose, I have personally used this peptide alongside Semaglutide with phenomenal success.

But using AOD-9604 alone, you can go one of two ways:

  • A once-a-day subcutaneous injection of 300 mcg, preferably in the morning while fasted (before cardio, or 1 hour before your first meal )
  • A twice-a-day subcutaneous injection of 250 mcg, once in the morning before fasted cardio (or at least 1 hour before your first meal) and once before bedtime (1-4 hours after your last meal).

(Credit goes to Dr. William Seeds for recommending the second protocol)

You can do a cycle as short as 6 weeks or as long as 6 months with either method you choose, taking a one-week break to reset before beginning another cycle where necessary.

Additionally, you can choose to fast for 3-4 hours after your first morning injection and see if that increases the rate of fat loss.

You’ll also get the best results when you inject AOD-9604 into the “fattest” parts of your body, especially around your mid-section.

Make sure to give your chosen protocol at least 3 months of use to judge how effective AOD-9604 is at reaching your ideal weight / body fat percentage.

(NOTE: It was very interesting to see how only IV infusions or oral formulations were used in the clinical trials for a peptide designed to LOSE BODY FAT, which probably explains why Metabolic Pharmaceuticals was unable to get favorable weight loss results… but that’s just me)

And while some peptide clinics endorse combining AOD-9604 with NAD+, but I personally cannot vouch for this.

Last but not least, make sure you are storing your reconstituted AOD-9604 at refrigerator temperature and use up the entire bottle within 2-4 weeks.

AOD-9604’s Side Effects & Safety Profile

Despite some of the disappointing results in human clinical trials, AOD-9604 is extremely safe to use.

The Food and Drug Administration would agree with this, having given the peptide human GRAS status (“Generally Recognized As Safe”).

Here’s what this means (Source):

“GRAS status allows AOD9604 to be sold as a nutrient supplement in conventional and functional foods, drinks and dietary supplements in the USA

As such it is exempt for these designated food uses from further pre-market approval requirements of food and drink ingredients in the USA.”

However, a 2014 study examining AOD9604’s metabolism in vitro makes this important clarification:

“AOD9604 is not approved for use in humans although the oral form of the peptide has been granted GRAS status or ‘generally recognized as safe’ by the US Food and Drug Administration (FDA).

Since the oral form of the peptide is not available commercially and injection of the peptide is not approved by the FDA, no metabolism experiments could be performed in humans”

If we go back to the 2014 review of six randomized, double-blind, placebo-controlled trials involving just over 900 patients, we see the following results:

“AOD9604 had no effect on serum IGF-1 levels, which confirms the hypothesis that AOD9604 does not act via IGF-1. Results of oral glucose tolerance test demonstrated that, in contrast with hGH, AOD9604 has no negative effect on carbohydrate metabolism.

There were no anti-AOD9604 antibodies detected in any of the patients selected for antibody assay. In none of the studies did a withdrawal or serious adverse event occur related to intake of AOD9604.

AOD9604 displayed a very good safety and tolerability profile indistinguishable from placebo. AOD9604 did not result in any of the adverse effects associated with full-length hGH treatment.”

Here were some of the most commonly reported side effects of AOD-9604, with none of them being severe:

  • Headache
  • Fatigue
  • Dizziness
  • Cough
  • Mild to moderate euphoria
  • Chest construction/tightness
  • Palpitations
  • Nasopharyngitis
  • Swelling, bruising, itching, and/or redness at the injection site (where relevant)

Knowing AOD-9604’s safety profile is excellent and its side effects are both infrequent and mild, I do have to highlight many biohackers who experienced mixed fat loss results with the peptide.

Here are some of the most important comments I found:

So don’t expect any miracles when you use AOD-9604 for burning fat unless you have the fundamentals of health locked in!

One last warning: AOD-9604 was classified as a banned substance by the World Anti-Doping Association in 2011 under the S0 status of “Non-Approved Substances”.

AOD-9604 was part of a major 2013 doping scandal within the Australian Football League when players admitted to using it, and a chronological description of the events that unfolded can be found at this website (along with why the Australian Sports Anti-Doping Authority dropped the peptide from their line of inquiry).

How To Buy Pharma-Grade AOD-9604 Online

Buying AOD-9604 online is not as easy as you would expect.

There are an awful number of peptide vendors who will attempt to slap the label “AOD-9604” on something that doesn’t even remotely resemble the peptide itself.

And that’s not even getting into peptide purity and quality.

In Fact, Dr. William Sears provides the following warning in his book “Peptide Protocols, Volume 1”:

“Frag 176-191 is a knockoff of AOD; it’s supposed to represent an AOD fragment, but it doesn’t have a di-sulfide bond to promote stability, which makes it less effective”

Remember the chemical structure of AOD-9604 I showed you at the very start of the article?

The “di-sulfide bridge” are the two sulfur atoms (“S”) attached to one another, which gives this peptide a cyclical component.

Two podcasts – Biohacking Superhuman Performance and VigorousSteve – go extensively into the differences between HGH Frag 176-191 and AOD-9604.

But if you want genuine ultra-pure AOD-9604 and nothing else, Limitless Life Nootropics is the place to go.

Use code JAY15 to get 15% off your order!

CONCLUSION: Should I Use AOD-9604 Or Not?

Please understand that using AOD-9604 for fat loss is an entirely individual experience.

While Dr. Eberwein has obviously seen great success in his obese patients when combining it alongside Semaglutide, and I have as well despite being below 10% body fat, we are all N of 1.

Your diet, your training regimen, and many other factors also play a role in the success you will achieve.

But definitely check out AOD-9604 if you’re looking for an alternative to HGH that only shreds stubborn body fat and nothing else.

As always…

Raise Your Vibration To Optimize Your Love Creation!

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