Side-by-side · Research reference

AOD-9604vsPE 22-28

Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.

APhase 2HUMAN-REVIEWED10/47 cited

BAnimal-StrongHUMAN-REVIEWED16/47 cited

AOD-9604

HGH 176-191 · β3-AR Lipolytic

250–300 mcgDaily doseHeffernan 2001

Phase 2Evidence levelHeffernan 2001 Ng 2000

~30 minHalf-life

SQ · Abdomen · Daily fasted

PE 22-28

TREK-1 Antagonist · Pre-Clinical

0.12 nMTREK-1 IC50Djillani 2017

7 AAPeptide lengthDjillani 2017

AnimalEvidence stage

IP · SQ · Once Daily (animal models)Djillani 2017 Pietri 2019

01Mechanism of Action

Parameter

AOD-9604

PE 22-28

Primary target

β3-adrenergic receptor (proposed)Ng 2000

TREK-1 two-pore-domain potassium channelDjillani 2017 Ma 2020

Pathway

β3-AR activation → cAMP → hormone-sensitive lipase activation → triglyceride breakdown to FFA + glycerolNg 2000

TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity

Downstream effect

Lipolysis of adipose tissue triglycerides; FFA release for oxidation; minimal IGF-1 / insulin impactHeffernan 2001

Antidepressant-like activity in forced swim test and tail suspension test; reduced A1-like reactive astrocyte activation; neuroprotection via NF-κB pathway modulationDjillani 2017 Cong 2023 Wu 2021

Feedback intact?

No GH-axis or IGF-1 feedback

N/A — direct ion channel blockade; not receptor-mediated endocrine axis

Origin

Synthetic modified C-terminal hexadecapeptide fragment of human GH (176-191) with N-terminal Tyr substitutionNg 2000

Synthetic truncation of spadin (PE 12-28), itself derived from the sortilin propeptide C-terminus. Residues 22-28: Val-Val-Arg-Gly-Trp-Leu-Arg.Djillani 2017 Mazella 2018

Antibody development

—

Not reported in animal studies

02Dosage Protocols

Parameter

AOD-9604

PE 22-28

Standard dose

250–300 mcg / dayHeffernan 2001

Anecdotal SQ range. Phase 2 trial dose 1 mg/day oral.

—

Frequency

Once daily, fasted

Once daily

Sustained antidepressant effect over 7+ days.

Lower / starter dose

150 mcg / day

—

Evidence basis

Phase 2 trials + animal-strongHeffernan 2001 Ng 2000

Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017 Qi 2018 Wu 2021

Duration

8–12 weeks per cycle

—

Reconstitution

Bacteriostatic water, 1 mL per 2 mg vial → 2 mg/mL

—

Timing

Morning fasted preferred (pre-cardio)

Aligns with circadian lipolysis.

—

Half-life

~30 min plasma

—

Animal dose (antidepressant)

—

0.3–3 µg/kg IP

Effective in forced swim test, tail suspension test, CUMS models.

Animal dose (neuroprotection)

—

0.03 µg/kg IPPietri 2019

Low-dose TREK-1 activation post-stroke for 7 days, then high-dose blockade.

Onset (animal)

—

Within hours (acute); full effect 4–7 days

Duration (animal)

—

7–28 days testedQi 2018 Pietri 2019

Comparison to fluoxetine

—

PE 22-28 outperforms fluoxetine in CUMS-sensitive rats by day 7

Chronic administration shows superior long-term efficacy.

Human equivalent (extrapolated)

—

Not established — no clinical trials

Allometric scaling from rodent data unavailable.

04Side Effects & Safety

Parameter

AOD-9604

PE 22-28

Injection site reaction

Mild erythema

—

GI symptoms

Rare mild nausea

—

Cardiovascular

Possible mild HR increase via β3-AR (theoretical β1 cross-reactivity)

—

IGF-1 elevation

None — designed to lack GH-axis activityHeffernan 2001

—

Insulin sensitivity

Neutral — no glucose impairmentHeffernan 2001

—

Cancer risk

No GH/IGF-1 axis activity → lower theoretical risk vs HGH

—

Pregnancy / OB

Avoid

—

Toxicity (animal)

—

No adverse effects reported at therapeutic doses

Cardiovascular (theoretical)

—

TREK-1 expressed in cardiac tissue; arrhythmia risk unclear

Weight change

—

Not reported in animal studies

Neurological

—

No seizures or behavioral abnormalities noted

Long-term safety

—

Unknown — longest animal study 28 days

Absolute Contraindications

AOD-9604

·Pregnancy / breastfeeding
·Severe cardiovascular disease (caution with β-receptor agonists)

PE 22-28

·Human use — no clinical safety data available

Relative Contraindications

AOD-9604

·Concurrent β-blocker therapy (theoretical antagonism)
·Pheochromocytoma

PE 22-28

·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)

05Administration Protocol

Parameter

AOD-9604

PE 22-28

1. Reconstitution

Add 1 mL bacteriostatic water to 2 mg vial → 2 mg/mL = 200 mcg per 0.1 mL.

Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.

2. Injection site

SQ — abdomen preferred. Rotate sites.

Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017

3. Timing

Morning, fasted, ideally pre-cardio for amplified fat oxidation.

Enhanced CNS bioavailability vs full spadin, likely due to smaller size. Mechanism (passive diffusion vs active transport) not fully characterized.

4. Storage

Lyophilised: room temp, light-protected. Reconstituted: refrigerate, ≤30 days.

Not established — peptide synthesis methods for research use only. No pharmaceutical-grade formulation available.

5. Needle

29–31G, 4–8 mm insulin syringe.

—

06Stack Synergy

AOD-9604

+ MOTS-c

Moderate

View MOTS-c →

AOD-9604 mobilises FFAs from adipose via β3-AR; MOTS-c upregulates AMPK / PGC-1α / FAO machinery so that mobilised FFAs are efficiently oxidised. The pathways are sequential — supply (AOD) plus demand (MOTS-c) — and produce more durable lipolytic effects than either alone in anecdotal protocols.

AOD-9604: 250–300 mcg SQ · morning fasted (daily)
MOTS-c: 5 mg SQ · 2–3× per week (pre-workout)
Primary benefit: Fat mobilisation + mitochondrial oxidation, no IGF-1 concern

PE 22-28

— no documented stacks