Side-by-side · Research reference
ACE-031vsPE 22-28
Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.
APhase 2HUMAN-REVIEWED10/44 cited
BAnimal-StrongHUMAN-REVIEWED16/47 cited
ACE-031
ActRIIB-Fc Fusion · Phase 2 Halted
SQ · Weekly dosing investigated
PE 22-28
TREK-1 Antagonist · Pre-Clinical
IP · SQ · Once Daily (animal models)Djillani 2017Pietri 2019
01Mechanism of Action
Parameter
ACE-031
PE 22-28
Primary target
Myostatin, GDF11, activin A — TGF-β superfamily ligands
TREK-1 two-pore-domain potassium channelDjillani 2017Ma 2020
Pathway
Soluble decoy receptor binds circulating myostatin/TGF-β ligands → prevents ActRIIB activation → SMAD2/3 pathway inhibition
TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity
Downstream effect
Disinhibition of myogenic signaling, increased skeletal muscle mass and strength
Antidepressant-like activity in forced swim test and tail suspension test; reduced A1-like reactive astrocyte activation; neuroprotection via NF-κB pathway modulationDjillani 2017Cong 2023Wu 2021
Feedback intact?
—
N/A — direct ion channel blockade; not receptor-mediated endocrine axis
Origin
Recombinant fusion protein: human ActRIIB extracellular domain + IgG1-Fc fragmentReichel 2025
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 2017Mazella 2018
Antibody development
—
Not reported in animal studies
02Dosage Protocols
Parameter
ACE-031
PE 22-28
Clinical dosing
Weekly or biweekly SQ injections (exact doses undisclosed pre-halt)
Phase 2 DMD trial protocol not fully published.
—
Black market products
Variable purity; 12/14 tested products contained target protein plus contaminantsReichel 2025
SDS-PAGE revealed multiple protein bands; quality control absent.Reichel 2025
—
Evidence basis
Phase 2 trial discontinued — incomplete dataset
Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017Qi 2018Wu 2021
Half-life
Days to weeks (Fc-fusion typical kinetics)
IgG1-Fc domain confers extended circulation time.
—
Duration investigated
12–24 weeks (trial cut short)
—
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.
Frequency
—
Once daily
Sustained antidepressant effect over 7+ days.
Onset (animal)
—
Within hours (acute); full effect 4–7 days
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
ACE-031
PE 22-28
Epistaxis (nosebleeds)
Significant incidence in Phase 2 DMD trial — primary safety signal
—
Telangiectasia
Dilated capillaries / spider veins observed
—
Vascular abnormalities
Mechanism: ActRIIB/ALK1 pathway disruption affects vascular homeostasis
—
Injection site reactions
Local erythema, induration (biologics class effect)
—
Antibody development
Potential for anti-drug antibodies (Fc-fusion proteins); incidence not reported
—
Black market contaminants
12/14 tested products contained multiple unidentified proteins alongside ACE-031Reichel 2025
—
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
ACE-031
- ·History of vascular disorders (epistaxis, telangiectasia, HHT)
- ·Pregnancy (TGF-β pathway critical for fetal development)
- ·Active malignancy (myostatin inhibition may affect tumour growth)
- ·Use of non-pharmaceutical grade ACE-031 (contamination risk)Reichel 2025
PE 22-28
- ·Human use — no clinical safety data available
Relative Contraindications
ACE-031
- ·Coagulation disorders or anticoagulant use (epistaxis risk)
- ·Hereditary hemorrhagic telangiectasia (HHT) family history
- ·Cardiovascular disease (vascular remodeling effects unknown)
PE 22-28
- ·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)
05Administration Protocol
Parameter
ACE-031
PE 22-28
1. Pharmaceutical status
ACE-031 is not FDA-approved or commercially available. Phase 2 development was discontinued in 2011 due to safety concerns. Any ACE-031 on the black market is unregulated research chemical.
Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.
2. Black market quality
12 of 14 tested black market ACE-031 products contained the target protein but also carried multiple unidentified protein contaminants detectable by SDS-PAGE. Two products contained no ACVR2B-immunoreactive material.Reichel 2025
Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017
3. Detection in sport
ACE-031 is prohibited under WADA S4.3 (Myostatin Inhibitors). Gel electrophoresis and Western blotting using ACVR2B-specific antibodies can detect the ~58.4 kDa protein in biological samples.Reichel 2025
Enhanced CNS bioavailability vs full spadin, likely due to smaller size. Mechanism (passive diffusion vs active transport) not fully characterized.
4. Clinical trial route
Phase 2 protocol used subcutaneous injections at weekly or biweekly intervals. Exact dosing protocols remain unpublished.
Not established — peptide synthesis methods for research use only. No pharmaceutical-grade formulation available.