Side-by-side · Research reference
PE 22-28vsTesofensine
Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.
AAnimal-StrongHUMAN-REVIEWED16/47 cited
BPhase 3AUTO-DRAFTED10/40 cited
PE 22-28
TREK-1 Antagonist · Pre-Clinical
IP · SQ · Once Daily (animal models)Djillani 2017Pietri 2019
Tesofensine
SNDRI · Phase 3 obesity candidate
Oral · Once daily morning
01Mechanism of Action
Parameter
PE 22-28
Tesofensine
Primary target
TREK-1 two-pore-domain potassium channelDjillani 2017Ma 2020
Serotonin / norepinephrine / dopamine transporters (SERT / NET / DAT)Astrup 2008
Pathway
TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity
Triple monoamine reuptake inhibition → ↑synaptic 5-HT, NE, DA → appetite suppression + thermogenesisAstrup 2008
Downstream effect
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
Strong appetite suppression, mild thermogenic effect, weight lossAstrup 2008
Feedback intact?
N/A — direct ion channel blockade; not receptor-mediated endocrine axis
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Origin
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
Small molecule developed by NeuroSearch (Denmark) for CNS indications, repurposed for obesityAstrup 2008
Antibody development
Not reported in animal studies
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02Dosage Protocols
Parameter
PE 22-28
Tesofensine
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.
Once daily, morning
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.
—
Evidence basis
Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017Qi 2018Wu 2021
Phase 2b + ongoing Phase 3Astrup 2008
Lower / starter dose
—
0.125 mg / day
Duration
—
24 weeks per studied cycle
Form
—
Oral capsule
Timing
—
Morning to avoid sleep disruption
Half-life
—
~9 days (very long)
04Side Effects & Safety
Parameter
PE 22-28
Tesofensine
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
—
Insomnia
—
Dose-related; mitigate with morning timing
Dry mouth
—
Common
Nausea
—
Common
Mood changes
—
Anxiety / agitation possible
Cardiovascular events
—
Phase 3 trial monitoring; not yet FDA-cleared
Pregnancy / OB
—
Contraindicated
Absolute Contraindications
PE 22-28
- ·Human use — no clinical safety data available
Tesofensine
- ·Pregnancy / breastfeeding
- ·Severe cardiovascular disease
- ·Concurrent MAOI use
Relative Contraindications
PE 22-28
- ·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)
Tesofensine
- ·Hypertension
- ·Anxiety disorder
- ·Insomnia
05Administration Protocol
Parameter
PE 22-28
Tesofensine
1. Animal protocol (IP)
Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.
Oral capsule (investigational; not commercial).
2. Stability
Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017
Swallow whole with water, morning only.
3. BBB penetration
Enhanced CNS bioavailability vs full spadin, likely due to smaller size. Mechanism (passive diffusion vs active transport) not fully characterized.
Morning to mitigate insomnia. Do not dose evening.
4. Human formulation
Not established — peptide synthesis methods for research use only. No pharmaceutical-grade formulation available.
Room temp ≤25 °C, dry place.
5. Caveat
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Monitor BP + HR + mood. Avoid stimulants + MAOIs.