Tesofensine
Weight Loss / CNS Compound (Triple Reuptake Inhibitor)investigationalAlso known as: NS2330, TE
A triple monoamine reuptake inhibitor (serotonin, norepinephrine, dopamine) originally developed for Parkinson's and Alzheimer's disease, repurposed as a potent weight-loss agent.
Overview
Tesofensine is a small-molecule triple monoamine reuptake inhibitor that blocks the reuptake of serotonin, norepinephrine, and dopamine. Originally developed by NeuroSearch for neurodegenerative diseases (Parkinson's and Alzheimer's), it was unexpectedly found to produce significant weight loss in clinical trials โ patients lost substantially more weight than with any approved anti-obesity drug at the time. This led to its repurposing as an anti-obesity compound. In a Phase II trial, tesofensine 0.5mg produced an average weight loss of 12.8 kg over 24 weeks, far exceeding results seen with sibutramine or other available agents. It reduces appetite through central appetite suppression and increases resting energy expenditure via sympathetic activation. While technically not a peptide, tesofensine is commonly included in peptide clinic weight-loss protocols. It is currently in Phase III trials in several countries and has regulatory approval in some markets (Mexico as Tesomet in combination with metoprolol).
Mechanism of Action
Tesofensine acts on central monoamine systems: (1) Inhibits reuptake of serotonin (5-HT), reducing appetite and increasing satiety signaling; (2) Inhibits norepinephrine reuptake, increasing sympathetic tone and resting energy expenditure; (3) Inhibits dopamine reuptake, enhancing reward signaling and reducing food-seeking behavior; (4) Increases thermogenesis through elevated catecholamine activity; (5) Reduces overall caloric intake by 26-32% without formal dietary restriction; (6) Has a long half-life (~9 days) allowing once-daily dosing.
Molecular Formula
C17H23NO3
Molecular Weight
289.37 g/mol
Sequence
N/A โ small molecule, not a peptide
Dosage Protocols
Dose Range
0.25mg โ 0.5mg
Frequency
Once daily
Route
oral
Cycle Length
12-24 weeks
Start at 0.25mg and titrate to 0.5mg after 1-2 weeks. Take in the morning to avoid sleep disruption. 1.0mg was tested but caused unacceptable cardiovascular effects. Long half-life (~9 days) means steady state takes weeks. Often combined with beta-blocker (metoprolol) to mitigate heart rate increase.
Source: Phase II clinical trial protocols
Side Effects
| Effect | Severity |
|---|---|
| Increased heart rate | moderate |
| Dry mouth | mild |
| Insomnia | mild |
| Constipation | mild |
| Elevated blood pressure | moderate |
| Mood changes | moderate |
Pros & Cons
Produced the largest weight loss of any drug in Phase II trials at the time โ 12.8 kg average in 24 weeks
Oral administration with once-daily dosing due to long half-life
Dual mechanism: reduces appetite AND increases energy expenditure
Potential cognitive/mood benefits from dopamine reuptake inhibition
Cardiovascular side effects (heart rate, blood pressure) require monitoring and possible beta-blocker co-therapy
Not yet FDA-approved โ limited availability in most countries
CNS-active compound with potential for mood changes and sleep disruption
Long half-life means side effects persist for days if they occur
Research Studies
Legal Status
Not FDA-approved. Phase III clinical trials ongoing. Approved in Mexico as part of Tesomet (tesofensine + metoprolol). Available from some compounding pharmacies and research chemical suppliers. Prescription-only where approved.
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