Tesofensine: Complete Guide
Tesofensine is a triple monoamine reuptake inhibitor that blocks the reuptake of serotonin, norepinephrine, and dopamine. Originally developed by NeuroSearch for Parkinson's disease and Alzheimer's disease, it was repurposed for obesity after clinical trial participants experienced significant weight loss. While not technically a peptide, tesofensine is widely discussed in peptide research communities for its potent appetite-suppressing and metabolic effects.
Last updated: 2026-01-29
Quick Facts
- Category
- therapeutic
- Also Known As
- Tesofensine
- Related Goals
- weight loss
Who Researches Tesofensine?
Tesofensine is researched by people exploring potent appetite suppressants for weight loss who are comparing options beyond GLP-1 agonists like semaglutide. Its triple reuptake mechanism (serotonin, norepinephrine, dopamine) distinguishes it from single-target approaches. Researchers studying monoamine neurotransmission, appetite regulation, and metabolic rate enhancement will find it relevant. Note that cardiovascular safety concerns (heart rate and blood pressure elevations) have been a regulatory hurdle.
Related Resources
- Comparisons: Tesofensine vs Semaglutide
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What Is Tesofensine?
Tesofensine was originally developed by Danish pharmaceutical company NeuroSearch A/S as a treatment for Parkinson's disease and Alzheimer's disease. During Phase 2 trials for neurological indications, researchers observed unexpectedly significant weight loss in participants — a finding that led to its redevelopment as an obesity treatment.
The compound is a small molecule (not a peptide) that inhibits presynaptic reuptake of all three monoamine neurotransmitters. By increasing synaptic concentrations of serotonin, norepinephrine, and dopamine simultaneously, it produces appetite suppression through multiple complementary pathways — more comprehensive than single-target agents like lorcaserin (serotonin only) or phentermine (norepinephrine/dopamine).
Mechanism of Action
Tesofensine inhibits the reuptake transporters for three monoamines:
- Serotonin (5-HT): Enhances satiety signaling in the hypothalamus — reduces appetite and food-seeking behavior
- Norepinephrine (NE): Increases sympathetic nervous system activity — promotes thermogenesis and energy expenditure
- Dopamine (DA): Modulates reward processing — may reduce hedonic (pleasure-based) eating and food cravings
The combined effect is both reduced caloric intake (appetite suppression) and increased caloric output (thermogenesis), producing a dual mechanism for weight loss.
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Dosage Overview
Clinical trial dosing: 0.25 mg, 0.5 mg, or 1.0 mg orally once daily. The 0.5 mg dose showed the best efficacy-safety balance in Phase 2, producing ~10.6% weight loss over 24 weeks. The 1.0 mg dose showed greater weight loss (~13%) but with more cardiovascular effects.
Tesofensine is an oral capsule — no reconstitution required.
Side Effects & Safety
- Elevated heart rate: Mean increase of 7–8 bpm at therapeutic doses — the primary safety concern
- Dry mouth: Very common, related to noradrenergic activity
- Insomnia: Dopamine and norepinephrine elevation can disrupt sleep
- Constipation: Related to serotonergic effects
- Mood changes: Anxiety, irritability reported in some participants
- Blood pressure: Modest increases in some patients
The cardiovascular effects (heart rate, blood pressure) have been the primary regulatory concern and a barrier to FDA approval. Long-term cardiovascular safety data is limited.