Tesofensine
Tesofensine (NS2330)
Triple monoamine reuptake inhibitor for weight loss
About
Tesofensine is a small-molecule (not a peptide) triple monoamine reuptake inhibitor that blocks reabsorption of dopamine, norepinephrine, and serotonin in the brain. Originally developed for Parkinson's and Alzheimer's disease, weight loss emerged as a striking side effect, redirecting development toward obesity. Phase 2 trials showed roughly twice the weight loss of approved drugs at the time, though cardiovascular and psychiatric signals at higher doses delayed FDA approval. It remains investigational in the US as of 2026, with conditional approval pathways advancing in Mexico.
Mechanism
Inhibits presynaptic reuptake of dopamine, norepinephrine, and serotonin, prolonging hypothalamic monoamine signaling — suppressing appetite and modestly raising resting energy expenditure.
Dosage
When to take: Morning, with or without food. Evening dosing causes insomnia due to long half-life and dopaminergic activity.
Reconstitution
Vial size (mg): N/A · BAC water (mL): N/A · Concentration: N/A
Oral compound — no reconstitution needed.
Benefits
- ~10% body weight loss at 0.5 mg over 24 weeks (Phase 2)
- Roughly twice the weight loss of older approved anti-obesity drugs
- Once-daily oral dosing — no injections required
- Early appetite suppression within 1-2 weeks
- Possible mood and motivation lift from dopaminergic activity
Side effects
- Dry mouth, nausea, constipation, abdominal pain
- Insomnia and sleep disturbance
- Heart rate increase of 5-10 bpm at 0.5 mg
- Blood pressure elevation at 1.0 mg (dose discontinued)
- Anxiety, irritability, mood changes
- ~20% withdrawal rate due to adverse events in trials
Gender notes
Cautions
- Uncontrolled hypertension or significant cardiovascular disease
- Anxiety disorders, bipolar disorder, or psychosis history
- Current MAO inhibitor use (serotonin syndrome risk)
- Concurrent SSRI, SNRI, or other serotonergic medications
- Strong CYP3A4 inhibitors (certain antifungals, antibiotics)
- Pregnancy, pregnancy planning, or breastfeeding
- Children and adolescents
Research
- Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial
The Lancet · 2008
Phase 2 trial in 203 obese Danish adults over 24 weeks. Tesofensine 0.5 mg produced ~10% weight loss (placebo-subtracted), approximately double that of approved anti-obesity agents of the era.
- The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men
International Journal of Obesity · 2010
Mechanistic study confirming tesofensine reduces appetite and modestly raises 24-hour energy expenditure in overweight men, supporting the dual appetite/thermogenesis mechanism.
- Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity
Journal of Clinical Endocrinology & Metabolism · 2022
Combination of tesofensine + metoprolol (Tesomet) showed weight loss in hypothalamic obesity while metoprolol blunted the heart-rate signal — informing safer dosing approaches.