Tesofensine
NS2330
~9–10% placebo-subtracted weight loss at 0.5 mg over 24 weeks (TIPO-1)
Overview
Tesofensine is an orally active small molecule — not a peptide — that inhibits the reuptake of three monoamine neurotransmitters: serotonin, noradrenaline, and dopamine. By raising synaptic levels of all three, it reduces appetite and increases satiety. It was first developed for neurodegenerative disease, where it underperformed, but trial participants lost weight, which redirected it toward obesity.
In the 24-week Phase 2 TIPO-1 trial (203 adults with obesity, combined with a modest calorie deficit), the 0.5 mg dose produced roughly 9–10% placebo-subtracted weight loss — about double what the obesity drugs of that era achieved — with the 0.25 and 1.0 mg arms bracketing it on a dose–response curve. The loss was predominantly fat mass with relative preservation of lean mass. Its very long ~9-day half-life supports simple once-daily oral dosing.
The trade-off is its monoaminergic, stimulant-like profile: the same trial measured a roughly 7–8 bpm rise in heart rate at 0.5 mg, alongside dose-related effects on sleep, mood, and blood pressure that have shaped its cautious clinical development. Because it is an oral small molecule, there is no reconstitution. All figures here summarize the published trial data and are an educational research reference only.
Key parameters
- Dose range
- 0.25–1 mg daily (trial range)
- Frequency
- Once daily (oral)
- Half-life
- ~9 days (~220 hours)
- Route
- Oral
- Vial sizes
- —
- Regulatory status
- Investigational oral small molecule (a triple monoamine reuptake inhibitor), not a peptide. Originally developed for Parkinson's and Alzheimer's disease, then repurposed for obesity. Not approved by the FDA or EMA; later studied in combination with metoprolol for hypothalamic obesity. Included here for completeness within the metabolic category.
Mechanism of action
Serotonin reuptake inhibition
Blocks the serotonin transporter, raising synaptic serotonin to enhance satiety — the same axis exploited by several appetite-suppressing agents.
Noradrenaline reuptake inhibition
Increases synaptic noradrenaline, contributing to reduced appetite and a mild rise in energy expenditure but also to the observed heart-rate and blood-pressure effects.
Dopamine reuptake inhibition
Raises synaptic dopamine, which modulates food reward and motivation; this stimulant-like component also underlies its potential effects on sleep and mood.
Dosing protocol & phases
| Phase | Weeks | Dose | Notes |
|---|---|---|---|
| Trial range | 24 weeks (TIPO-1) | 0.25–1 mg once daily (oral) | 0.5 mg was the lead efficacy dose; 1.0 mg added efficacy but more monoaminergic side effects. |
| Lead dose | Ongoing | 0.5 mg once daily | Best efficacy-to-tolerability balance reported in Phase 2. |
Supplies needed
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Recommended supply
Tesofensine — research vial
From our verified partner Dynotides, with a third-party certificate of analysis per batch.
Injection supplies
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Bacteriostatic water
Diluent for reconstituting lyophilized vials.
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Insulin syringes (U-100)
0.3–0.5 mL, 29–31 G for accurate small draws.
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Alcohol prep pads
Sterile swabs for the vial stopper and site.
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Sharps container
Safe disposal of used needles.
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Storage fridge
Keeps reconstituted vials at 2–8 °C.
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Insulated travel case
Cooled, TSA-friendly case for travel.
Missed-dose guidance
No approved-label guidance exists because tesofensine is investigational. Given its very long (~9-day) half-life, a single missed daily dose has limited impact on overall exposure; the practical convention is to resume the normal once-daily schedule rather than doubling up.
Side effects & safety
| Category | Effect | Trial incidence |
|---|---|---|
| Neurological | Insomnia / disturbed sleepA common dose-related effect of the dopaminergic/noradrenergic activity. | — |
| Cardiovascular | Increased heart rateAbout +7.4 bpm at 0.5 mg versus placebo in TIPO-1 (statistically significant); larger at 1 mg. | — |
| Cardiovascular | Blood-pressure changesSignificant increases were not seen at 0.25–0.5 mg in TIPO-1 but became a concern at higher doses, prompting combination studies with the beta-blocker metoprolol. | — |
| Psychiatric | Mood changes / irritability / anxietyDose-related monoaminergic effects. | — |
| Gastrointestinal | Dry mouth, nausea, constipation | — |
| General | Headache | — |
Clinical trials & evidence
TIPO-1 (Astrup et al.)
Phase 224 weeks · 203 adults with obesity (BMI 28–40)
~9–10% placebo-subtracted weight loss at 0.5 mg; predominantly fat mass; +7.4 bpm heart rate at 0.5 mg.
Trial identifier needs verification
Tesofensine + metoprolol in hypothalamic obesity
Phase 2Up to 48 weeks · Adults with hypothalamic injury-induced obesity
Studied to manage weight while mitigating cardiovascular effects with a beta-blocker.
NCT03845075 ↗
Storage & handling
- Lyophilized
- Not applicable (oral small molecule).
- Reconstituted
- Not applicable.
Comparisons
| Vs. | Target | Half-life | Dosing | Efficacy | Status |
|---|---|---|---|---|---|
| Semaglutide | Triple monoamine reuptake inhibitor (oral) vs GLP-1 agonist (injectable) | ~9 d vs ~7 d | 0.25–1 mg daily oral vs 0.25–2.4 mg weekly subQ | ~9–10% placebo-subtracted (Phase 2) vs −14.9% (Phase 3, STEP 1) | Investigational vs approved |
| Tirzepatide | CNS monoamine mechanism vs GIP/GLP-1 incretin mechanism | ~9 d vs ~5 d | Oral daily vs weekly subQ | ~9–10% (Phase 2) vs up to −20.9% (Phase 3) | Investigational vs approved |
Sources & references
- [1]Astrup A et al. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients (TIPO-1). Lancet 2008;372:1906–1913. ↗ source
- [2]Lehr T et al. Population pharmacokinetic modelling of NS2330 (tesofensine) in patients with Alzheimer's disease. Br J Clin Pharmacol 2007. ↗ source
Frequently asked questions
Is tesofensine a peptide?
No — it is an orally active small molecule, a triple monoamine reuptake inhibitor. It is included in the metabolic category for completeness because it is widely discussed as a weight-loss compound, but it is mechanistically and structurally unrelated to the injectable peptides on this site.
How does it compare to GLP-1 drugs?
Its Phase 2 weight loss (~9–10% placebo-subtracted at 0.5 mg) is meaningful but below what semaglutide and tirzepatide achieved in Phase 3. It also acts through brain monoamines rather than incretin hormones, giving it a more stimulant-like side-effect profile, including heart-rate and sleep effects.
Why was development cautious despite good weight loss?
The same monoaminergic activity that suppresses appetite raises heart rate and can affect blood pressure, sleep, and mood. These cardiovascular and CNS effects — not lack of efficacy — are the main reason its path to approval has been slow, and they motivated later studies pairing it with a beta-blocker.
Related protocols
Semaglutide
Ozempic
−14.9% mean body weight at 68 weeks (STEP 1)
Tirzepatide
Mounjaro
−20.9% body weight at 72 weeks, 15 mg (SURMOUNT-1)
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For educational and research reference only. Not intended for human consumption, not medical advice. Compounds discussed are sold and used for laboratory research purposes only.