Tesofensine (NS2330) is an oral small-molecule drug candidate that inhibits the presynaptic reuptake of noradrenaline, dopamine and serotonin (Astrup 2008). It is not a peptide: PubChem gives its formula as C17H23Cl2NO, a tropane-based structure with a molecular weight of 328.3 (PubChem). It was first tested in Parkinson’s and Alzheimer’s disease, then studied for obesity after weight loss showed up in those trials. It is not approved by the FDA (Drugs@FDA).
Semaglutide, tirzepatide and retatrutide are peptides: chains of amino acids that bind cell-surface hormone receptors. Tesofensine is different. Its IUPAC name, (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane, describes a small organic molecule with a dichlorophenyl ring on a bicyclic tropane core (PubChem). In the human trials cited in this article it was taken by mouth once a day.
It is also long-lived in the body. A population pharmacokinetic analysis of 320 people in an Alzheimer’s disease study estimated a half-life of 234 hours for tesofensine and 374 hours for its major metabolite, M1 (Lehr 2007). Female sex and lower creatinine clearance were the covariates with a meaningful effect on steady-state exposure.
Tesofensine began as a candidate for neurodegenerative disease. Boehringer Ingelheim sponsored phase 2 trials in early Parkinson’s disease (NCT00148486), advanced Parkinson’s disease (NCT00148512) and mild to moderate Alzheimer’s dementia (NCT00153010).
The Alzheimer’s program did not succeed either. A modeling paper describes the 14-week phase 2b proof-of-concept trial in 430 people with Alzheimer’s disease as negative (Lehr 2010).
The weight signal led to a pooled analysis of four 14-week Parkinson’s and Alzheimer’s trials (740 people on tesofensine, 228 on placebo) with no diet or lifestyle program. No effect on blood pressure was found, and the authors wrote that tesofensine was then being developed for obesity management (Astrup, Obesity 2008).
| Daily dose in the pooled trials | Weight change at 14 weeks (all participants) | Heart rate change at 14 weeks |
|---|---|---|
| Placebo | +0.5% | -0.4 bpm |
| 0.125 mg | -0.5% | +2.1 bpm |
| 0.25 mg | -0.9% | +4.2 bpm |
| 0.5 mg | -1.8% | +6.0 bpm |
| 1.0 mg | -2.8% | +6.8 bpm |
Figures are from the published abstract (Astrup, Obesity 2008).
The main human efficacy data for tesofensine come from a single phase 2 trial run at five Danish obesity centres and registered as NCT00394667. After a 2-week run-in, 203 adults with a BMI of 30 to 40 were put on an energy-restricted diet and randomized to tesofensine 0.25 mg, 0.5 mg or 1.0 mg, or placebo, once daily for 24 weeks. The primary outcome was percentage change in body weight, and 161 participants (79%) completed the study (Astrup 2008).
| Group (with energy-restricted diet) | Randomized (n) | Mean weight loss at 24 weeks (SE) |
|---|---|---|
| Placebo | 52 | 2.0% (0.60) |
| Tesofensine 0.25 mg | 52 | 4.5% (0.87) |
| Tesofensine 0.5 mg | 50 | 9.2% (0.91) |
| Tesofensine 1.0 mg | 49 | 10.6% (0.84) |
All three tesofensine groups lost more weight than diet plus placebo (p<0.0001). The most common adverse events were dry mouth, nausea, constipation, hard stools, diarrhea and insomnia. The authors wrote that tesofensine 0.5 mg “might have the potential” to double the weight loss of drugs approved at the time, and that the findings needed confirmation in phase 3 trials (Astrup 2008).
A companion 140-participant study of long-term safety in obesity is registered as completed (NCT00481104), but we did not find its results in PubMed or posted on the registry, so they are not reported here.
Blocking three transporters at once does not show which one drives the weight effect. Several studies tried to separate the pieces.
A PET study in humans measured how much of the dopamine transporter (DAT) tesofensine occupies at steady state. Mean striatal DAT occupancy rose with dose from 18% to 77% across 0.125 mg to 1 mg. The model put maximum achievable occupancy at about 80%, with half of that reached at about 0.25 mg and a plasma concentration of 4 ng/ml (Appel 2014). A 2025 cryo-EM study solved the structure of DAT bound to tesofensine and found that it holds the transporter in an outward-facing conformation (Li 2025).
In diet-induced obese rats, tesofensine produced a dose-dependent drop in food intake. That effect was almost fully reversed by prazosin, an α1-adrenoceptor antagonist, and partly reversed by SCH23390, a dopamine D1 antagonist. Blockers of α2, D2, D3 and 5-HT2A/C receptors had no effect (Axel 2010). So, in this model, the appetite effect ran mainly through indirect α1 and D1 stimulation, not the serotonin receptors tested.
A 2024 study in mice and rats found that tesofensine inhibited a subset of GABAergic neurons in the lateral hypothalamus that promote feeding. It also produced few if any head-weaving stereotypies at the doses tested, unlike phentermine (Perez 2024).
A 2-week respiration-chamber study in 32 overweight or moderately obese men tested whether tesofensine works by suppressing appetite or by raising energy expenditure. The study compared 2.0 mg daily for 7 days, then 1.0 mg daily for 7 days, with placebo.
On appetite, tesofensine produced 1.8 kg more weight loss than placebo, higher ratings of satiety and fullness, and lower prospective food intake.
On energy expenditure, it did not significantly change the 24-hour total. Night-time energy expenditure was 4.6% higher after adjustment for body composition, and 24-hour fat oxidation rose by 18 g (Sjödin 2010). The authors concluded that the main effect is on appetite, with a slight effect on energy expenditure at night.
Because tesofensine raises synaptic noradrenaline, cardiovascular effects have been the main safety question. The findings, by study:
These are small, short trials. None was designed to measure cardiovascular events, and we found no published long-term outcome data for tesofensine.
Tesofensine is not approved by the FDA; searches of Drugs@FDA and FDA’s openFDA dataset returned no application for it. As of September 2026, a search of ClinicalTrials.gov returns 13 tesofensine studies, all phase 1 or phase 2, sponsored by Boehringer Ingelheim, NeuroSearch and Saniona (ClinicalTrials.gov). The registry lists no phase 3 tesofensine trial. We found no published phase 3 results in a PubMed search (September 2026), so this article does not report phase 3 or foreign registration claims.
Tesofensine is often discussed next to incretin drugs, but the two groups share almost nothing at the molecular level. The table compares them by mechanism. The weight figures come from separate trials of different lengths and populations and are not head-to-head results.
| Compound | Molecule type | Primary target | Route in trials | Key published weight result |
|---|---|---|---|---|
| Tesofensine | Small molecule (C17H23Cl2NO) | Noradrenaline, dopamine and serotonin reuptake transporters | Oral, once daily | -10.6% at 1.0 mg vs -2.0% placebo, 24 weeks (Astrup 2008) |
| Semaglutide | Peptide | GLP-1 receptor | Subcutaneous, once weekly | -14.9% vs -2.4% placebo, 68 weeks (Wilding 2021) |
| Tirzepatide | Peptide | GLP-1 and GIP receptors | Subcutaneous, once weekly | -20.9% at 15 mg vs -3.1% placebo, 72 weeks (Jastreboff 2022) |
| Retatrutide | Peptide | GLP-1, GIP and glucagon receptors | Subcutaneous, once weekly | -24.2% at 12 mg vs -2.1% placebo, 48 weeks (Jastreboff 2023) |
For receptor-level comparisons, lab reference material is available for semaglutide and tirzepatide. Our retatrutide research guide covers the triple agonist’s trial data in detail.
No. It is a small organic molecule with a tropane core and a molecular weight of 328.3 (PubChem). It was taken by mouth in the human trials cited here.
No. It has no FDA approval for any use (Drugs@FDA). As of September 2026, ClinicalTrials.gov lists no phase 3 trial for it (ClinicalTrials.gov), and a PubMed search (September 2026) returned no published phase 3 results.
Parkinson’s disease and Alzheimer’s disease. The Parkinson’s trials did not show a sustained or dose-related benefit (Hauser 2007; Rascol 2008), and the Alzheimer’s proof-of-concept trial was negative (Lehr 2010). Weight loss seen across the Parkinson’s and Alzheimer’s trials led to its study in obesity (Astrup, Obesity 2008).
Tesofensine raises heart rate. Rat work showed that metoprolol blocked the cardiovascular effects while keeping the effect on food intake (Bentzen 2013), and the combination was later tested in hypothalamic obesity (Huynh 2022).
HPLC measures purity; mass spectrometry confirms identity against the C17H23Cl2NO formula (MW 328.3). Unlike peptides, there is no amino-acid sequence to verify, though material supplied as tesofensine citrate (C23H31Cl2NO8, MW 520.4) should state its salt form (PubChem). A 2026 LC-HRMS study identified four principal human urinary metabolites (three dealkylated and one hydroxylated and glucuronidated) and noted that tesofensine is listed as an S6 stimulant on the World Anti-Doping Agency Prohibited List (Krug 2026). Peptides For Sale lists tesofensine for laboratory research with a Certificate of Analysis per batch, labeled for research use only.
Research use only disclaimer: Tesofensine is an investigational small molecule that is not approved by the FDA for any indication. This article summarizes published research for educational purposes and is not medical advice. Products sold by this store are intended strictly for in vitro and laboratory research by qualified professionals. They are not for human or veterinary use, and not for use as food, drugs, cosmetics or household chemicals.
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