Tesofensine

Tesofensine (development code NS2330; INN tesofensine) is an orally active small-molecule triple monoamine reuptake inhibitor — it is not a peptide. It inhibits the presynaptic reuptake of three monoamine neurotransmitters: dopamine, norepinephrine, and serotonin, with reported in vitro IC₅₀ values in rat brain synaptosomes of approximately 6.5 nM (dopamine), 1.7 nM (norepinephrine), and 11 nM (serotonin). The compound was originally developed by the Danish pharmaceutical company NeuroSearch as a candidate for Alzheimer’s disease and Parkinson’s disease, where it lacked efficacy in the neurology trials but produced unexpected weight loss as an adverse-event signal. The program was repurposed for obesity and subsequently licensed to the Danish biotech Saniona, which has partnered with the Mexican pharmaceutical company Productos Medix for development and commercialization in Mexico and Argentina.

The most widely cited tesofensine clinical-trial publication is the Astrup 2008 Phase 2 randomized, double-blind, placebo-controlled trial (TIPO-1), published in The Lancet, in 203 obese patients (BMI 30–40 kg/m²) treated with placebo or tesofensine 0.25, 0.5, or 1.0 mg once daily for 24 weeks alongside an energy-restricted diet. The trial reported mean placebo-corrected weight loss of 4.5, 9.1, and 10.6 kg (2.5%, 7.2%, 8.6%) at the three amounts respectively, with the most common adverse events being dry mouth, nausea, constipation, hard stools, diarrhea, and insomnia, and with heart rate increased by 7.4 beats per minute in the 0.5 mg group [1]. The Lancet published an Expression of Concern about the TIPO-1 publication in 2013 following a Danish Health and Medicines Authority inspection of completed trials in November 2011 [2]; researchers consulting the Astrup 2008 paper should be aware of the editorial Expression of Concern and the associated regulatory-inspection context.

Tesofensine subsequently advanced through Phase 3 development in Mexico under Saniona’s partnership with Medix. The Phase 3 trial enrolled 372 adult patients with obesity at sites in Mexico, randomized to tesofensine 0.25 mg, tesofensine 0.5 mg, or placebo once daily for 24 weeks, with topline results announced by press release in December 2018 reporting that the trial met its primary endpoint and key secondary endpoints. Medix submitted a New Drug Application to the Mexican regulatory authority COFEPRIS in December 2019; COFEPRIS’s New Molecules Technical Committee issued a favorable opinion on tesofensine for obesity in February 2023. As of March 2025, Saniona was awaiting potential final regulatory approval in Mexico in the first half of 2025. Tesofensine is not approved by the FDA, EMA, or any other regulatory authority outside of the Mexican regulatory process described above, and has not been advanced into Phase 3 development in the United States or European Union.

Important Note on the Evidence Base

Important note on the evidence base: The peer-reviewed tesofensine clinical-trial literature consists primarily of the Astrup 2008 Phase 2 publication in The Lancet (TIPO-1; reference [1] below) and supporting pharmacokinetic, mechanism, and energy-expenditure studies. The Phase 3 Mexico program data has been reported via press release and conference proceedings; no peer-reviewed publication of the full Phase 3 dataset has appeared to date. Researchers consulting the Astrup 2008 paper should be aware of The Lancet‘s 2013 Expression of Concern about that publication, which followed a Danish Health and Medicines Authority inspection of completed trials. The Astrup 2008 trial has also documented cardiovascular adverse-event signals (heart rate increase of 7.4 beats per minute at 0.5 mg, with greater increases at 1.0 mg) and psychiatric adverse-event observations (insomnia, depressed mood); the cardiovascular safety profile of tesofensine has been a recurring topic in the editorial commentary on the program. Researchers planning protocols should consult both the Astrup 2008 paper and the 2013 Expression of Concern, and should treat the Phase 3 press-release data as preliminary in the absence of peer-reviewed full-dataset publication.

Mechanism of Action

Tesofensine is a triple monoamine reuptake inhibitor — a small-molecule compound that inhibits the presynaptic reuptake of dopamine, norepinephrine, and serotonin at the corresponding monoamine transporters (DAT, NET, SERT). The class is mechanistically distinct from GLP-1 receptor agonists (the class to which semaglutide, tirzepatide, and retatrutide belong) and from the dual and triple incretin agonists; it acts on central neurotransmitter systems rather than on peripheral gut-hormone signaling.

Transporter inhibition and dopamine transporter occupancy. In rat brain synaptosome assays, tesofensine inhibits dopamine, norepinephrine, and serotonin reuptake with IC₅₀ values of approximately 6.5, 1.7, and 11 nM respectively. Positron emission tomography studies in humans using the dopamine-transporter radioligand [¹¹C]βCIT-FE have documented concentration-dependent DAT occupancy following multiple oral tesofensine amounts across the 0.125–1 mg range, confirming central monoamine-transporter engagement at the amounts used in the obesity trials [3].

Appetite suppression via α₁-adrenoceptor and dopamine D₁-receptor pathways. Mechanistic work in the diet-induced obese rat by Axel and colleagues, published in Neuropsychopharmacology in 2010, characterized tesofensine’s appetite-suppressive effect as mediated by indirect stimulation of central α₁-adrenoceptor and dopamine D₁-receptor pathways. The study used systematic pharmacological-antagonist co-administration to identify the downstream receptors responsible for the hypophagic response: pretreatment with the α₁-adrenoceptor antagonist prazosin and the dopamine D₁-receptor antagonist SCH-23390 each attenuated tesofensine-induced food-intake reduction, while serotonin-receptor antagonists were less effective [4]. The mechanism framing positions tesofensine’s primary anti-obesity effect as a central appetite-suppression effect rather than a peripheral metabolic effect.

Energy expenditure. Sjödin and colleagues investigated tesofensine’s effect on energy expenditure in overweight and moderately obese men using whole-body indirect calorimetry over a 7-day administration protocol. The study reported that tesofensine produced modest increases in 24-hour energy expenditure in addition to the appetite-suppression effect, suggesting that the weight-loss effect characterized in the Astrup 2008 obesity trial reflects both reduced intake and increased expenditure components [5]. The energy-expenditure contribution to total weight loss is generally considered smaller than the appetite-suppression contribution.

Distinction from GLP-1 receptor agonists. Tesofensine’s central-monoaminergic mechanism is mechanistically distinct from the GLP-1 receptor agonist class. GLP-1 agonists act primarily through peripheral gut-hormone signaling with downstream central effects on appetite via vagal and area-postrema pathways. Tesofensine acts directly on central monoamine systems via reuptake inhibition. The two mechanism classes produce overlapping clinical outcomes (weight loss, appetite reduction) through different molecular routes, with different adverse-event profiles (GLP-1 agonists are characterized by gastrointestinal side effects predominantly; tesofensine is characterized by dry mouth, insomnia, cardiovascular signals, and the catecholaminergic profile expected from a monoamine reuptake inhibitor).

Available Forms

Omnix Peptides supplies tesofensine in a single research format. Each lot is independently characterized by HPLC and LC–MS, with a batch-specific Certificate of Analysis available on the product page.

• Tesofensine Capsules 500 mcg, 30-count — oral capsule format at the 500 mcg (0.5 mg) strength that corresponds to the middle amount arm of the Astrup 2008 TIPO-1 Phase 2 trial and to one of the two active amounts in the Medix Phase 3 Mexico trial.

Tesofensine is classified under the Metabolic & Weight Research research category. For research framed around the GLP-1 receptor agonist class, see the semaglutide, tirzepatide, and retatrutide hubs. For research framed around the small-molecule oral GLP-1 receptor agonist class specifically, see the orforglipron hub.

Amount in the Published Research Literature

The following administration ranges describe the protocols used in the peer-reviewed clinical-trial and rodent literature on tesofensine. They are reported here for research-reference purposes only and do not constitute administration recommendations of any kind. No human-equivalent amount translation outside of the published trial protocols has been validated in the peer-reviewed literature.

Astrup 2008 TIPO-1 Phase 2 trial (obesity, with Expression of Concern). The TIPO-1 Phase 2 trial randomized 203 obese patients (BMI 30–40 kg/m²) at five Danish obesity-management centers to placebo (n=52), tesofensine 0.25 mg (n=52), tesofensine 0.5 mg (n=50), or tesofensine 1.0 mg (n=49) once daily for 24 weeks, alongside an energy-restricted diet, following a 2-week run-in phase. The primary endpoint was percentage change in bodyweight; mean placebo-corrected weight loss was 4.5 kg, 9.1 kg, and 10.6 kg at the 0.25, 0.5, and 1.0 mg amounts respectively. Heart rate was increased by 7.4 beats per minute in the 0.5 mg group (p=0.0001), with greater increases at 1.0 mg; systolic and diastolic blood pressure showed no significant increase at 0.25 or 0.5 mg [1]. As noted in the lead and the Evidence Base Disclosure block above, The Lancet published an Expression of Concern about this publication in 2013 [2]; researchers should consult both publications together.

Phase 3 Mexico trial (Medix, press-release data). The Medix Phase 3 trial in Mexico randomized 372 adult patients with obesity to tesofensine 0.25 mg, tesofensine 0.5 mg, or placebo once daily for 24 weeks following a 2-week run-in. Topline results were announced by Saniona in December 2018, reporting that the trial met its primary endpoint of weight reduction and key secondary endpoints (proportions of patients achieving ≥5% and ≥10% weight loss, glycemic endpoints, quality-of-life measures). The press release also reported a statistically significant heart rate increase across active amounts with no significant blood pressure effect, consistent with the TIPO-1 cardiovascular profile. A peer-reviewed publication of the full Phase 3 dataset has not appeared to date; researchers should treat the press-release readout as preliminary.

Rodent diet-induced obesity protocols. The Axel 2010 mechanism study used tesofensine at 2.0 mg/kg subcutaneous in diet-induced obese rats for 16 days, characterizing the α₁-adrenoceptor and dopamine D₁-receptor mechanism via systematic pharmacological-antagonist co-administration in a 12-hour nocturnal food-intake monitoring system [4]. The rodent amounts are higher on a per-kilogram basis than the human clinical-trial amounts; researchers planning rodent protocols should consult the primary literature directly rather than applying allometric scaling from the human data.

Researchers planning protocols are referred to the original primary literature cited in the References section for full methodological detail, including the cardiovascular monitoring protocols used in the human trials and the indirect-calorimetry methods used in the Sjödin 2010 energy-expenditure study.

Frequently Asked Questions

References

1. Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9653):1906-1913. doi:10.1016/S0140-6736(08)61525-1 · PubMed: 18950853
2. [No authors listed.] Expression of concern—effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9873):1167. doi:10.1016/S0140-6736(13)60778-3
3. Appel L, Söderman M, Collste K, et al. Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET. Eur Neuropsychopharmacol. 2014;24(2):251-261. doi:10.1016/j.euroneuro.2013.10.007 · PubMed: 24239329
4. Axel AM, Mikkelsen JD, Hansen HH. Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of α₁ adrenoceptor and dopamine D₁ receptor pathways in the diet-induced obese rat. Neuropsychopharmacology. 2010;35(7):1464-1476. doi:10.1038/npp.2010.16 · PubMed: 20200511
5. Sjödin A, Gasteyger C, Nielsen AL, et al. The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men. Int J Obes (Lond). 2010;34(11):1634-1643. doi:10.1038/ijo.2010.87 · PubMed: 20060172

For Research Use Only. The products described on this page are sold strictly for in vitro laboratory research and are not intended for human or animal consumption, diagnostic use, or therapeutic use. The published research summarized above is provided as scientific reference material. Nothing on this page constitutes medical advice, a therapeutic claim, or a recommendation for any use outside of a properly resourced and ethically reviewed research setting.