Tesofensine

Key Benefits#

• Potent appetite suppression via triple monoamine reuptake inhibition
• Significant weight loss (8-12% body weight in phase II trials at 0.5 mg)
• Increases basal metabolic rate and energy expenditure
• Reduces fat mass preferentially over lean mass
• Potential cognitive benefit via dopaminergic and noradrenergic enhancement
• Longer half-life than sibutramine allows once-daily dosing

Mechanism of Action#

Tesofensine inhibits the serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) with roughly equal potency. This elevates synaptic concentrations of all three monoamines in the hypothalamus and mesolimbic system, producing strong appetite suppression, reduced food intake, and increased basal metabolic rate. Unlike sibutramine (which it resembles mechanistically), tesofensine also engages dopaminergic reward circuits, reducing food reward. It additionally has mild cholinergic modulatory activity contributing to satiety.

Dosing Protocols#

Side Effects#

• Elevated heart rate and blood pressure (sympathomimetic)
• Dry mouth
• Insomnia and sleep disturbances
• Nausea
• Constipation
• Headache
• Potential for mood changes, anxiety, or irritability
• Abuse potential given dopaminergic activity

Contraindications#

Cardiovascular disease or uncontrolled hypertensionHistory of psychiatric disorders or substance abuseMAOI use or within 14 days of MAOI discontinuationConcurrent use of other serotonergic agents (serotonin syndrome risk)Pregnancy and breastfeeding: contraindicatedHyperthyroidism

Storage#

Store at room temperature in original container away from moisture and light. No special refrigeration required.

1. 1.
   Structural basis for pharmacotherapeutic action of triple reuptake inhibitors

   Li Y, Meng Y, Li N, Zhao J, Li R, Bai Q et al. · Nature communications · 2025PubMed Verified

2. 2.
   Sex-specific effects of appetite suppressants on stereotypy in rats

   Lopez A, Gil-Lievana E, Gutierrez R · PloS one · 2025PubMed Verified

3. 3.
   Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons

   Perez CI, Luis-Islas J, Lopez A, Diaz X, Molina O, Arroyo B et al. · PloS one · 2024PubMed Verified

4. 4.
   Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity

   Huynh K, Klose M, Krogsgaard K, Drejer J, Byberg S, Madsbad S et al. · European journal of endocrinology · 2022RCTPubMed Verified

5. 5.
   New insights into potential nutritional effects of dietary saponins in protecting against the development of obesity

   Jeepipalli SPK, Du B, Sabitaliyevich UY, Xu B · Food chemistry · 2020ReviewPubMed Verified

6. 6.
   Anorectic state of obesity medications in the United States. Are leaner times ahead?

   Li X, Bello NT · Expert opinion on pharmacotherapy · 2020ReviewPubMed Verified

7. 7.
   Centrally Acting Agents for Obesity: Past, Present, and Future

   Coulter AA, Rebello CJ, Greenway FL · Drugs · 2018ReviewPubMed Verified

8. 8.
   Future Pharmacotherapy for Obesity: New Anti-obesity Drugs on the Horizon

   Srivastava G, Apovian C · Current obesity reports · 2018ReviewPubMed Verified

9. 9.
   Approaches for the Development of Drugs for Treatment of Obesity and Metabolic Syndrome

   Maksimov ML, Svistunov AA, Tarasov VV, Chubarev VN, Ávila-Rodriguez M, Barreto GE et al. · Current pharmaceutical design · 2016ReviewPubMed Verified

10. 10.
    The many different faces of major depression: it is time for personalized medicine

    Korte SM, Prins J, Krajnc AM, Hendriksen H, Oosting RS, Westphal KG et al. · European journal of pharmacology · 2015ReviewPubMed Verified

11. 11.
    Safety of antiobesity drugs

    Cheung BM, Cheung TT, Samaranayake NR · Therapeutic advances in drug safety · 2013PubMed Verified

12. 12.
    Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine

    Heal DJ, Gosden J, Smith SL · Neuropharmacology · 2014ReviewPubMed Verified

13. 13.
    Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET

    Appel L, Bergström M, Buus Lassen J, Långström B · European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology · 2014PubMed Verified

14. 14.
    New and emerging drug molecules against obesity

    George M, Rajaram M, Shanmugam E · Journal of cardiovascular pharmacology and therapeutics · 2014ReviewPubMed Verified

15. 15.
    Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat

    Hansen HH, Jensen MM, Overgaard A, Weikop P, Mikkelsen JD · Pharmacology, biochemistry, and behavior · 2013PubMed Verified

16. 16.
    Under-reporting of adverse effects of tesofensine

    Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM · Lancet (London, England) · 2013PubMed Verified

17. 17.
    Anti-hypertensive treatment preserves appetite suppression while preventing cardiovascular adverse effects of tesofensine in rats

    Bentzen BH, Grunnet M, Hyveled-Nielsen L, Sundgreen C, Lassen JB, Hansen HH · Obesity (Silver Spring, Md.) · 2013PubMed Verified

18. 18.
    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 (London, England) · 2013PubMed Verified

19. 19.
    Anti-obesity drugs: a review about their effects and their safety

    Derosa G, Maffioli P · Expert opinion on drug safety · 2012ReviewPubMed Verified

20. 20.
    Serotonergic anti-obesity agents: past experience and future prospects

    Halford JC, Boyland EJ, Lawton CL, Blundell JE, Harrold JA · Drugs · 2011ReviewPubMed Verified

21. 21.
    Neuropsychiatric adverse effects of centrally acting antiobesity drugs

    Nathan PJ, O'Neill BV, Napolitano A, Bullmore ET · CNS neuroscience & therapeutics · 2011ReviewPubMed Verified

22. 22.
    Triple monoamine inhibitor tesofensine decreases food intake, body weight, and striatal dopamine D2/D3 receptor availability in diet-induced obese rats

    van de Giessen E, de Bruin K, la Fleur SE, van den Brink W, Booij J · European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology · 2012PubMed Verified

23. 23.
    The effect of tesofensine on appetite sensations

    Gilbert JA, Gasteyger C, Raben A, Meier DH, Astrup A, Sjödin A · Obesity (Silver Spring, Md.) · 2012RCTPubMed Verified

24. 24.
    Comparative efficiency and safety of pharmacological approaches to the management of obesity

    Hainer V · Diabetes care · 2011PubMed Verified

25. 25.
    Pharmacotherapies for obesity: past, current, and future therapies

    Ioannides-Demos LL, Piccenna L, McNeil JJ · Journal of obesity · 2011PubMed Verified

26. 26.
    New approaches to the pharmacological treatment of obesity: can they break through the efficacy barrier?

    Kennett GA, Clifton PG · Pharmacology, biochemistry, and behavior · 2010ReviewPubMed Verified

27. 27.
    Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users

    Schoedel KA, Meier D, Chakraborty B, Manniche PM, Sellers EM · Clinical pharmacology and therapeutics · 2010RCTPubMed Verified

28. 28.
    The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men

    Sjödin A, Gasteyger C, Nielsen AL, Raben A, Mikkelsen JD, Jensen JK et al. · International journal of obesity (2005) · 2010RCTPubMed Verified

29. 29.
    The novel triple monoamine reuptake inhibitor tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant

    Hansen HH, Hansen G, Tang-Christensen M, Larsen PJ, Axel AM, Raben A et al. · European journal of pharmacology · 2010PubMed Verified

30. 30.
    Pharmacological management of appetite expression in obesity

    Halford JC, Boyland EJ, Blundell JE, Kirkham TC, Harrold JA · Nature reviews. Endocrinology · 2010ReviewPubMed Verified

31. 31.
    Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat

    Axel AM, Mikkelsen JD, Hansen HH · Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2010PubMed Verified

32. 32.
    Quantitative pharmacology approach in Alzheimer's disease: efficacy modeling of early clinical data to predict clinical outcome of tesofensine

    Lehr T, Staab A, Trommeshauser D, Schaefer HG, Kloft C · The AAPS journal · 2010RCTPubMed Verified

33. 33.
    Semi-mechanistic population pharmacokinetic drug-drug interaction modelling of a long half-life substrate and itraconazole

    Lehr T, Staab A, Trommeshauser D, Schaefer HG, Kloft C · Clinical pharmacokinetics · 2010PubMed Verified

34. 34.
    Society for Neuroscience - 39th Annual Meeting. Part 2 - Novel therapies for neurodegenerative disorders and other CNS diseases

    Al-Shamahi A, Kirkham K, Hookes L · IDrugs : the investigational drugs journal · 2009PubMed Verified

35. 35.
    Gateways to clinical trials

    Tomillero A, Moral MA · Methods and findings in experimental and clinical pharmacology · 2009PubMed Verified

36. 36.
    Tesofensine, a monoamine reuptake inhibitor for the treatment of obesity

    Bello NT, Zahner MR · Current opinion in investigational drugs (London, England : 2000) · 2009ReviewPubMed Verified

37. 37.
    A quantitative enterohepatic circulation model: development and evaluation with tesofensine and meloxicam

    Lehr T, Staab A, Tillmann C, Trommeshauser D, Schaefer HG, Kloft C · Clinical pharmacokinetics · 2009RCTPubMed Verified

38. 38.
    Tesofensine--a novel potent weight loss medicine. Evaluation of: Astrup A, 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;372:1906-13

    Doggrell SA · Expert opinion on investigational drugs · 2009PubMed Verified

39. 39.
    Tesofensine and weight loss

    Sommet A, Pathak A, Montastruc JL · Lancet (London, England) · 2009PubMed Verified

40. 40.
    Tesofensine and weight loss

    Tsai AG · Lancet (London, England) · 2009PubMed Verified

41. 41.
    Gateways to clinical trials

    Tomillero A, Moral MA · Methods and findings in experimental and clinical pharmacology · 2008PubMed Verified

42. 42.
    Is new hope on the horizon for obesity?

    Bray GA · Lancet (London, England) · 2008PubMed Verified

43. 43.
    Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial

    Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM · Lancet (London, England) · 2008RCTPubMed Verified

44. 44.
    Tesofensine (NS 2330), a monoamine reuptake inhibitor, in patients with advanced Parkinson disease and motor fluctuations: the ADVANS Study

    Rascol O, Poewe W, Lees A, Aristin M, Salin L, Juhel N et al. · Archives of neurology · 2008RCTPubMed Verified

45. 45.
    Weight loss produced by tesofensine in patients with Parkinson's or Alzheimer's disease

    Astrup A, Meier DH, Mikkelsen BO, Villumsen JS, Larsen TM · Obesity (Silver Spring, Md.) · 2008Meta-AnalysisPubMed Verified

46. 46.
    Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach

    Lehr T, Staab A, Tillmann C, Nielsen EØ, Trommeshauser D, Schaefer HG et al. · British journal of pharmacology · 2008PubMed Verified

47. 47.
    Gateways to clinical trials

    Bayés M, Rabasseda X, Prous JR · Methods and findings in experimental and clinical pharmacology · 2007PubMed Verified

48. 48.
    Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease

    Lehr T, Staab A, Tillmann C, Trommeshauser D, Raschig A, Schaefer HG et al. · British journal of clinical pharmacology · 2007RCTPubMed Verified

49. 49.
    Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease

    Hauser RA, Salin L, Juhel N, Konyago VL · Movement disorders : official journal of the Movement Disorder Society · 2007RCTPubMed Verified

50. 50.
    Expression of brain derived neurotrophic factor, activity-regulated cytoskeleton protein mRNA, and enhancement of adult hippocampal neurogenesis in rats after sub-chronic and chronic treatment with the triple monoamine re-uptake inhibitor tesofensine

    Larsen MH, Rosenbrock H, Sams-Dodd F, Mikkelsen JD · European journal of pharmacology · 2007PubMed Verified