Tesofensine
A pill that blocks the reuptake of dopamine, noradrenaline and serotonin: it failed in Alzheimer's and Parkinson's, then roughly doubled the weight loss of 2008-era obesity drugs in a phase 2 trial, and it is still not approved anywhere.
Tesofensine (NS2330) is a small molecule, not a peptide, that keeps three brain chemicals active for longer. Developed for neurodegenerative disease, it made patients lose weight instead, and a 24-week obesity trial found 9 to 11% more weight loss than placebo. It raises heart rate, lasts about ten days in the body, and a Mexican application has not been approved.
What is it?
Tesofensine was developed by the Danish company NeuroSearch, with Boehringer Ingelheim, as a treatment for Alzheimer's and Parkinson's disease. It blocks the transporters that clear dopamine, noradrenaline and serotonin from the gaps between nerve cells, which should strengthen all three signals. In the neurological trials it did little for the diseases: early Parkinson's patients did no better than on placebo over 14 weeks, and advanced patients improved only modestly without a clear dose response. What the trials did show was weight loss, which a pooled analysis of four trials put at about 4% more than placebo in 14 weeks with no diet at all.
That turned it into an obesity drug candidate. In a 2008 phase 2 trial in 203 obese Danish adults on a calorie-restricted diet, tesofensine at 0.25, 0.5 and 1.0 mg a day produced 4.5%, 9.2% and 10.6% more weight loss than diet and placebo over 24 weeks, about twice what the approved drugs of the time achieved. Studies of how it works found it strongly increased feelings of fullness and slightly raised night-time energy expenditure and fat burning, and rat studies traced its appetite effect to dopamine D1 and alpha-1 adrenergic signalling and to calming feeding-promoting neurons in the hypothalamus.
The price was on the heart. At 0.5 mg heart rate rose by 7.4 beats a minute in the obesity trial, and higher doses raised blood pressure too; in rats a blood-pressure drug controlled the pressure rise but not the heart-rate rise. Tesofensine also lasts a long time: a population model in 320 patients put its half-life at 234 hours and its active metabolite's at 374 hours, so it takes weeks to reach steady levels and weeks to wash out. An abuse-potential study in recreational stimulant users found it no more attractive than bupropion or atomoxetine.
Western development did not reach approval, and the Mexican company Medix ran a phase 3 programme of 372 patients and applied to Mexico's regulator COFEPRIS. The application received a favourable committee opinion in 2023 but was not approved in November 2024; Medix resubmitted a revised dossier in February 2025, and no approval had been announced as of September 27, 2026. Tesofensine is not approved anywhere, and it is prohibited in sport in competition as a stimulant; a 2026 study noted it is sold online as a dietary supplement.
Mechanism of Action
Tesofensine keeps dopamine, noradrenaline and serotonin in the synapse longer. Its weight effect comes mostly from appetite, through dopamine and noradrenaline signalling in the brain; the same sympathetic stimulation raises heart rate.
Triple reuptake inhibition
It blocks the dopamine, noradrenaline and serotonin transporters. Its main metabolite, M1, is somewhat less potent at the dopamine transporter in mice but reaches about eight times higher levels, so it contributes to the effect.
Appetite, through dopamine and noradrenaline
In obese rats its appetite suppression was blocked by alpha-1 adrenergic and dopamine D1 antagonists but not by others. In mice it silenced a subset of feeding-promoting GABA neurons in the lateral hypothalamus, without the stereotyped movements phentermine causes.
Satiety and energy use in people
In 32 overweight men it strongly increased fullness, raised night-time energy expenditure by 4.6% and increased 24-hour fat burning by 18 g. In the phase 2 trial the satiety boost faded as weight fell and returned when the drug was restarted.
Heart rate and blood pressure
Sympathetic stimulation raises heart rate at doses from 0.25 mg upward. In rats, the blood-pressure drug telmisartan reversed only part of the blood-pressure rise and none of the heart-rate rise, suggesting different adrenergic receptors drive weight loss and cardiovascular effects.
Published Research
Our evidence set holds 42 papers that name tesofensine or NS2330. Twenty-two name it in their titles and have an abstract; 18 are carded below: 9 studies in people, 8 in animals and 1 pooled analysis. A secondary publication of the phase 2 trial, a commentary on it, a review and a modelling paper are left out. The Mexican phase 3 programme has not been published in a journal we could find.
Population pharmacokinetics, 320 patients
Using 1,969 tesofensine and 1,714 metabolite concentrations from a 14-week Alzheimer's trial, a one-compartment model found low clearance and large volumes of distribution, giving half-lives of 234 hours for tesofensine and 374 hours for its metabolite M1. Only kidney function and sex changed exposure meaningfully: women with reduced kidney function had 62% higher exposure.
Early Parkinson's disease, 261 patients
Untreated patients diagnosed within five years took 0.25, 0.5 or 1.0 mg or placebo daily. At 14 weeks no dose improved Parkinson's scores significantly; 1.0 mg was better than placebo at week 6 but the effect faded. Weight loss and a faster heart rate were common at 1.0 mg.
Hippocampal genes and new cells, rats
Fourteen days of tesofensine raised BDNF mRNA by 35% in hippocampal region CA3 and Arc mRNA by 65% in CA1, and increased markers of new cell formation; five days did not. The authors read this as antidepressant-like potential.
Advanced Parkinson's disease
In a 14-week phase 2 pilot in patients with levodopa-related motor fluctuations, 0.5 mg improved combined daily-living and motor scores by 4.7 points and 0.25 mg cut 'off' time by 68 minutes against placebo, but other doses did not, no dose response was found, and side effects were commoner at higher doses.
Weight loss in four neurological trials
Pooling four 14-week trials in Parkinson's and Alzheimer's disease (740 on tesofensine, 228 on placebo), weight changed by +0.5% on placebo and −0.5, −0.9, −1.8 and −2.8% on 0.125 to 1.0 mg, with no diet. Heart rate rose by up to 6.8 beats a minute from 0.25 mg upward, without a blood-pressure effect, and the authors recommended developing it for obesity.
The active metabolite M1, mice
Pharmacokinetic and pharmacodynamic modelling in mice found M1 was four to five times less potent than tesofensine at the dopamine transporter but reached about eight times higher steady-state levels, so M1 contributes to tesofensine's overall activity.
Phase 2 obesity trial, 203 adults
Obese adults (BMI 30 to 40) on an energy-restricted diet took 0.25, 0.5 or 1.0 mg or placebo daily for 24 weeks; 79% completed. Weight fell 2.0% on placebo and 4.5%, 9.2% and 10.6% more on the three doses. Dry mouth, nausea, constipation, diarrhoea and insomnia were commonest; at 0.5 mg heart rate rose 7.4 beats a minute without a significant blood-pressure change.
Enterohepatic recirculation
A pharmacokinetic model built from intravenous tesofensine data described the multiple peaks in its blood-concentration curve as enterohepatic circulation, the drug being excreted in bile and reabsorbed, which also prolongs its apparent half-life.
Appetite and energy expenditure, 32 men
Overweight or moderately obese men took 2.0 mg for seven days then 1.0 mg for seven days, or placebo, while told to keep eating and moving as usual. Tesofensine strongly reduced appetite, raised night-time energy expenditure by 4.6% after adjustment for body composition and increased 24-hour fat oxidation by 18 g.
Abuse potential, 52 stimulant users
In a single-dose crossover against placebo, d-amphetamine 30 mg, bupropion and atomoxetine, tesofensine's liking and other abuse-related effects were lower than amphetamine's on all primary measures and no higher than bupropion's or atomoxetine's, so the authors judged recreational abuse unlikely.
How it suppresses appetite, obese rats
Diet-induced obese rats given 2.0 mg/kg for 16 days weighed significantly less because they ate less. The appetite effect was blocked by an alpha-1 adrenergic antagonist and a dopamine D1 antagonist, but not by alpha-2, D2, D3 or serotonin 2A/C antagonists.
Sustained weight loss, obese rats
Over 28 days, 1.0 and 2.5 mg/kg by mouth reduced weight by 5.7% and 9.9%, against 7.6% for sibutramine and a transient loss with rimonabant. Only tesofensine lowered the insulin response to glucose below what matched food restriction achieved, and the authors attribute its effect to reduced appetite plus higher energy use.
Satiety over 60 weeks
In 158 trial participants, tesofensine raised a composite satiety score by week 12 in proportion to dose, and the rise correlated with weight loss (r = 0.36), but the score drifted back toward baseline by week 24. After a drug-free period, restarting 0.5 or 1.0 mg in 113 people raised it again at week 60.
Dopamine receptors in obese rats
Twenty-eight days of 2.0 mg/kg reduced food intake and weight gain in diet-induced obese rats and lowered striatal dopamine D2/D3 receptor availability, but the receptor change did not correlate with intake or weight, so the authors saw it as a drug effect rather than the cause of weight loss.
Controlling the cardiovascular effects, rats
A blood-pressure drug given with tesofensine preserved its appetite suppression but only partly reversed the rise in systolic blood pressure and did not affect the raised heart rate, suggesting sympathetic activation through different adrenergic receptors drives the weight and cardiovascular effects.
Restoring forebrain dopamine, obese rats
Tesofensine suppressed appetite and reduced weight while reversing the low dopamine levels in the nucleus accumbens and prefrontal cortex of diet-induced obese rats, supporting a role for raised dopaminergic activity in its anti-obesity effect.
Hypothalamic feeding neurons, rats and mice
Tesofensine caused more weight loss in obese than lean rats and inhibited a subset of feeding-promoting GABA neurons in the lateral hypothalamus; silencing those neurons strengthened its effect. Unlike phentermine it caused little or no stereotyped head-weaving, and its effect did not depend on taste aversion.
Metabolism and detection in urine
Six volunteers took 483 µg of tesofensine sold as a dietary supplement. Four main metabolites were identified; urine concentrations peaked at 1 to 4 ng/mL after 4 to 46 hours, with detection windows up to 500 hours. The authors note it is prohibited in competition only under WADA's stimulant class.
Dosing Data
Tesofensine has no approved dose. The obesity trial used 0.25, 0.5 and 1.0 mg once daily by mouth with a calorie-restricted diet for 24 weeks; the neurological trials used 0.125 to 1.0 mg for 14 weeks. The half-life of about ten days means steady levels take weeks to reach.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
→ Full Tesofensine dosage guide — the trial doses, why the long half-life matters, and the heart-rate effect at 0.5 mg and above
Side Effects & Contraindications
Reported Side Effects
From the trials above.
Contraindications & Cautions
No approved label exists. These cautions follow from its pharmacology and the trials.
Legal Status
Tesofensine is not approved as a medicine anywhere.
Frequently Asked Questions
?How much weight did people lose on tesofensine?
In the 2008 phase 2 trial, with a calorie-restricted diet, 4.5%, 9.2% and 10.6% more than placebo on 0.25, 0.5 and 1.0 mg over 24 weeks; placebo plus diet lost 2.0%. Without a diet, pooled neurological trials found about 4% more than placebo over 14 weeks, as their authors estimated.
?Is tesofensine approved in Mexico?
No. Its application received a favourable committee opinion in 2023 but was not approved in November 2024. Medix resubmitted in February 2025, and no approval had been announced as of September 27, 2026.
?Does tesofensine raise heart rate?
Yes. At 0.5 mg heart rate rose 7.4 beats a minute against placebo in the obesity trial, and higher doses also raised blood pressure. It is a sympathetic stimulant.
?How long does tesofensine stay in the body?
A long time: a population model put its half-life at 234 hours and its active metabolite's at 374 hours. In urine it was detectable for up to 500 hours after a single small dose.
?Is tesofensine addictive?
A 2010 study in recreational stimulant users found its abuse-related effects no greater than bupropion's or atomoxetine's and well below amphetamine's. That is one study of single doses.
?Is tesofensine a peptide?
No. It is a small tropane-derived molecule taken as a tablet. It appears in peptide guides because it is sold alongside peptide weight-loss products.
References
- [Human] Lehr T, et al. "Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease." Br J Clin Pharmacol, 2007;64(1):36-48. PMID: 17324246.
- [Human] Hauser RA, et al. "Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease." Mov Disord, 2007;22(3):359-65. PMID: 17149725.
- [Animal] Larsen MH, et al. "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." Eur J Pharmacol, 2007;555(2-3):115-21. PMID: 17112503.
- [Human] Rascol O, et al. "Tesofensine (NS 2330), a monoamine reuptake inhibitor, in patients with advanced Parkinson disease and motor fluctuations: the ADVANS Study." Arch Neurol, 2008;65(5):577-83. PMID: 18474731.
- [Review] Astrup A, et al. "Weight loss produced by tesofensine in patients with Parkinson's or Alzheimer's disease." Obesity (Silver Spring), 2008;16(6):1363-9. PMID: 18356831.
- [Animal] Lehr T, et al. "Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach." Br J Pharmacol, 2008;153(1):164-74. PMID: 17982477.
- [Human] Astrup A, et al. "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. PMID: 18950853.
- [Human] Lehr T, et al. "A quantitative enterohepatic circulation model: development and evaluation with tesofensine and meloxicam." Clin Pharmacokinet, 2009;48(8):529-42. PMID: 19705923.
- [Human] Sjödin A, 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):1634-43. PMID: 20479765.
- [Human] Schoedel KA, et al. "Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users." Clin Pharmacol Ther, 2010;88(1):69-78. PMID: 20520602.
- [Animal] Axel AM, et al. "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." Neuropsychopharmacology, 2010;35(7):1464-76. PMID: 20200509.
- [Animal] Hansen HH, et al. "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." Eur J Pharmacol, 2010;636(1-3):88-95. PMID: 20385125.
- [Human] Gilbert JA, et al. "The effect of tesofensine on appetite sensations." Obesity (Silver Spring), 2012;20(3):553-61. PMID: 21720440.
- [Animal] van de Giessen E, et al. "Triple monoamine inhibitor tesofensine decreases food intake, body weight, and striatal dopamine D2/D3 receptor availability in diet-induced obese rats." Eur Neuropsychopharmacol, 2012;22(4):290-9. PMID: 21889317.
- [Animal] Bentzen BH, et al. "Anti-hypertensive treatment preserves appetite suppression while preventing cardiovascular adverse effects of tesofensine in rats." Obesity (Silver Spring), 2013;21(5):985-92. PMID: 23784901.
- [Animal] Hansen HH, et al. "Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat." Pharmacol Biochem Behav, 2013;110:265-71. PMID: 23932919.
- [Animal] Perez CI, et al. "Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons." PLoS One, 2024;19(4):e0300544. PMID: 38656972.
- [Human] Krug O, et al. "Investigations Into the Metabolism and Elimination of Tesofensine in Human Urine." Drug Test Anal, 2026;18(9):1163-1173. PMID: 42320973.
Sources & Citations
Every citation on this page is PubMed-indexed and has been checked against its record; the Mexican application history comes from the partner company's releases. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.