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Tesofensine

Also known as NS-2330, NS 2330, Tesomet (with metoprolol)

Not a peptide: an oral triple monoamine reuptake inhibitor studied for obesity, approved by no regulator.

early-clinical Metabolic & weight research chemical

At a glance

Category
Metabolic & weight
Status
research chemical
Route
oral tablet, once daily
Half-life
long, but this site has not verified a figure. The commonly quoted value of roughly nine days could not be traced to a primary human pharmacokinetic paper. What is documented is that after a single 483 microgram dose, urinary detection windows extended to 500 hours, with peak concentrations of 1-4 ng/ml reached anywhere between 4 and 46 hours and marked variation between individuals 1
Onset
appetite suppression within the first weeks; weight loss measured over 24 weeks in the trials 2
Sequence
None — tesofensine is not a peptide. It is a synthetic small molecule, a phenyltropane derivative.

Not approved by the FDA or the EMA. It is widely stated online that tesofensine was approved in Mexico by COFEPRIS in 2023, sometimes under the brand names Tesomet or Nupenta. This site could not verify that claim, and the primary sources point the other way. What COFEPRIS issued in February 2023 was a favourable opinion from its technical committee on new molecules, and the licensor's own announcement states explicitly that this 'does not represent a market authorization or rejection' and is a non-binding step in the review of new molecules 6. On 6 November 2024 Saniona announced that its partner Medix 'has not received approval from the Mexican regulatory agency (Cofepris) for tesofensine for the treatment of obesity' 7; a clarification six days later said COFEPRIS might not yet have reviewed the entire application package 8. In February 2025 Saniona announced that Medix would resubmit a revised dossier 9. No announcement of an approval could be found from any party as of July 2026. The claim of a 2023 Mexican approval appears to originate in commercial and secondary sources rather than in any regulator or licensee document, and this entry does not repeat it. Separately, and regardless of its regulatory status, tesofensine is sold online as a dietary supplement promoted for weight management — a fact recorded in the peer-reviewed literature by anti-doping researchers, who obtained such a product and dosed six volunteers with it 1.

Doping status: Prohibited in-competition only (WADA S6, stimulants)

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Tesofensine is included here for the same reason as MK-677 and noopept: people searching peptide references encounter it. It is not a peptide. It is a small molecule that inhibits the presynaptic reuptake of noradrenaline, dopamine and serotonin — a triple monoamine reuptake inhibitor, in the same broad pharmacological family as sibutramine, which was withdrawn from most markets in 2010 over cardiovascular events.

By blocking all three transporters it raises synaptic concentrations of all three monoamines. The appetite effect is attributed mainly to increased noradrenergic and dopaminergic tone in hypothalamic and mesolimbic circuits that regulate food intake and its reward value. Rodent work has since described a more specific action: tesofensine silences a population of GABAergic hypothalamic neurons associated with feeding 10, and reduces striatal dopamine D2/D3 receptor availability in diet-induced obese rats.

Its origin is unusual and worth stating, because it explains the shape of the evidence. NeuroSearch developed NS-2330 for Parkinson's disease and Alzheimer's disease, on the reasoning that a dopamine reuptake inhibitor might improve parkinsonian signs. Two randomised trials were run in Parkinson's disease — one in early disease in 261 patients 4 and one, the ADVANS study, in advanced disease with motor fluctuations, in which improvements were modest and no dose-response relationship for efficacy could be established while adverse events increased with dose 5. The neurology programme was dropped. Weight loss had been recurring as an adverse event throughout, and the compound was redirected to obesity.

The Tesomet formulation is a response to a specific problem. A triple reuptake inhibitor raises heart rate — the 0.5 mg dose in the phase 2 obesity trial increased it by 7.4 beats per minute 2 — so Saniona combined tesofensine 0.5 mg with the beta-blocker metoprolol 50 mg to blunt that effect, and studied the combination in hypothalamic obesity and in Prader-Willi syndrome rather than in general obesity 3.

What the research shows

One 24-week phase 2 obesity trial with a large effect, published in the Lancet in 2008 and subsequently the subject of a formal Expression of Concern from that journal 211. A phase 3 trial was run in Mexico by a licensee and reported through company announcements rather than in a peer-reviewed journal. Two small randomised Tesomet trials in rare forms of obesity, of 21 and 18 participants. Two negative-to-modest Parkinson's disease trials from the compound's first life. That is a thin and, in one important respect, compromised evidence base for a drug that has been in development since the 1990s.

Research in humans

The pivotal published trial (Lancet, 2008) randomised 203 people with a BMI of 30-40 to tesofensine 0.25, 0.5 or 1.0 mg once daily or placebo for 24 weeks, all on an energy-restricted diet. Mean weight loss was 4.5%, 9.2% and 10.6% respectively against 2.0% on placebo. The most common adverse events were dry mouth, nausea, constipation, hard stools, diarrhoea and insomnia; heart rate rose by 7.4 beats per minute in the 0.5 mg group 2. A long-term safety trial in 140 people with obesity ran from 2007 to 2008 12. In hypothalamic obesity, a randomised trial of Tesomet in 21 adults over 24 weeks reported an additional mean weight change of -6.3% against placebo, with sleep disturbance in 50% of the Tesomet group against 13% on placebo, dry mouth in 43% against 0% and headache in 36% against 0%; one participant discontinued after exacerbation of pre-existing anxiety 3. A parallel Tesomet trial in 18 people with Prader-Willi syndrome has been registered 13. In Parkinson's disease, the ADVANS study found modest improvement without a dose-response relationship 5, and a trial in 261 patients with early disease was also run 4. The phase 3 obesity trial conducted in Mexico by Medix is described in the licensor's announcements as having enrolled 372 patients with roughly 10% mean weight loss over 24 weeks 7; no peer-reviewed publication of it could be located.

Animal and lab research

Tesofensine reduced food intake and body weight and lowered striatal dopamine D2/D3 receptor availability in diet-induced obese rats. Later work reported that it silences GABAergic neurons in the lateral hypothalamus, offering a more specific account of the appetite effect than transporter blockade alone 10. A separate study reported sex-specific effects of appetite suppressants including tesofensine on stereotypy in rats 14 — relevant because stereotyped behaviour is a recognised consequence of raising dopaminergic tone, and it is one of the reasons a triple reuptake inhibitor is not a neutral appetite suppressant.

Caveats. The most serious problem is with the pivotal trial itself. In April 2013 the Lancet issued an Expression of Concern about the 2008 tesofensine paper 11. It followed an inspection by the Danish Health and Medicines Authority, which raised three issues: informed consent had been delegated to non-medical personnel at one site; the integrity of the blinding was questioned; and the recording and assessment of adverse events by the contract research organisation was incomplete, because its staff did not treat the recurrence of events as noteworthy. The editors' conclusion, as reported, was that the side-effect profile published in the Lancet 'is not in accordance with the actual course of the trial' 15. That is a statement about the tolerability data specifically, which for a triple monoamine reuptake inhibitor is the part that matters most. Beyond that: the phase 3 obesity data have never been published in a peer-reviewed journal and exist publicly only as company announcements; the Tesomet trials involve 21 and 18 participants; the Tesomet trials and much of the recent work are sponsored by Saniona, whose employees are co-authors 3; and the whole programme's regulatory history is one of repeated non-approval. Sibutramine, the closest marketed comparator, was withdrawn over cardiovascular outcomes, and no cardiovascular outcome trial of tesofensine exists.

What it is used for

  • Obesity — the indication pursued since the mid-2000s, and the subject of the phase 2 and phase 3 trials; not approved by any regulator this site could verify 2
  • Hypothalamic obesity, as Tesomet — a rare condition with no approved pharmacological treatment, studied in 21 adults 3
  • Prader-Willi syndrome, as Tesomet — studied in 18 participants 13
  • Historically, Parkinson's disease and Alzheimer's disease, both abandoned after the trials did not support continuing 45
  • Sold and taken outside any medical setting as an online 'dietary supplement' for weight loss, a use documented in the anti-doping literature and supported by no regulator anywhere 1

Dosing

Dose
Trial doses only: 0.25 mg, 0.5 mg or 1.0 mg once daily in the phase 2 obesity trial; 0.5 mg with metoprolol 50 mg as Tesomet
Frequency
once daily
Route
Oral tablet
Duration
24 weeks in the pivotal trials; a 48-week safety extension was run
  • These are the doses used in registered clinical trials under medical supervision. No regulator this site could verify has approved a dose of tesofensine, and nothing here is a recommendation.
  • The dose range is narrow and the effects are not gentle across it. At 0.5 mg the phase 2 trial recorded 9.2% weight loss and a 7.4 beat-per-minute rise in heart rate; at 1.0 mg, 10.6% weight loss with adverse events more frequent still 2. The developer selected 0.5 mg for later work, not the highest dose.
  • Tesomet is a fixed combination of tesofensine 0.5 mg with metoprolol 50 mg. The beta-blocker is there to blunt the cardiovascular effect and is not optional in that formulation 3.
  • The anti-doping study that dosed volunteers used 483 micrograms of tesofensine taken as an online dietary supplement — close to the 0.5 mg trial dose, which indicates that products sold this way are not being sold at trivial concentrations 1.
  • Elimination is slow and varies markedly between people; in that study, urinary detection continued for up to 500 hours after a single dose 1. A slow-clearing monoamine reuptake inhibitor accumulates, which is a reason dose changes should not be made quickly.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Phase 2 obesity trial schedule (24 weeks)

published trial

Source: Phase 2, five Danish obesity centres, ClinicalTrials.gov NCT00394667

24 weeksTesofensine 0.25 mg orally once daily, with an energy-restricted diet
24 weeksTesofensine 0.5 mg orally once daily, with an energy-restricted diet
24 weeksTesofensine 1.0 mg orally once daily, with an energy-restricted diet
24 weeksMatching placebo once daily, with an energy-restricted diet

203 participants; 161 completed. This is the trial that the Lancet later made the subject of an Expression of Concern over possible under-reporting of neuropsychiatric adverse events, so the tolerability picture it gives should be treated as incomplete.

Tesomet trial schedule (hypothalamic injury-induced obesity)

published trial

Source: Phase 2, Saniona, ClinicalTrials.gov NCT03845075

Up to 48 weeksTesofensine 0.5 mg with metoprolol 50 mg orally once daily, or placebo

21 participants. A separate 24-week randomised phase of this programme was published in the European Journal of Endocrinology and reported an additional 6.3% weight loss against placebo, with sleep disturbance in half the treated group.

Tesomet trial schedule (Prader-Willi syndrome)

published trial

Source: Phase 2, Saniona, ClinicalTrials.gov NCT03149445

Per protocolTesofensine with metoprolol orally once daily, or placebo

18 participants with a confirmed genetic diagnosis of Prader-Willi syndrome. A trial of this size can characterise tolerability only very approximately and cannot establish efficacy.

Online weight-loss self-dosing (user-reported)

user protocol — not validated

Source: Weight-loss and biohacker forum reports, vendor labelling, and an anti-doping study that dosed volunteers with an online product

This is not a validated schedule. It is a pattern that circulates among users and sellers, reproduced because it is what people actually follow — not because it has been tested. No trial established these doses, this interval or this duration, and nobody is checking what is in the vial. Treat every number below as an assertion, not a finding.

Commonly reported starting dose0.25 mg (250 mcg) once daily in the morning
Commonly reported maintenance0.5 mg (500 mcg) once daily, the dose the developer selected for later work
Reported courserun continuously for weeks to a few months, mirroring the 24-week trial length

Unusually for a grey-market compound, this practice is documented in the peer-reviewed literature: anti-doping researchers bought a product sold online as a dietary supplement and dosed six volunteers with 483 micrograms of tesofensine, close to the 0.5 mg trial dose, which shows these products are not being sold at trivial strengths 1. The circulating doses track the trial doses precisely because that is where the numbers came from - but taken without the medical supervision, the cardiovascular monitoring or the metoprolol of the Tesomet formulation, which exists specifically to blunt the heart-rate rise 3. Two hazards attach to self-dosing this compound. The dose is in the sub-milligram range, so a 0.25 versus 0.5 versus 1.0 mg mix-up is a doubling or quadrupling, and the content of a capsule sold as a supplement is verified by nobody. And elimination is slow and varies widely between people - urinary detection ran to 500 hours after a single dose in that study 1 - so the drug accumulates and a dose increase does not show its full effect for days.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Storage
No approved product exists, so no manufacturer storage instruction can be quoted.

Worked example

Not applicable. Tesofensine is an oral tablet. There is nothing to reconstitute, dissolve or inject.

Because tesofensine is a small molecule rather than a peptide, the handling considerations that apply to injectable peptides do not arise. The relevant uncertainty with material bought online is not storage but content: nobody has verified the dose in a capsule sold as a supplement.

Safety

Side effects

  • Dry mouth, nausea, constipation, hard stools, diarrhoea and insomnia — the most common events in the phase 2 obesity trial 2
  • Increased heart rate: 7.4 beats per minute at 0.5 mg against placebo, which is the reason the Tesomet combination with metoprolol exists 23
  • Sleep disturbance in 50% of the Tesomet group against 13% on placebo in hypothalamic obesity, dry mouth in 43% against 0%, headache in 36% against 0% 3
  • Neuropsychiatric effects including anxiety; one participant in the Tesomet trial discontinued after exacerbation of pre-existing anxiety 3. The side-effect profile of the pivotal obesity trial should be read with the Lancet's Expression of Concern in view: adverse-event recording in that trial was found incomplete, and the editors concluded the published side-effect profile did not accord with the actual course of the trial 1115
  • Blood pressure did not rise significantly at 0.25 and 0.5 mg over 24 weeks in the phase 2 trial 2; that finding covers 24 weeks in 203 people and is not a cardiovascular safety conclusion
  • Effects consistent with raised dopaminergic tone, including stereotyped behaviour, have been described in rodents 14
  • Abuse potential: the subjective and objective effects of tesofensine were formally studied in recreational stimulant users, which is the assessment a triple monoamine reuptake inhibitor requires 17
  • No cardiovascular outcome trial exists. Sibutramine, the closest marketed comparator, was withdrawn from most markets over cardiovascular events

Do not use if

  • There is no approved product and no official contraindication list. What follows is inference from the pharmacology and from the trials
  • Cardiovascular disease, uncontrolled hypertension, arrhythmia or a history of stroke — a drug that raises heart rate through monoamine reuptake inhibition is a poor fit for any of these
  • Concurrent use of a monoamine oxidase inhibitor, or use within the washout period of one
  • Psychiatric illness including anxiety disorder, depression, bipolar disorder or psychosis; the neuropsychiatric adverse-event record for this compound is specifically unreliable 1115
  • History of stimulant or other substance use disorder
  • Pregnancy and breastfeeding
  • Uncontrolled thyroid disease, phaeochromocytoma and glaucoma, by analogy with other monoaminergic anorectics

Interactions

Not systematically studied in a published dedicated programme. The predictable and serious interaction is with anything else that raises synaptic monoamines: monoamine oxidase inhibitors, SSRIs, SNRIs, tricyclic antidepressants, triptans, tramadol, linezolid, other stimulants and sympathomimetic decongestants, with serotonin syndrome and hypertensive effects as the concerns. Combining it with another appetite suppressant of the same class would compound both the efficacy and the cardiovascular effect. The Tesomet formulation deliberately combines tesofensine with a beta-blocker, so anyone taking tesofensine alongside cardiovascular medication is in an interaction that the developer treated as a design problem rather than an incidental one 3. Slow and variable elimination means an interaction does not resolve quickly after stopping 1.

Sources