Tesofensine

Tesofensine was originally developed for Parkinson's and Alzheimer's disease, where it failed, but produced consistent unintended weight loss. It inhibits reuptake of noradrenaline, dopamine and serotonin with roughly comparable potency, increasing hypothalamic monoamine tone and reducing food intake while modestly raising energy expenditure. This is amphetamine-adjacent pharmacology without the direct releasing action, and the side-effect profile reflects that: dry mouth, insomnia, elevated heart rate and blood pressure, and mood changes. The Tesomet formulation adds metoprolol specifically to blunt the cardiovascular effects.

Targets: Noradrenaline transporter, Dopamine transporter, Serotonin transporter

• · Trials used 0.25, 0.5 and 1.0 mg daily; 0.5 mg gave about 9-11% weight loss over 24 weeks and is the dose taken forward. The 1.0 mg dose raised blood pressure and heart rate unacceptably and was abandoned.

Work out your exact syringe units →

• very commonInsomnia— Very hard to avoid with a 9-day half-life; morning dosing helps but does not eliminate it.
• very commonDry mouth
• commonIncreased heart rate and blood pressure— Dose-dependent and the main reason the 1 mg dose was dropped; the Tesomet formulation adds metoprolol for this.
• commonAnxiety, agitation and mood change— Monoaminergic; can unmask or worsen underlying anxiety.
• commonConstipation
• uncommonDependence and abuse potential— Dopaminergic reuptake inhibition carries some misuse liability, though less than releasing agents.

• Uncontrolled hypertension or tachyarrhythmia.
• Coronary artery disease or recent cardiovascular event.
• Concurrent MAO inhibitor use - risk of hypertensive crisis and serotonin syndrome.
• Bipolar disorder, psychosis or history of stimulant misuse.
• Glaucoma.
• Pregnancy and breastfeeding.

• synergysemaglutide — Different mechanisms and commonly stacked in off-label protocols; the GLP-1 provides satiety while tesofensine provides drive, but nothing has been trialled formally.
• cautionmelanotan-ii — Both suppress appetite and both raise blood pressure; combined cardiovascular load is worth watching.
• conflictmk-677 — Ghrelin agonism drives appetite in the opposite direction and disrupts sleep, compounding tesofensine's insomnia.

• · Blood pressure and resting heart rate at least weekly.
• · Sleep quality and duration.
• · Mood.
• · Weight.

Approved in Mexico for obesity; never approved by the FDA or EMA. Widely sold grey-market as a research chemical.

• Astrup et al. 2008, TIPO-1 phase 2 obesity trial, The Lancet (trial)
• Huynh et al. 2022, Tesomet randomised trial in hypothalamic obesity (trial)

Tesofensine is in this class only by association - it is a monoamine reuptake inhibitor, not a gut hormone, and it works upstream of everything else here. By blocking the noradrenaline, dopamine and serotonin transporters it raises synaptic concentrations of all three in the hypothalamus and mesolimbic system, suppressing appetite through noradrenergic and serotonergic satiety circuits while reducing food reward through dopamine. It was originally developed for Parkinson's disease and Alzheimer's disease, and the weight loss was an unexpected finding in those trials - which is a familiar origin story for appetite drugs and historically not a reassuring one. The pharmacokinetic property that matters most clinically is the half-life: around eight to nine days, which is extraordinarily long for a stimulant-like drug. That means effects accumulate for four to six weeks after starting or after any dose change, and people who feel little in the first week and increase the dose are titrating against a moving target and will be substantially overdosed by week five. It also means that when something goes wrong - insomnia, tachycardia, blood pressure elevation, agitation - stopping the drug does not fix it for over a week. TIPO-1 showed roughly 10% weight loss at 0.5 mg over 24 weeks, which is competitive with early GLP-1 agents, but the phase 3 programme was never completed in the US or EU and the only approval is in Mexico. The honest characterisation is a real drug with real phase 2 data, real monoaminergic side effects and no Western regulatory oversight.

Almost everything that goes wrong with tesofensine traces back to the eight-to-nine-day half-life. People take it, feel little for a week, increase the dose, feel little for another week, increase again - and then arrive at week five with three doses' worth of accumulated drug, a resting heart rate of 105, blood pressure of 150/95 and no sleep. The correct approach is one dose, six weeks, then assess. The second problem is that it is a dopamine reuptake inhibitor sold as a research chemical, with the psychiatric and abuse-liability considerations that implies. Third, its only approval is in Mexico, so grey-market material has no oversight and dose accuracy in a 0.25 mg tablet or capsule is not something you can verify at home.

1. 250 mcgWeeks 1-6 — 0.25 mg daily. Because the half-life is 8-9 days, steady state takes 4-6 weeks - do not judge this dose before then, and do not increase it because week one felt like nothing.
2. 500 mcgWeek 7 onward — 0.5 mg daily, the TIPO-1 dose that produced roughly 10% weight loss at 24 weeks. Higher doses were studied and produced more monoaminergic side effects without proportionate benefit.

• Noradrenaline transporter (NET) — Potent reuptake inhibitor; specific values not verified

  Raised synaptic noradrenaline, driving appetite suppression and also the blood pressure and heart rate increases that are the drug's main safety issue.

• Dopamine transporter (DAT) — Potent reuptake inhibitor; specific values not verified

  Raised synaptic dopamine, reducing food reward - and carrying the abuse-liability and psychiatric considerations that come with any DAT inhibitor.

• Serotonin transporter (SERT) — Reuptake inhibitor, generally reported as the weakest of the three

  Contributes to satiety. Also the reason serotonergic interactions matter.

• TIPO-1 Phase 2 · n=203 · 24 weeks · 2008

  Mean weight loss of approximately 10% at 0.5 mg daily over 24 weeks, with dose-dependent increases in heart rate and blood pressure.

Appetite suppression within days, but the drug keeps accumulating for four to six weeks, so what you feel in week one is roughly a third of what you will feel in week five. Weight loss over 24 weeks in TIPO-1. Stopping: effects persist for well over a week because of the half-life.

The combination people actually run is tesofensine plus a GLP-1 agonist, on the theory that the mechanisms are entirely separate - one is a gut hormone axis, the other is central monoamine reuptake. Mechanistically that is true and there is no trial evidence for it whatsoever. The cardiovascular arithmetic is worth doing before you do it: GLP-1 agonists raise resting heart rate by 3-10 bpm, tesofensine raises it further along with blood pressure, and nobody has studied the combination. Absolute conflicts: MAOIs, and any other stimulant. Serious caution with SSRIs, SNRIs, triptans and tramadol because of serotonin syndrome risk. If you are running it, own a blood pressure cuff and use it.

Against GLP-1 agonists: TIPO-1's roughly 10% at 24 weeks is comparable to liraglutide and clearly below semaglutide or tirzepatide, achieved with a cardiovascular and psychiatric side-effect profile the incretins do not have. Against phentermine and other sympathomimetics: tesofensine is more effective and much longer-acting, which cuts both ways. Against sibutramine, the closest historical analogue: sibutramine was withdrawn worldwide after the SCOUT trial showed increased cardiovascular events, and tesofensine has never had a cardiovascular outcomes trial - that comparison is the single most relevant piece of context anyone considering it should hold in mind.

$40–$150/month. Grey market and Mexican pharmacy pricing. Market observation, not verified pricing.

• ?No verifiable pharmacokinetic parameters beyond the approximate half-life.
• ?The Mexican product information was not accessible for verification, so the approved dosing there is not confirmed here.
• ?Specific transporter binding affinities were not verified.
• ?No cardiovascular outcomes trial has ever been conducted, which given the sibutramine precedent is the most important gap in the evidence.
• ?The phase 3 programme was never completed in the US or EU, so the 10% figure rests on a single phase 2 trial.
• ?Cost figures are market observations, not verified pricing.

• Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial Astrup A et al., Lancet, 2008 · PMID 18950853

  TIPO-1. The trial the entire tesofensine reputation rests on, and the source for the cardiovascular and psychiatric side-effect profile.