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Metabolic Modulators

Tesofensine

Oral appetite suppressant that blocks reuptake of three brain neurotransmitters; strong weight-loss trials, but raises heart rate and blood pressure.

InvestigationalEvidence level 4 of 5: Human RCTs or approved abroadAlso: NS2330

Overview

Tesofensine was originally developed for Parkinson's and Alzheimer's disease, where it failed, but trial participants lost weight. It blocks the reuptake of norepinephrine, dopamine and serotonin, increasing their activity in brain circuits that control hunger and fullness. In a 24-week randomized trial, it produced about 5–11% more weight loss than placebo, and later phase 3 trials in Mexico reported similar results. The main concerns are increased heart rate and blood pressure, insomnia, dry mouth and mood effects, and long-term cardiovascular safety has not been proven. It is not approved in the United States and requires close blood-pressure and heart-rate monitoring.

Classification
Small-molecule triple monoamine (norepinephrine, dopamine, serotonin) reuptake inhibitor; not a peptide
Route
Oral
Half-life
~8–9 days (oral)

Mechanism of action

Primary targetNET, DAT and SERT monoamine transporters
  1. Blocks reuptake transportersInhibits norepinephrine, dopamine and serotonin transporters in the brain.
  2. Synaptic monoamines riseNeurotransmitters remain active longer in hypothalamic circuits.
  3. Hypothalamic satiety signalingEnhanced fullness signals and reduced hunger drive.
  4. Reduced food intakeLower calorie intake leads to sustained weight loss.
  5. Sympathetic activationRaised noradrenergic tone increases energy expenditure, heart rate and blood pressure.
Downstream effects
  • Appetite suppression
  • Weight loss
  • Raised heart rate and BP

Researched for

  • Obesity
  • Hypothalamic obesity / Prader-Willi syndrome
  • Parkinson's disease (discontinued)
  • Alzheimer's disease (discontinued)

Research notes

  • Phase 2 RCT (Astrup 2008, Lancet): 24-week weight loss 6.7–12.8% on drug vs 2.2% on placebo, all with diet.
  • Heart rate rose dose-dependently; blood pressure increased at higher doses.
  • Phase 3 trials in Mexico (Medix) reported clinically meaningful weight loss; full peer-reviewed data are limited.
  • Being studied for hypothalamic obesity; no long-term cardiovascular outcome trial exists.

Reported side effects

  • Increased heart rate and blood pressure
  • Insomnia
  • Dry mouth
  • Nausea or constipation
  • Anxiety, irritability or mood changes

Contraindications & cautions

  • Uncontrolled hypertension
  • Recent heart attack, arrhythmia or heart failure
  • Use of MAOIs or other serotonergic/stimulant drugs
  • Untreated anxiety, bipolar disorder or eating disorder
  • Pregnancy or breastfeeding

Lab monitoring

  • Blood pressure and heart rate (frequent)
  • Baseline ECG
  • CMP with electrolytes
  • Fasting glucose, HbA1c, lipid panel
  • Thyroid panel

Dosing and pricing for Tesofensine

Dosing references and compound pricing are available to established patients in the secure portal after a medical evaluation.

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