Tesofensine
Tesofensine — the Alzheimer's drug repurposed for obesity: the accidental discovery and triple-monoamine mechanism

Class: small_molecule
Synonyms: Tesofensine
NS-2330 (original code)
Function tags: weight management / obesity (appetite ↓ + energy expenditure ↑)
CNS monoamine modulation
(originally: neurodegeneration — modest)
Overall evidence grade: B
WADA prohibited: no
Last updated: 2026-07-13

In brief: Tesofensine (NS-2330) is a small-molecule triple monoamine reuptake inhibitor — it raises dopamine, norepinephrine, and serotonin at once — and its story is a gem of pharmacological serendipity. It was developed for Parkinson's and Alzheimer's, where it worked only modestly, but trial participants lost weight so reliably that the program pivoted entirely to obesity — a weight-loss effect discovered, not designed. A pooled analysis of neurology trials revealed the dose-dependent effect, and a Phase 2 obesity trial (Lancet 2008) showed ~10% weight loss in 24 weeks — about double the approved drugs of that era. Mechanistically it's an outlier here: it works centrally, on two fronts at once (appetite suppression via serotonin, energy expenditure via norepinephrine), rather than through gut incretin or amylin hormones. The honest caveats are real: it's a small molecule (not a peptide), unapproved, its mechanism is cousin to withdrawn appetite drugs (sibutramine), and it carries a cardiovascular signal (raised heart rate). And its headline "twice the weight loss" belongs to a pre-GLP-1 world — today's semaglutide/tirzepatide have reset the bar. So: a fascinating, twice-serendipitous CNS weight-loss drug with a genuinely interesting mechanism — but unapproved, cardiovascularly watchful, and overtaken by the incretin era.

## Identity a **synthetic small molecule** that **simultaneously blocks the reuptake transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT)** — raising all three monoamine neurotransmitters in the brain. It acts **centrally** (in the brain), a mechanism **completely different** from the GLP-1/amylin/incretin peptides that dominate this register. Investigated for **obesity** — though that's not where it started. ## Mechanism (as proposed) tesofensine **blocks all three monoamine transporters** — **SERT** (serotonin), **NET** (norepinephrine), and **DAT** (dopamine) — increasing synaptic levels of each. The weight effects come from **combining** these: **serotonin** prolongs **hypothalamic satiety signaling** (reducing intake — the same broad pathway older appetite drugs used, but here one of three); **norepinephrine** drives **adrenergic activation** that **raises energy expenditure**; and **dopamine** modulates **reward/food-craving** circuitry (a stimulatory dopaminergic response in the nucleus accumbens and prefrontal cortex has been observed). So tesofensine attacks obesity from **both the intake and the expenditure side** — pharmacologically elegant, but also why it looks like an **antidepressant-class mechanism** (SSRIs/SNRIs/DRIs combined) rather than a metabolic-hormone drug, and why the **cardiovascular and CNS side-effect profile** needs respect. Its human weight-loss mechanism is officially **"unresolved,"** an honest scientific footnote.

Evidence grades by outcome:
outcome: Weight loss / obesity
grade: B
base: Phase 2 (Astrup, Lancet 2008): significant at all doses, ~10%/24 wk; "~2× era's drugs"
caveat: Solid Phase 2 — but not Phase 3-confirmed for approval, and the "2×" was pre-GLP-1 (incretins now exceed it)
outcome: Energy expenditure + appetite (dual mechanism)
grade: B
base: Respiration-chamber (Sjödin 2010): ↑24-h EE, ↑fat oxidation, ↓appetite
caveat: Genuinely dual-action; full human mechanism "unresolved"
outcome: Parkinson's / Alzheimer's (original use)
grade: D
base: Four RCTs: limited efficacy
caveat: Failed to become a neuro drug — the reason it was repurposed
outcome: Cardiovascular safety
grade: C
base: Phase 2: heart rate +~7 bpm (p=0.0001); BP not significantly raised at 24 wk
caveat: The key caveat — HR increase (mechanistic cousin to withdrawn sibutramine); needs careful CV monitoring
outcome: Tolerability
grade: C
base: Dry mouth, nausea, constipation, insomnia
caveat: Stimulant-type AEs; dopaminergic component raises theoretical mood/dependence questions

Legal status:
region: US
status: not an approved obesity drug in major markets
note: not an approved obesity drug in major markets; investigational (reached Phase 2/3). Some regional/combination development has occurred, but no broad approval.

Cosmetic claims:

Note: The brain drug that lost weight by accident. Tesofensine is one of the register's best serendipity stories — and a mechanistic outlier. Beautiful facts: (1) it was built for Parkinson's and Alzheimer's, worked only modestly there, but made patients lose weight so consistently the whole program pivoted to obesity — a weight-loss effect that was discovered, not engineered; (2) it's a triple monoamine reuptake inhibitor — it raises dopamine, norepinephrine, AND serotonin at once (an antidepressant-style mechanism), utterly unlike the GLP-1/amylin drugs around it; (3) it loses weight two ways at once — cutting appetite and raising energy expenditure. It's a small molecule, not a peptide — with a real cardiovascular caveat.
Status note: status: Phase 2/3 investigational; the open questions are Phase 3 confirmation and cardiovascular safety — and whether any CNS-monoamine drug can compete with the incretin era

Sources:
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;372:1906-1913 (Phase 2; ~2× era's drugs; HR +~7 bpm).
Astrup A, Meier DH, Mikkelsen BO, Villumsen JS. Weight loss produced by tesofensine in patients with Parkinson's or Alzheimer's disease. Obesity 2008;16:1363-1369 (the pooled neurology analysis that revealed dose-dependent weight loss).
Sjödin A, et al. The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite… Int J Obes 2010 (↑energy expenditure + ↓appetite; mechanism "unresolved").
NeuroSearch/Saniona development history (NS-2330 → obesity pivot → Phase 3; tesofensine/metoprolol combination for heart-rate management). (Not an approved obesity drug in major markets; small molecule, not a peptide.)