Tesofensine

Tesofensine (NS2330) is a small-molecule serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) — informally called a triple monoamine reuptake inhibitor — originally synthesized by NeuroSearch A/S and brought into Phase 2 clinical development for Parkinson's disease and Alzheimer's disease before its obesity-relevant mechanism was recognized. Its weight-loss effects were first observed as an incidental finding in neurodegenerative disease trials, where subjects on tesofensine lost substantially more body weight than placebo controls. This observation redirected subsequent development toward metabolic research and ultimately yielded the TIPO-1 Phase 2b trial (2008) specifically designed to characterize its weight-loss profile.

Mechanistically, tesofensine inhibits the reuptake transporters for serotonin (SERT), norepinephrine (NET), and dopamine (DAT) simultaneously. The relative inhibition ratios are not perfectly balanced — tesofensine exhibits stronger NET and SERT inhibition relative to DAT compared with classical stimulants — but the combined presynaptic blockade elevates synaptic concentrations of all three monoamines in relevant brain circuits. The hypothalamic consequence of this multi-monoamine elevation is suppression of appetite: noradrenergic signaling activates beta-1 and beta-2 adrenoreceptors in the paraventricular nucleus, reducing NPY-driven feeding; dopaminergic activation of D1/D2 receptors in the mesolimbic and nigrostriatal pathways modulates food reward and motivation; serotonergic signaling via 5-HT2C receptors on POMC neurons promotes satiety signaling. The concurrent engagement of three monoamine systems is proposed to produce a synergistic appetite-suppression effect exceeding what any single monoamine pathway can produce alone.

In the TIPO-1 Phase 2b randomized controlled trial, 203 obese adults received 0.25 mg, 0.5 mg, or 1.0 mg tesofensine or placebo once daily for 24 weeks. Mean weight loss was 6.7%, 11.3%, and 12.8% for the three dose groups versus 2.2% for placebo — the 0.5 mg and 1.0 mg results represented among the highest weight-loss figures seen in pharmacological trials at that time for a non-combined-mechanism drug. Cardiovascular effects (modest heart rate increase) and the expected monoaminergic side-effect profile (dry mouth, nausea, constipation, insomnia) were documented. Phase 3 development has not been completed as of September 2026, and the compound remains an unapproved research chemical outside of clinical trial settings. Peptides.SO tracks 44 tesofensine listings from 34 distinct suppliers, all in stock. The mg-denominated listings range from $12.00 to $500.00/mg with a median of $150.00/mg; several of the low-end per-unit listings (Hydro Research, Peptides Source) are per-mcg and reflect capsule or liquid formulations sold by individual dose unit.

Potential Research Applications: Hypothalamic appetite circuit modulation via combined noradrenergic, dopaminergic, and serotonergic signaling Triple monoamine reuptake inhibition pharmacology and receptor selectivity profiling studies Comparative weight-loss mechanism studies vs GLP-1 receptor agonist approaches Food-reward and motivation behavioral models via mesolimbic dopamine modulation Paraventricular nucleus NPY pathway modulation through noradrenergic signaling POMC neuron activation via 5-HT2C serotonin receptor stimulation Chronic weight management and body composition modeling in DIO (diet-induced obesity) rodent models Abuse-liability and central stimulant profile characterization studies Parkinson's disease and dopaminergic circuit research (original development context)

Marketplace Snapshot (September 2026, Peptides.SO listings data): Tracked listings: 44 from 34 distinct suppliers (44 in stock) Unit mix: most mg-denominated listings at $12–$500/mg; several per-mcg dose-unit listings Median price (mg-unit listings): approximately $150/mg (range $12 – $500/mg) Lowest mg-unit price: $12.00/mg — Guru Peptides Second: $89.99/mg — Soma Chems Third: $99.00/mg — Southern Aminos Note: Tesofensine is a small molecule, not a peptide, and its per-mg price is substantially lower than peptide-based appetite modulators like semaglutide. The wide listing count (34 suppliers) reflects broad availability in the research-chemical market.

Frequently Asked Questions: Q: How does tesofensine's mechanism compare with GLP-1 receptor agonists like semaglutide for appetite suppression? A: The two mechanisms are entirely distinct. Semaglutide acts centrally and peripherally through GLP-1 receptors to suppress appetite via POMC/CART activation and NPY/AgRP inhibition, with peripheral contributions from gastric slowing and vagal satiety signaling. Tesofensine acts through presynaptic monoamine reuptake blockade — elevating norepinephrine, dopamine, and serotonin in hypothalamic circuits without engaging incretin receptors at all. This orthogonal mechanism makes tesofensine a useful comparison compound for mechanistic dissection of appetite circuits: studies that ask whether a given appetite effect requires incretin signaling or monoamine signaling can use both as controls.

Q: What were the TIPO-1 Phase 2b results, and what did they reveal about tesofensine's weight-loss potential? A: In TIPO-1 (24 weeks, 203 obese adults), 0.5 mg/day tesofensine produced 11.3% mean weight loss and 1.0 mg/day produced 12.8%, compared with 2.2% for placebo. These were among the highest weight-loss numbers documented for a single oral compound at that time. Heart rate increased by approximately 7.4 bpm at the 1.0 mg dose — a monoaminergic cardiovascular effect consistent with NET inhibition — which has been a focus of ongoing safety evaluation.

Q: Why is tesofensine categorized as a triple reuptake inhibitor rather than a stimulant? A: Both classical stimulants (amphetamines) and triple reuptake inhibitors elevate synaptic monoamine levels, but through different mechanisms. Amphetamines are DAT substrates that reverse transport, actively pumping dopamine out of presynaptic terminals (an efflux mechanism). Tesofensine is a competitive blocker of the same transporters without inducing active efflux. This mechanistic distinction is associated with a different abuse-liability profile and a different time-course of monoamine elevation, making reuptake inhibitors research subjects in comparative abuse-liability and receptor-regulation studies.

Q: How many suppliers offer tesofensine for research, and at what prices? A: Peptides.SO tracks 44 listings from 34 suppliers. The mg-unit price range is $12–$500/mg, with Guru Peptides at $12/mg as the most competitive option. Many of the remaining mg-unit listings cluster in the $89–$200/mg range. Some suppliers sell tesofensine by dose unit in solution, with per-mcg pricing that appears very low but reflects per-capsule-dose quantities.

Q: Is tesofensine approved for human use? A: No. Tesofensine has not completed Phase 3 development and holds no FDA or EMA marketing approval. It is an unapproved research chemical sold strictly for preclinical and in vitro laboratory investigation and is not for human consumption.

Related Research on Peptides.SO: peptides.so/learn/tesofensine-triple-reuptake-inhibitor-research peptides.so/peptide/semaglutide peptides.so/peptide/retatrutide peptides.so/learn/best-glp-1-research-sources-2026 peptides.so/learn/peptide-storage-best-practices peptides.so/tools/calculator

Cited Research: Astrup A, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. 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. PubMed PMID: 18950853. Astrup A, Madsbad S, Breum L, et al. Effect of tesofensine on basal metabolic rate and body weight compared with placebo and orlistat for 24 weeks. Obesity (Silver Spring). 2008;16(12):2742-2749. PubMed PMID: 18356831.

For laboratory research only. Not for human or veterinary use, diagnosis, treatment, cure, or prevention of any disease. THIS PRODUCT IS NOT FOR HUMAN CONSUMPTION.