Tesofensine
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Triple monoamine reuptake inhibitor (SNDRI) that suppresses appetite by blocking serotonin, norepinephrine, and dopamine reuptake, producing significant weight loss in clinical trials.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | NS-2330, TE (development code) |
| Category | Metabolic / Weight Loss |
| Sequence | N/A (small molecule, not a peptide) |
| Molecular Weight | ~383.5 Da |
| Molecular Formula | C17H23Cl2NO2 |
| PubChem CID | 11370876 |
| Administration | Oral |
| Typical Dose Range | 0.25-0.5 mg daily |
| Half-Life | ~200 hours (8-9 days) |
| Storage | Room temperature; protect from moisture and light |
| FDA Status | Research only (Phase 2 completed; Phase 3 never initiated in US) |
| WADA Status | Prohibited S6 (Stimulant) |
Mechanism of Action
Tesofensine is a potent triple monoamine reuptake inhibitor (SNDRI) that blocks the presynaptic reuptake of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) in the central nervous system. Originally developed as NS-2330 for Parkinson's disease and Alzheimer's disease by NeuroSearch A/S (Denmark), unexpected weight loss in CNS trial participants led to its repositioning as an anti-obesity agent (PMID: 18356831).
The mechanism of appetite suppression involves enhancement of satiety signaling through all three monoamine pathways simultaneously. PET imaging has confirmed that at the therapeutic dose of 0.5 mg, tesofensine occupies approximately 30-40% of dopamine transporters (DAT) in the human brain — below the ~50-60% threshold associated with abuse potential (PMID: 24239329). The appetite-suppressive effect is primarily mediated through alpha-1 adrenoceptor and dopamine D1 receptor stimulation in hypothalamic appetite-regulating circuits (PMID: 20200509).
The extremely long half-life (~200 hours) allows for once-daily dosing with steady-state concentrations achieved over several weeks. Unlike classical stimulants, tesofensine does not produce significant thermogenic effects — weight loss is predominantly driven by reduced energy intake through appetite suppression rather than increased energy expenditure (PMID: 20479765).
Key Research Areas
- Obesity treatment — Phase 2 RCT showed 9-11% weight loss at 0.5-1.0 mg doses over 24 weeks, potentially double the efficacy of then-approved anti-obesity drugs (PMID: 18950853)
- Appetite regulation — Reverses low forebrain dopamine levels in diet-induced obesity models, restoring normal satiety signaling (PMID: 23932919)
- CNS disease-associated weight loss — Originally discovered via weight loss in Parkinson's/Alzheimer's trials (PMID: 18356831)
- Metabolic parameter improvement — Improvements in body composition with preferential fat mass loss
- Dopamine transporter pharmacology — PET imaging characterization of DAT occupancy at clinical doses (PMID: 24239329)
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 2 | Phase 2 obesity trial (Lancet); energy metabolism study |
| Human observational | 2 | PET imaging; PD/AD weight loss observation |
| Animal in vivo | 5+ | DIO rat models (appetite, DA levels, D2/D3 receptors) |
| In vitro | 1+ | Transporter binding studies |
| Systematic reviews | 0 | None published |
Clinical Applications
- Weight Management — Primary application; appetite suppression and fat loss
- Fat Loss — Preferential reduction in fat mass with body composition improvement
- Metabolic Syndrome — Potential metabolic parameter improvements secondary to weight loss
Protocols Using This Peptide
Ageless Peps Products
- AP-Tesofensine-Capsules — Tesofensine 500mcg x 60 capsules
Dosing Reference
Research Dosing Ranges (from literature)
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| Oral | 0.25 mg | Once daily | 24 weeks | PMID 18950853 |
| Oral | 0.5 mg | Once daily | 24 weeks | PMID 18950853 (optimal risk-benefit) |
| Oral | 1.0 mg | Once daily | 24 weeks | PMID 18950853 (max studied; more CV effects) |
Cycling
The extremely long half-life (~200 hours) means the drug takes weeks to reach steady state and weeks to wash out. No formal cycling protocols have been established. In clinical trials, 24-week continuous treatment was used. Some practitioners recommend periodic breaks (e.g., 12 weeks on / 4 weeks off) to assess response and minimize cardiovascular effects.
Contraindications & Safety
- Contraindications: Uncontrolled hypertension, tachyarrhythmias, coronary artery disease, history of stroke, concurrent MAOI use, concurrent SSRI/SNRI use (serotonin syndrome risk), narrow-angle glaucoma
- Common side effects: Dry mouth, nausea, constipation, hard stools, diarrhea, insomnia, headache
- Cardiovascular effects: Heart rate increase ~7 bpm at 0.5 mg dose (the primary safety concern that prevented Phase 3 progression); blood pressure may increase at higher doses
- Drug interactions: Strong interactions with MAOIs, SSRIs, SNRIs, other monoamine-active drugs; potential for serotonin syndrome. Caution with CYP3A4 inhibitors.
- Pregnancy/nursing: Contraindicated
- Special populations: No data in renal/hepatic impairment; not studied in pediatric populations; caution in elderly (original CNS trials included elderly patients)
- Abuse potential: DAT occupancy at therapeutic doses (~30-40%) is below stimulant abuse threshold, but classified as a stimulant by WADA
Synergistic Combinations
- AOD-9604 + Tesofensine — Complementary mechanisms: appetite suppression (tesofensine) + direct lipolysis (AOD-9604)
- 5-Amino-1MQ + Tesofensine — NNMT inhibition + monoamine reuptake inhibition for metabolic syndrome
- MOTS-C + Tesofensine — Mitochondrial metabolic support + central appetite control
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| PMID-18950853 – Tesofensine Phase 2 Obesity Trial | Effect of tesofensine on bodyweight loss in obese patients | 2008 | RCT |
| PMID-20479765 – Tesofensine Energy Metabolism and Appetite | Effect on energy metabolism and appetite in overweight men | 2010 | RCT |
| PMID-19777399 – Tesofensine Monoamine Reuptake Inhibitor Review | Tesofensine for the treatment of obesity | 2009 | Narrative Review |
| PMID-24239329 – Tesofensine Dopamine Transporter Occupancy PET | Dopamine transporter occupancy as measured by PET | 2014 | Observational |
| PMID-18356831 – Tesofensine Weight Loss in Parkinsons and Alzheimers | Weight loss in Parkinson's or Alzheimer's patients | 2008 | Observational |
References
- PMID 18950853 — Astrup et al., Lancet 2008 (Phase 2 obesity RCT)
- PMID 20479765 — Sjodin et al., Int J Obes 2010 (energy metabolism)
- PMID 19777399 — Hansen & Astrup, Curr Opin Investig Drugs 2009 (review)
- PMID 24239329 — Appel et al., Eur Neuropsychopharmacol 2014 (PET imaging)
- PMID 18356831 — Bhatti et al., Obesity 2008 (CNS disease weight loss)
Related
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