Tesofensine
A triple monoamine reuptake inhibitor (serotonin, dopamine, and norepinephrine) originally developed for Alzheimer's and Parkinson's disease that showed significant weight loss as an unexpected clinical trial finding. Reduces appetite through combined monoaminergic signaling in hypothalamic appetite centers. Represents a CNS-based approach to obesity treatment distinct from GLP-1 agonists and other peptide-based mechanisms.
Typical Dosage
Clinical trials: 0.25-1.0 mg oral once daily in the morning. Phase II demonstrated dose-dependent weight loss. 0.5 mg dose showed optimal efficacy/safety balance. No established commercial dosing.
Administration
Oral (capsule)
Mechanism of Action
Tesofensine is a novel triple monoamine reuptake inhibitor (TRI) that simultaneously blocks the presynaptic reuptake transporters for serotonin (SERT), norepinephrine (NET), and dopamine (DAT). Originally developed by NeuroSearch as NS2330 for neurodegenerative diseases, it was repurposed for obesity after clinical trials for Alzheimer's and Parkinson's disease unexpectedly revealed significant weight loss in treated patients.
The weight loss mechanism involves all three monoamine systems working in concert. Serotonin (5-HT) reuptake inhibition increases serotonergic tone in the hypothalamic appetite centers, particularly the paraventricular nucleus and ventromedial hypothalamus. Elevated synaptic serotonin activates 5-HT2C receptors on POMC neurons, promoting the release of alpha-MSH, which activates MC4R and produces satiety. This is the same pathway targeted by lorcaserin (Belviq), but tesofensine adds two additional mechanisms. Norepinephrine reuptake inhibition activates alpha-1 and beta-adrenergic receptors in the lateral hypothalamus, reducing appetite and increasing sympathetic nervous system activity, which raises basal metabolic rate and thermogenesis.
The dopamine reuptake inhibition component may be the most important differentiator. By increasing dopamine availability in the mesolimbic reward pathway (nucleus accumbens, ventral tegmental area), tesofensine may reduce the drive for food reward-seeking behavior — the compulsive eating of palatable, high-calorie foods that is mediated by dopamine signaling in the same circuits involved in addiction. This addresses a component of obesity that pure appetite suppressants miss: the hedonic (pleasure-driven) eating that overrides homeostatic satiety signals. Phase II clinical trials demonstrated remarkable efficacy — the 0.5 mg dose produced approximately 12.8 kg weight loss over 6 months, roughly double what GLP-1 receptor agonists typically achieve — though cardiovascular monitoring is necessary due to increases in heart rate associated with the noradrenergic and dopaminergic effects.
Regulatory Status
Not FDA approved. Phase III trials ongoing (Saniona). Approved in Mexico (2023) for obesity. Available through some international pharmacies and compounding sources.
Risks & Safety
Common: increased heart rate, dry mouth, insomnia, constipation, nausea, dizziness. Serious: cardiovascular effects (sustained tachycardia due to norepinephrine reuptake inhibition), mood changes and potential psychiatric effects (all three monoamine systems affected), suicidal ideation (class warning for CNS-active drugs). Rare: serotonin syndrome if combined with other serotonergic drugs, significant cardiac arrhythmia. Cardiovascular monitoring recommended. Not FDA approved.
Research Papers
No research papers indexed yet. Papers are fetched from PubMed weekly.
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