Tesofensine — Research, Dosing & Price Guide

Tesofensine is a triple monoamine reuptake inhibitor (serotonin, norepinephrine, and dopamine) originally developed for Alzheimer's and Parkinson's disease that was repurposed for obesity treatment after clinical trials revealed dramatic weight loss as a side effect. It is one of the most potent appetite suppressants studied in clinical trials, with Phase II data showing over 10% weight loss — far exceeding other centrally-acting anti-obesity agents.

Tesofensine inhibits the reuptake of three key monoamine neurotransmitters — serotonin (5-HT), norepinephrine (NE), and dopamine (DA) — by blocking their respective transporters (SERT, NET, DAT). This triple reuptake inhibition produces a multifaceted appetite-suppressive effect: serotonin elevation reduces hunger and promotes satiety via hypothalamic 5-HT2C receptors, norepinephrine increases sympathetic tone and thermogenesis while reducing appetite via α1 receptors, and dopamine modulates the reward circuitry to reduce hedonic eating. The dopamine component is what distinguishes tesofensine from SSRIs or SNRIs — by reducing the drive to eat for pleasure (not just hunger), it addresses a major contributor to obesity. Tesofensine also increases resting energy expenditure by approximately 6% through sympathetic activation, providing a dual mechanism of reduced intake plus increased output. In preclinical studies, it also improved insulin sensitivity and lipid profiles independent of weight loss.

• Phase II TIPO-1 trial (2008, Lancet, n=203): 0.5 mg dose produced 11.3% body weight loss vs. 2.2% placebo over 24 weeks — the largest weight loss for any monotherapy drug at that time
• The 1.0 mg dose produced 12.8% weight loss but with more side effects
• Resting energy expenditure increased by 6% at the 0.5 mg dose
• Heart rate increased by an average of 7.4 bpm, the main safety signal
• Blood pressure was not significantly affected at the 0.5 mg dose
• Improved HbA1c and lipid profiles were observed independent of weight loss
• Phase III development has been initiated by Saniona under the name Tesomet (tesofensine + metoprolol to offset heart rate increase)

• Phase II trial doses: 0.25 mg, 0.5 mg, or 1.0 mg orally once daily
• The 0.5 mg dose showed the best efficacy-to-side-effect ratio in trials
• Take in the morning to avoid insomnia due to noradrenergic/dopaminergic stimulation
• No food timing restrictions for oral administration
• Typical cycle: 8–24 weeks based on Phase II trial durations
• Dose escalation from 0.25 mg for the first week may reduce initial side effects
• Half-life is approximately 8 days, requiring 4–6 weeks to reach steady state

Known Side Effects

• Increased heart rate (5–8 bpm on average) — the primary safety concern and reason for development delays
• Dry mouth (reported in 30–40% of participants)
• Insomnia and difficulty sleeping, especially at higher doses or with late-day dosing
• Constipation and gastrointestinal discomfort
• Headache and dizziness in the first 1–2 weeks
• Mood changes including anxiety or irritability (monoaminergic stimulation)
• Potential for abuse/dependence due to dopamine reuptake inhibition, though clinical data has not shown this

Safety Profile

Tesofensine's primary safety concern is cardiovascular — the heart rate increase of 5–8 bpm observed in trials prompted regulatory caution and contributed to development delays. This effect is attributed to norepinephrine reuptake inhibition increasing sympathetic tone. The combination product Tesomet pairs tesofensine with metoprolol (a beta-blocker) to specifically mitigate this issue. Blood pressure effects have been modest and not clinically significant. The dopamine reuptake inhibition raises theoretical addiction concerns, but clinical trials have not demonstrated abuse liability or withdrawal symptoms. Psychiatric monitoring is advisable given the monoaminergic mechanism. Tesofensine should not be combined with MAO inhibitors, SSRIs, or other serotonergic drugs due to serotonin syndrome risk. Not recommended in patients with uncontrolled hypertension, cardiac arrhythmias, or history of substance abuse.

Week 1–2: Appetite reduction is noticeable within days due to rapid monoamine effects. Some stimulant-like feelings — increased alertness, mild euphoria. Dry mouth is common. Potential for mild insomnia. Week 2–4: Appetite suppression becomes pronounced. Food portions decrease naturally. Weight loss begins (2–4 lbs). Heart rate may be slightly elevated. Dry mouth typically persists. Week 4–12: Steady weight loss of 1–2 lbs per week. Steady state is reached. Appetite is consistently reduced. Energy levels are generally improved. Side effects tend to stabilize or improve. Week 12–24: Continued weight loss reaching 10–13% of body weight. Metabolic markers improve. Body composition changes become visually apparent. Cravings for hyperpalatable foods significantly diminish.

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