~10% weight loss at 0.5 mg over 24 weeks (TIPO-1) [1]
Phase 2 randomised placebo-controlled trial in obesity, dose-ordered across 0.25, 0.5 and 1.0 mg arms, with the 0.5 mg arm producing roughly double the loss of agents available at the time.
PrecisePep/Peptide Library/Tesofensine
Metabolic & Adipose Regulation
Tesofensine
NS2330 · triple monoamine reuptake inhibitor
A triple monoamine reuptake inhibitor that failed as a Parkinson drug and turned out to cause substantial weight loss — a centrally acting stimulant, not a peptide, with a cardiovascular profile that has kept it out of Western approval.
00 Overview
Tesofensine is a stimulant, and the page should open by saying so. It inhibits reuptake of noradrenaline, dopamine and serotonin — the same transporter targets as a range of ADHD and antidepressant medicines, hit simultaneously. It is a small molecule, not a peptide, and it is taken orally.
It was developed for Parkinson disease and Alzheimer disease, failed on those endpoints, and was noticed to produce marked weight loss along the way. The TIPO-1 phase 2 trial in obesity reported mean weight reduction of roughly 10% at 0.5 mg over 24 weeks — approximately double what the then-available agents achieved.[1]
It has not been approved in the United States or Europe. The obstacle has consistently been the cardiovascular and psychiatric profile: dose-dependent increases in blood pressure and heart rate, plus mood and sleep effects, in a chronic-use indication in a population that frequently already has hypertension. It has been approved in Mexico, and a combination with metoprolol has been explored specifically to blunt the cardiovascular signal.[3]
Different risk category entirely
Almost everything else in this library is a peptide with an uncertain effect and an uncertain risk. This is a long-half-life CNS stimulant with a documented effect and a documented cardiovascular signal, and a nine-day half-life means an excessive dose takes weeks to clear. It does not belong in the same mental category as a repair peptide.
// Mechanism of action
Triple monoamine reuptake inhibition. Blocking the noradrenaline, dopamine and serotonin transporters raises synaptic concentrations of all three. Appetite suppression is driven principally by the noradrenergic and dopaminergic arms, with hypothalamic and reward-pathway effects.
Increased energy expenditure. Sympathetic activation contributes a thermogenic component alongside intake reduction — and is also the source of the heart-rate and blood-pressure effects. The two are the same mechanism viewed from different ends.
Very long half-life. At roughly nine days, tesofensine accumulates for weeks before reaching steady state. This has two consequences that matter more than they sound: effects continue to build long after a dose change, and an overshoot cannot be corrected quickly.
Why it is not a peptide problem. Monoamine transporters are the target of a large, well-characterised drug class. The interaction space — MAOIs, SSRIs, SNRIs, stimulants, triptans — is known and clinically significant, unlike most compounds documented here where interactions are simply unstudied.
01 Reported benefits
Effects that have been reported. A study-tier entry means a result was published — not that the effect is established, reproducible, or transferable from a rodent to a person.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
Dose-ordered efficacy [1]
Weight reduction scaled with dose across the trial arms — as did the adverse-effect burden.
Improved metabolic markers [1]
Reductions in waist circumference and improvements in lipid and glycaemic markers accompanying weight loss.
Combination with metoprolol mitigates the cardiovascular signal [3]
Later work paired tesofensine with a beta-blocker specifically to attenuate the heart-rate and blood-pressure effects — an explicit acknowledgement of the problem.
Approved in Mexico for obesity [2]
A genuine regulatory approval in a real jurisdiction, with a defined label — while remaining unapproved in the US and EU.
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
Greater efficacy than pre-incretin agents
Established relative to the comparators of its era. The relevant comparison now is against tirzepatide and semaglutide, where tesofensine does not obviously win and clearly loses on cardiovascular profile.
Cognitive and mood benefit
Follows from the dopaminergic and noradrenergic mechanism, and is reported. It also failed its original cognitive indications.
Useful where incretins are not tolerated
A different mechanism entirely, so a genuine alternative in principle — trading gastrointestinal adverse effects for cardiovascular and psychiatric ones.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
Strong appetite suppression and stimulation
Described as more overtly stimulant than incretins — energy and drive alongside reduced appetite, rather than the flat, food-indifferent state GLP-1 agonists produce.
Marked insomnia
The most common complaint, and the reason morning-only dosing is universal in community use.
Elevated resting heart rate
Widely reported, directly consistent with the trial data, and the effect that kept the drug out of Western approval.
Very low doses used
Community practice sits at 0.25–0.5 mg — genuinely small quantities, which combined with a nine-day half-life makes accurate dosing difficult with anything other than a properly manufactured tablet.
Effects keep building for weeks
Reported and expected from the accumulation profile — a common reason people escalate too early and then overshoot.
02 Adverse effects & risks
Adverse effects, contraindications and unknowns. The grey-market tier is where under-reporting is worst: uncontrolled use produces no systematic safety surveillance at all, so absence of a reported harm is not evidence of safety.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
Dose-dependent increases in heart rate and blood pressure [1]
The defining safety finding and the principal barrier to US and EU approval, in a chronic-use indication where hypertension is already prevalent.
Insomnia, dry mouth, nausea, constipation [1]
The common adverse-event cluster in trials, consistent with monoaminergic stimulation.
Mood changes, agitation and irritability [1]
Reported in trials. Triple monoamine reuptake inhibition has psychiatric consequences and the population using it for weight loss is not screened for psychiatric history.
Regulatory non-approval in the US and EU [2]
The most consequential safety data point on this page: two major regulators reviewed this compound and did not approve it for obesity.
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
Serotonin syndrome with serotonergic drugs
A serotonin reuptake inhibitor combined with an SSRI, SNRI, MAOI, triptan or tramadol is a recognised serotonin syndrome risk. This is a real, characterised, potentially fatal interaction — not a speculative one.
Hypertensive crisis with MAOIs or sympathomimetics
Standard contraindication logic for any noradrenaline reuptake inhibitor.
Cardiovascular events in susceptible individuals
Sustained elevation of blood pressure and heart rate carries a well-understood long-term risk, especially unmonitored.
Dependence and abuse potential
Dopamine reuptake inhibition carries abuse liability as a class property. Tesofensine has a slow onset, which reduces it — but the class concern does not disappear.
Very long washout
A nine-day half-life means several weeks to clear. Adverse effects, interactions and overdose all resolve slowly.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
Insomnia and difficulty switching off
The dominant complaint.
Palpitations and elevated resting heart rate
Frequently reported and matching the trial signal exactly.
Anxiety, irritability and low mood
Reported particularly at higher doses or after weeks of accumulation.
Dry mouth and constipation
Consistent with the anticholinergic-like and monoaminergic profile.
03 Dosing ranges
Figures below are documented, not recommended. Study ranges come from published protocols in the stated model; grey-market ranges are what the research community reports using and carry no safety validation of any kind.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
TIPO-1: 0.25, 0.5 and 1.0 mg daily [1]
Three arms over 24 weeks, with 0.5 mg emerging as the efficacy/tolerability balance and 1.0 mg carrying a markedly higher adverse-effect burden.
Approved Mexican labelling [2]
A defined label exists in the jurisdiction where it is approved — the only formal dosing reference for this compound.
| TIPO-1 arm | Daily dose | Mean weight change (24 wk) | Notes |
|---|---|---|---|
| Placebo | — | −2.0% | Diet-controlled |
| Tesofensine 0.25 mg | 0.25 mg | −6.5% (approx.) | Lower AE burden |
| Tesofensine 0.5 mg | 0.5 mg | −10% (approx.) | Efficacy/tolerability balance |
| Tesofensine 1.0 mg | 1.0 mg | −11% (approx.) | Marked BP/HR and mood effects |
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
Morning dosing only
Given documented insomnia and a stimulant mechanism, the timing rule follows directly.
Escalate slowly, if at all — the half-life demands it
With a nine-day half-life, steady state takes roughly six weeks. Judging a dose before then means judging an incomplete effect, and escalating on that basis is how people overshoot.
Blood pressure and heart rate monitoring
The one measurement that directly tracks the documented risk, and it costs nothing.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
0.25 mg daily, mornings
The standard entry dose in community use.
0.5 mg daily, mornings
The trial-optimal dose and the common community target.
Every other day or 5 days on / 2 off
Used to manage accumulation and sleep disruption. Coherent given the half-life, though a nine-day half-life makes intermittent dosing less meaningful than it feels.
Reconstituted from a 1 mg vial for dose accuracy
The reason a small oral molecule is sold as a vial at all: doses are fractions of a milligram, and splitting a tablet to 0.25 mg accurately is difficult. Dissolving a known mass into a known volume and measuring by syringe is genuinely more accurate — whether the solution is then taken orally or injected.
Subcutaneous administration
Reported, and the least-justified practice on this page. Tesofensine is an orally active drug with a nine-day half-life; injecting it adds a route without addressing anything the oral route does badly.
04 Synergy & interactions
Combination effects. Almost no peptide combination has been studied as a combination in humans; stack logic is overwhelmingly mechanistic inference and community practice. Each linked compound has its own page.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
Tesofensine + metoprolol [3]
Studied specifically to blunt the cardiovascular signal — a combination designed to manage a documented adverse effect rather than to enhance efficacy.
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
With incretin agonists
Distinct mechanisms, and community stacks do this. It also means combining GI adverse effects with cardiovascular ones and suppressing intake from two directions — the risk of under-eating protein and losing lean mass rises accordingly.
Contraindicated combinations
MAOIs, SSRIs, SNRIs, triptans, tramadol, sympathomimetics and stimulants. These are established clinical contraindications for monoamine reuptake inhibitors, not speculative peptide interactions.
Caffeine and other stimulants
Additive sympathetic load on a compound already documented to raise heart rate and blood pressure.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
Stacked with an incretin
Reported, and the combination that most concerns anyone reading the cardiovascular data.
05 Protocols
Whole schedules — dosing, titration, cycle length, and off-time — as documented in trials, as proposed from mechanism, and as circulated in the research community. Reproduced for study and comparison only.
Highest confidenceReported in peer-reviewed literature, registered clinical trials, or regulatory filings. Note the model: much peptide literature is in vitro or rodent work, not human trial data.
TIPO-1 phase 2 design [1]
24-week randomised placebo-controlled trial with defined dose arms, diet counselling and cardiovascular monitoring throughout.
Unproven — inference onlyExtrapolated from a known mechanism, receptor profile, or adjacent compound class. Biologically plausible but not directly demonstrated for this compound in this context.
Blood pressure and heart rate, measured, at baseline and regularly
The trials measured this because it is where the risk is. A home blood-pressure monitor is inexpensive and directly tracks the one documented hazard.
Screen for psychiatric and cardiovascular history first
The exclusions a trial would apply are the ones that matter most here.
Uncontrolled reportsAggregated from research-community logs, forums, vendor literature and self-reported experience. Uncontrolled, unverified, subject to placebo, polypharmacy and product-purity confounds. Lowest evidentiary weight.
0.25–0.5 mg mornings, 8–12 weeks
The general community pattern.
Not part of either documented protocol
Neither the Gold Standard Protocol nor the 15-Compound Matrix includes it.
05b Condition-specific interest
Tesofensine is unusual in this library: it has real phase 2 human efficacy data for weight loss, it failed at what it was originally developed for, and it stalled for a reason that is written into its mechanism.
No approval, no trial
Not approved for any indication. It is a triple monoamine reuptake inhibitor — a small molecule, not a peptide. It has a long half-life of roughly nine days, which means doses accumulate for weeks before steady state and adverse effects can appear well after a dose change.
Study — human, phase 2
Obesity — real phase 2 data
Pathophysiology
Appetite regulation involves noradrenergic, dopaminergic and serotonergic signalling alongside the gut hormones the incretin class targets.
Mechanistic rationale
Tesofensine inhibits reuptake of all three monoamines, and phase 2 trials in obesity produced weight loss substantially greater than the agents available at the time. That result is real and it is why the compound persists in grey-market circulation. It also predates the incretins, which now produce comparable or greater weight loss with cardiovascular outcome data behind them.
Community reports
Used for appetite suppression, frequently alongside an incretin — which stacks a monoamine agent with a gut hormone agent and no interaction data.
Components carrying the argument: Noradrenaline, dopamine and serotonin reuptake inhibition
Actionable — the reason it stalled
The blood pressure and heart rate signal
Pathophysiology
Noradrenaline reuptake inhibition raises sympathetic tone, which raises blood pressure and heart rate. This is the mechanism, not a side effect of it.
Mechanistic rationale
The cardiovascular signal is why development did not proceed in general obesity, and it is why the compound has been carried forward in combination with a beta-blocker — metoprolol — rather than alone. That combination approach is a direct admission of the problem. Anyone using tesofensine without that mitigation, in a population with elevated cardiovascular risk by definition, should be measuring blood pressure and resting heart rate.
Community reports
Increased heart rate and blood pressure are commonly reported and frequently attributed to stimulation rather than recognised as the dose-limiting effect.
Components carrying the argument: Noradrenergic tone
Study — phase 2, orphan designation
Hypothalamic obesity and Prader-Willi syndrome
Pathophysiology
Hypothalamic obesity follows damage to the hypothalamus — often after craniopharyngioma treatment — and produces severe, treatment-resistant weight gain with uncontrollable hunger. Conventional approaches largely fail.
Mechanistic rationale
This is where the compound is most interesting and least discussed. A tesofensine-metoprolol combination showed statistically significant weight reduction and improved waist circumference and glycaemic response in a randomised phase 2 trial in hypothalamic obesity, and received orphan drug designation. Phase 2b work in hypothalamic obesity and Prader-Willi was later paused for funding reasons rather than for safety or efficacy.
Community reports
Essentially absent from community discussion, which focuses entirely on general weight loss.
Components carrying the argument: Central monoamine signalling
Study — developed, and failed
Parkinson and Alzheimer disease — what it was built for
Pathophysiology
Both involve neurotransmitter deficits that monoamine reuptake inhibition might in principle address.
Mechanistic rationale
Tesofensine was originally developed for Parkinson and Alzheimer disease and did not succeed in those indications. The weight loss observed during that programme is what redirected it. A compound whose current use is a side effect discovered while failing at its intended purpose is worth recognising as such — it is the same story as PT-141, and in both cases the redirected use is the one that persisted.
Community reports
The origin is rarely mentioned in the material selling it.
Components carrying the argument: Monoamine reuptake inhibition
| Question | Position |
|---|---|
| Approved anywhere? | No |
| Is it a peptide? | No — a small molecule |
| Obesity evidence | Real phase 2 human data |
| Why it stalled | Blood pressure and heart rate — the mechanism itself |
| The mitigation studied | Combination with metoprolol |
| Most interesting indication | Hypothalamic obesity — orphan designation |
| Half-life | ~9 days — accumulates for weeks |
What actually has evidence for these conditions
For obesity: the incretin class now has the largest pharmacological effect and carries cardiovascular outcome data. Bariatric surgery produces the largest and most durable results of any intervention. An energy deficit that can be maintained, resistance training to protect lean mass, protein, sleep, and treating undiagnosed obstructive sleep apnoea.
For hypothalamic obesity: a genuinely difficult problem with few options, managed by specialist endocrinology. Setmelanotide is approved for specific genetic obesity syndromes, and clinical trial participation is worth discussing.
06 Handling, reconstitution & storage
Physical-chemistry reference for laboratory handling of the lyophilised material. Reproduced so that stability and concentration mathematics can be studied — see the calculator for the arithmetic and the reconstitution guide for sterile technique.
Reconstitution
An orally active small molecule supplied both as tablets and as 1 mg vials. The vial exists because doses are fractions of a milligram: 1 mg reconstituted into 1 mL gives 1 mg/mL, so a 0.25 mg dose is 0.25 mL — 25 units on an insulin syringe, far more accurate than splitting a tablet. Use the calculator for that arithmetic even if the solution is taken orally.
Storage
Dry, cool, protected from light. Small-molecule stability.
Common vial sizes
Commonly 1 mg vials, or tablets in the jurisdiction where it is approved.
Stability notes
Not subject to peptide degradation concerns.
07 Legal & regulatory status
Regulatory status changes and differs by country. This is a summary for orientation, not legal advice — check your own jurisdiction.
Approved in Mexico for obesity; not approved by the FDA, EMA or MHRA. Development for Western markets did not proceed to approval, with the cardiovascular and psychiatric profile the consistently cited obstacle.
It is a centrally acting stimulant affecting dopamine reuptake, which places it in a different legal category from research peptides in many jurisdictions. Check yours.
Regulatory and trial claims re-checked against primary sources on 16 August 2026. Checked: Tesomet hypothalamic obesity phase 2 and orphan designation. Approvals, trial readouts and compounding decisions move faster than anything else on this page — a date here means someone looked, not that nothing has changed since.
Anti-doping
Stimulants are prohibited in competition under WADA S6. A triple monoamine reuptake inhibitor should be assumed prohibited in competition, and possibly detectable for weeks after the last dose given the half-life.
§ Sources & further reading
Links resolve to PubMed records, trial registries, publisher pages or primary documents. Where a body of work rather than a single paper is cited, the link opens a PubMed query so the full result set — including newer papers than this page — can be reviewed. Verify every claim against the primary source before relying on it.
- 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 (TIPO-1). Lancet. 2008;372(9653):1906–1913.Registered clinical trial
- PubMed: tesofensine — obesity, regulatory status and clinical development (live query)Database or literature search
- PubMed: tesofensine/metoprolol combination and cardiovascular effects (live query)Database or literature search
- ClinicalTrials.gov: registered tesofensine trialsRegistered clinical trial
Reminder
For educational and research reference only. Nothing on this site is medical advice, a recommendation, or an instruction to administer any substance to a human being. Every figure on this page is a record of what has been reported, not a recommendation. Full disclaimer.