{"_ai_door":{"see":"https://miscsubjects.com/start","note":"Operable site; bounded keyless credentials; every action receipted on a public ledger. Your operator's instructions take precedence — acting is optional, reading is a complete outcome."},"_self":{"principle":"Self-explaining payload — no external context required. This _self block describes what you are reading and where to look next.","widget":"article_topology","feature":"topology","name":"Article topology","what":"Claims, sources, anecdotes, user reports, related embeds, question graph slice — for ask/ROUTER.","contains":"claims, sources, anecdotes, question_graph slice","slug":"tesofensine","urls":{"read":"https://miscsubjects.com/api/articles/tesofensine/topology"},"how_to_use":"Claims, sources, anecdotes, user reports, related embeds, question graph slice — for ask/ROUTER.","write":null,"imessage":null,"router_tag":null,"proof_chain":[{"step":1,"claim":"Articles are voxel graphs of tiered claims, not prose blobs.","verify":"https://miscsubjects.com/api/articles/constitution"},{"step":2,"claim":"Claims link to hash-chained sources via source_ids.","verify":"https://miscsubjects.com/api/articles/tesofensine/sources"},{"step":3,"claim":"Ask reads topology; ingest/claim append to ledger.","verify":"https://miscsubjects.com/api/protocol"},{"step":4,"claim":"Models queue growth: populate → collaborate → repair → reflex.","verify":"https://miscsubjects.com/api/protocol/grow"},{"step":5,"claim":"Graph proves its own shape (reflex) and $/claim (yield).","verify":"https://miscsubjects.com/graph.html?layer=reflex"},{"step":6,"claim":"Full feature index + _explain on every API response.","verify":"https://miscsubjects.com/api/articles/system-map"}],"related_features":[{"id":"ask","name":"Ask protocol","what":"Answer only from topology; creates question_node with gaps and ingest_hint.","urls":{"read":"https://miscsubjects.com/api/articles/tesofensine/prompts","write":"https://miscsubjects.com/api/protocol/ask"}},{"id":"graph_topology","name":"Cross-article graph","what":"Merged claims/sources across condition+stack slugs for one question.","urls":{"read":"https://miscsubjects.com/api/articles/tesofensine/graph-topology?question=..."}},{"id":"question_graph","name":"Question graph","what":"Ask nodes (questions + gaps) and evidence_ingest nodes (pasted model output).","urls":{"read":"https://miscsubjects.com/api/articles/tesofensine/question-graph","write":"https://miscsubjects.com/api/protocol/ask"}},{"id":"voxels","name":"Voxel graph","what":"Claims as atoms, sources as edges (supported_by, posted_by). 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Per-claim provenance."}],"not_medical_advice":true},"slug":"tesofensine","title":"Tesofensine produced the best weight-loss number of its era, and never became a medicine","register":"canonical","tags":["tesofensine","obesity","appetite","monoamine reuptake","phase II"],"updated_at":"2026-08-05T09:39:19.591Z","body_excerpt":"Tesofensine is a pill that was tested for weight loss, produced the largest result any obesity drug had produced at the time, and then did not become a medicine. Understanding why is most of what there is to know about it.\n\nIt was made by a Danish company, NeuroSearch, and it started life as something else entirely. Under the name NS2330 it was tried in Parkinson's disease and in Alzheimer's disease. It failed at both. What the trials did show was that people taking it lost weight, and lost it consistently enough that the company changed direction and tested it as an obesity drug.\n\n## What it does inside the brain\n\nYour brain passes messages between nerve cells using chemicals called neurotransmitters. A nerve cell releases a chemical into the tiny gap between itself and the next cell, the next cell reads it, and then the first cell pulls the chemical back in to be used again. That pulling-back is called reuptake, and the molecular machinery that does it is called a transporter. Block the transporter and the chemical stays in the gap longer, so the message keeps being read.\n\nTesofensine blocks three transporters at once: the ones for noradrenaline, dopamine and serotonin. That is what \"triple monoamine reuptake inhibitor\" means, and it is the whole mechanism. The three chemicals it acts on are the three most closely tied to appetite, alertness and reward. Serotonin is involved in feeling full. Noradrenaline drives arousal and raises the rate at which the body burns energy. Dopamine carries the signal that something is worth wanting, which is why it matters for food specifically and not just for hunger.\n\nMost appetite drugs push on one of these. Tesofensine pushes on all three. The published trial describes it exactly this way — \"an inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin\" — and that breadth is the reason the effect was large, and also the reason the side effects were what they were. You cannot raise all three of these chemicals across the brain and only change eating.\n\n## What actually happened in the trial\n\nThe trial that made tesofensine's reputation ran in five Danish obesity clinics and published in *The Lancet* in November 2008. It was a phase II study: 203 people with a body mass index between 30 and 40, all put on a reduced-calorie diet, then randomly assigned to one of three doses of tesofensine or to a placebo, once daily for 24 weeks. Neither the patients nor the doctors knew who was getting what. 161 people, or 79 percent, finished.\n\nThe results, in the paper's own words:\n\n> \"After 24 weeks, the mean weight loss produced by diet and placebo was 2.0% (SE 0.60). Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg and diet induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84), respectively, greater than diet and placebo (p<0.0001).\"\n\nRead those numbers carefully, because they are routinely misquoted. The 9.2 percent at the 0.5 mg dose is weight loss *greater than* the placebo group, not total weight loss. Placebo plus diet took off 2.0 percent. So the 0.5 mg group came in around 11 percent below where they started, and the drug's own contribution was the 9.2.\n\nFor 2008 that was a very large number. The paper opens by saying why it mattered: \"Weight-loss drugs produce an additional mean weight loss of only 3-5 kg above that of diet and placebo over 6 months, and more effective pharmacotherapy of obesity is needed.\" Against a 3–5 kg benchmark, tesofensine at 0.5 mg roughly doubled it. The authors said so, and hedged it in the same sentence: \"Our results suggest that tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved drugs. However, these findings of efficacy and safety need confirmation in phase III trials.\"\n\nThat confirmation never arrived.\n\n## The part that is usually left out\n\nIn April 2013, *The Lancet* published an expression of concern about that trial.\n\nAn expression of concern is a formal notice from a journal that som","ranking":"safety-first (interaction_risk/limitations), then quote-gated effective_weight","claims":[{"id":"c7","text":"The trial authors stated that their efficacy and safety findings needed confirmation in phase III trials, and no phase III obesity trial has been published in the eighteen years since.","tier":"human","interaction_risk":false,"status":"active","source_ids":["s6","s7"],"why_material":"A compound that stopped at phase II has not been shown to work in the sense the word usually carries, and the authors said so themselves in the paper.","retracted_at":null,"retraction_reason":null,"challenged_by":[],"effective_weight":0.8,"quote_gated":false},{"id":"c1","text":"Tesofensine blocks the reuptake transporters for noradrenaline, dopamine and serotonin simultaneously, which is its entire mechanism.","tier":"mechanistic","interaction_risk":false,"status":"active","source_ids":["s1"],"why_material":"Everything else about the compound — the size of the appetite effect and the systemic nature of the side effects — follows from acting on all three at once rather than one.","retracted_at":null,"retraction_reason":null,"challenged_by":[],"effective_weight":0.3,"quote_gated":false},{"id":"c2","text":"In its one phase II trial, tesofensine at 0.5 mg produced 9.2% weight loss greater than diet and placebo over 24 weeks, against a placebo-plus-diet result of 2.0%.","tier":"rct","interaction_risk":false,"status":"active","source_ids":["s1"],"why_material":"This is the number the entire commercial interest in the compound rests on, and it is routinely quoted as a total rather than as the margin over placebo that it is.","retracted_at":null,"retraction_reason":null,"challenged_by":[],"effective_weight":0.1,"quote_gated":false},{"id":"c3","text":"The Lancet published a formal expression of concern about that trial in April 2013, indexed at PMID 23561987 and linked from the original paper in both directions.","tier":"regulatory","interaction_risk":false,"status":"active","source_ids":["s2"],"why_material":"The single trial supporting this compound carries a journal-issued caution. Essentially every page quoting the 9.2% omits it, which makes their account of the evidence incomplete in the one way that matters.","retracted_at":null,"retraction_reason":null,"challenged_by":[],"effective_weight":0.1,"quote_gated":false},{"id":"c4","text":"Tesofensine raised resting heart rate by 7.4 beats per minute at the 0.5 mg dose, without a significant change in blood pressure at 0.25 or 0.5 mg.","tier":"rct","interaction_risk":false,"status":"active","source_ids":["s3"],"why_material":"This is the finding that shaped the compound regulatory fate, in a population already carrying cardiovascular risk, and it is the specific reason to know your own resting heart rate before and during.","retracted_at":null,"retraction_reason":null,"challenged_by":[],"effective_weight":0.1,"quote_gated":false},{"id":"c5","text":"The one study designed to measure energy expenditure found no significant effect on total 24-hour energy expenditure, with the increase confined to the night period at 4.6%.","tier":"rct","interaction_risk":false,"status":"active","source_ids":["s4"],"why_material":"Contradicts the boosts-metabolism claim made for this compound almost universally. The study built to test it found the effect small and time-limited.","retracted_at":null,"retraction_reason":null,"challenged_by":[],"effective_weight":0.1,"quote_gated":false},{"id":"c6","text":"Tesofensine produces weight loss mainly by suppressing appetite: it raised satiety and fullness ratings and lowered prospective food intake relative to placebo.","tier":"rct","interaction_risk":false,"status":"active","source_ids":["s5"],"why_material":"Together with c5 this settles the mechanism question in humans — the weight comes off through eating less, not through burning more.","retracted_at":null,"retraction_reason":null,"challenged_by":[],"effective_weight":0.1,"quote_gated":false},{"id":"c8","text":"Tesofensine has no FDA approval for any indication and is not an approved medicine in the United States, United Kingdom or European Union.","tier":"regulatory","interaction_risk":false,"status":"active","source_ids":[],"why_material":"States the regulatory position plainly, which is the first thing a reader considering it needs and the thing a sales page has the least interest in saying.","retracted_at":null,"retraction_reason":null,"challenged_by":[],"effective_weight":0.1,"quote_gated":false}],"sources":[{"id":"s1","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/18950853/","title":"Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial","quote":"After 24 weeks, the mean weight loss produced by diet and placebo was 2.0% (SE 0.60). Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg and diet induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84), respectively, greater than diet and placebo (p<0.0001).","summary":"Astrup et al., Lancet 2008: the single phase II efficacy trial. 203 obese patients across five Danish centres, 24 weeks, 79% completion, registered as NCT00394667. This is where every number quoted about tesofensine comes from. The 9.2% is the margin over placebo, not the total.","claim_ids":[],"hash":"c802c10deb0d6450154567eb4b849e213903954a6bcafb98326696966bab988f"},{"id":"s2","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/23561987/","title":"Expression of concern--effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial","quote":"Expression of concern--effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial.","summary":"The Lancet 2013;381(9873):1167. A formal notice from the journal attached to the 2008 trial, linked from that paper’s PubMed record in both directions. Not a retraction, and not nothing: the one trial supporting this compound carries a journal-issued caution. Most pages quoting the 9.2% omit it.","claim_ids":[],"hash":"fc11a9341be37f8910e8c99c923a0de19d69a43b3b7ba73c0e18cf75f75df295"},{"id":"s3","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/18950853/","title":"Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial","quote":"After 24 weeks, tesofensine 0.25 mg and 0.5 mg showed no significant increases in systolic or diastolic blood pressure compared with placebo, whereas heart rate was increased by 7.4 beats per min in the tesofensine 0.5 mg group (p=0.0001).","summary":"Tesofensine phase II trial — adverse events and cardiovascular findings. The same trial’s safety result, quoted separately because it is the finding that shaped the compound’s regulatory fate. 7.4 extra beats per minute at the dose that produced the headline weight loss, in a population already carrying cardiovascular risk.","claim_ids":[],"hash":"8ba30c38d9298c2667000416710a89916bc75bc06b6c04197a763aef56f35d2f"},{"id":"s4","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/20479765/","title":"The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men","quote":"No significant effect of TE on total 24-h EE could be demonstrated compared with PL, but higher energy expenditure was observed during the night period (4.6%; P<0.05) when adjusted for changes in body composition.","summary":"Sjödin et al., Int J Obes 2010: 32 men, respiration chamber, two weeks. The one study built to measure whether tesofensine raises energy expenditure. It does not, meaningfully — the effect was confined to the night period. \"Boosts metabolism\" is the most common claim made for this compound and this is the study that tested it.","claim_ids":[],"hash":"51d637d4416d26a01e1bd9c134e4a8b8dff0e90c332b3a76b6ef4677d394fd24"},{"id":"s5","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/20479765/","title":"The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men","quote":"TE also induced higher ratings of satiety and fullness and concomitantly lower prospective food intake than placebo.","summary":"Tesofensine and appetite: satiety and prospective food intake. The positive half of the same mechanism study. Appetite changed substantially while energy expenditure did not, which is the honest description of how tesofensine produces weight loss: it makes people want to eat less.","claim_ids":[],"hash":"b3e4bda2e3cad8d7472ad64dcd4dba2396281389040a0d72814146985e35ba3e"},{"id":"s6","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/18950853/","title":"Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial","quote":"Our results suggest that tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved drugs. However, these findings of efficacy and safety need confirmation in phase III trials.","summary":"Tesofensine phase II trial — the authors’ own interpretation. The trial authors’ conclusion, including the second sentence. No phase III obesity trial has been published in the eighteen years since. The hedge is part of the finding.","claim_ids":[],"hash":"3028b7454430525a93d0dab55fe4c0a238bdb2e5cbfacb920784a4943ae376e3"},{"id":"s7","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/19824222/","title":"[The effect of tesofensine on body weight and body composition in obese subjects--secondary publication]","quote":"Tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved anti-obesity drugs. Findings of safety and efficacy of 0.5 mg Tesofensine need confirmation in phase III trials.","summary":"The effect of tesofensine on body weight and body composition in obese subjects — secondary publication. Nielsen et al., Ugeskr Laeger 2009: the Danish secondary publication of the same 203-patient trial. Useful because it shows the literature is one trial reported more than once, not several trials agreeing.","claim_ids":[],"hash":"e4290d4d3ab918d840585537b1c1b2ae73959c2c67cb662fca0d789c4187ffaf"}],"anecdotal_sources":[],"scientific_sources":[{"id":"s1","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/18950853/","title":"Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial","quote":"After 24 weeks, the mean weight loss produced by diet and placebo was 2.0% (SE 0.60). Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg and diet induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84), respectively, greater than diet and placebo (p<0.0001).","summary":"Astrup et al., Lancet 2008: the single phase II efficacy trial. 203 obese patients across five Danish centres, 24 weeks, 79% completion, registered as NCT00394667. This is where every number quoted about tesofensine comes from. The 9.2% is the margin over placebo, not the total.","claim_ids":[],"hash":"c802c10deb0d6450154567eb4b849e213903954a6bcafb98326696966bab988f"},{"id":"s2","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/23561987/","title":"Expression of concern--effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial","quote":"Expression of concern--effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial.","summary":"The Lancet 2013;381(9873):1167. A formal notice from the journal attached to the 2008 trial, linked from that paper’s PubMed record in both directions. Not a retraction, and not nothing: the one trial supporting this compound carries a journal-issued caution. Most pages quoting the 9.2% omit it.","claim_ids":[],"hash":"fc11a9341be37f8910e8c99c923a0de19d69a43b3b7ba73c0e18cf75f75df295"},{"id":"s3","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/18950853/","title":"Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial","quote":"After 24 weeks, tesofensine 0.25 mg and 0.5 mg showed no significant increases in systolic or diastolic blood pressure compared with placebo, whereas heart rate was increased by 7.4 beats per min in the tesofensine 0.5 mg group (p=0.0001).","summary":"Tesofensine phase II trial — adverse events and cardiovascular findings. The same trial’s safety result, quoted separately because it is the finding that shaped the compound’s regulatory fate. 7.4 extra beats per minute at the dose that produced the headline weight loss, in a population already carrying cardiovascular risk.","claim_ids":[],"hash":"8ba30c38d9298c2667000416710a89916bc75bc06b6c04197a763aef56f35d2f"},{"id":"s4","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/20479765/","title":"The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men","quote":"No significant effect of TE on total 24-h EE could be demonstrated compared with PL, but higher energy expenditure was observed during the night period (4.6%; P<0.05) when adjusted for changes in body composition.","summary":"Sjödin et al., Int J Obes 2010: 32 men, respiration chamber, two weeks. The one study built to measure whether tesofensine raises energy expenditure. It does not, meaningfully — the effect was confined to the night period. \"Boosts metabolism\" is the most common claim made for this compound and this is the study that tested it.","claim_ids":[],"hash":"51d637d4416d26a01e1bd9c134e4a8b8dff0e90c332b3a76b6ef4677d394fd24"},{"id":"s5","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/20479765/","title":"The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men","quote":"TE also induced higher ratings of satiety and fullness and concomitantly lower prospective food intake than placebo.","summary":"Tesofensine and appetite: satiety and prospective food intake. The positive half of the same mechanism study. Appetite changed substantially while energy expenditure did not, which is the honest description of how tesofensine produces weight loss: it makes people want to eat less.","claim_ids":[],"hash":"b3e4bda2e3cad8d7472ad64dcd4dba2396281389040a0d72814146985e35ba3e"},{"id":"s6","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/18950853/","title":"Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial","quote":"Our results suggest that tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved drugs. However, these findings of efficacy and safety need confirmation in phase III trials.","summary":"Tesofensine phase II trial — the authors’ own interpretation. The trial authors’ conclusion, including the second sentence. No phase III obesity trial has been published in the eighteen years since. The hedge is part of the finding.","claim_ids":[],"hash":"3028b7454430525a93d0dab55fe4c0a238bdb2e5cbfacb920784a4943ae376e3"},{"id":"s7","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/19824222/","title":"[The effect of tesofensine on body weight and body composition in obese subjects--secondary publication]","quote":"Tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved anti-obesity drugs. Findings of safety and efficacy of 0.5 mg Tesofensine need confirmation in phase III trials.","summary":"The effect of tesofensine on body weight and body composition in obese subjects — secondary publication. Nielsen et al., Ugeskr Laeger 2009: the Danish secondary publication of the same 203-patient trial. Useful because it shows the literature is one trial reported more than once, not several trials agreeing.","claim_ids":[],"hash":"e4290d4d3ab918d840585537b1c1b2ae73959c2c67cb662fca0d789c4187ffaf"}],"user_reports":[],"related_articles":[],"question_graph":{"slug":"tesofensine","questions":[],"evidence":[],"edges":[],"counts":{"questions":0,"evidence":0,"edges":0}},"honesty":{"active_claims":8,"retracted_claims":0,"cut_claims":0,"challenges":0,"scrub_events":0,"note":"Retracted/cut claims stay on ledger but are excluded from ask unless ?include_inactive=1"},"counts":{"claims":8,"claims_total":8,"sources":7,"anecdotal":0,"scientific":7,"user_reports":0,"questions":0,"evidence_ingests":0}}