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Blocking it in obese mice made them lose fat. It has never been given to a person in a published trial.\n\nThat is the whole compound in three sentences, and the interesting part is not the fat loss. It is the junction.\n\n## What NNMT actually does, and why blocking it does several things at once\n\nThe enzyme is nicotinamide N-methyltransferase, NNMT. Its job is simple to state: it takes nicotinamide — a form of vitamin B3 — and attaches a methyl group to it. A methyl group is a single carbon with three hydrogens, the smallest chemical tag cells use to mark things. The result is 1-methylnicotinamide, which the cell then excretes.\n\nSo NNMT is a disposal enzyme. It takes vitamin B3 and throws it away in a form that cannot be recycled.\n\nNow look at what it consumes doing that, because this is where the compound gets interesting. The Nature paper that identified the target explains it precisely: \"NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation.\"\n\nUnpack that and you get three separate consequences of one enzyme running.\n\n**It destroys NAD⁺ precursor.** Nicotinamide is the raw material your cell uses to make NAD⁺, the molecule that carries electrons in every energy-producing reaction you run. Methylating nicotinamide takes it permanently out of that supply chain. Every NAD⁺ booster sold — nicotinamide riboside, NMN, plain niacinamide — is an attempt to push more material into the front of that chain. Inhibiting NNMT is an attempt to stop material leaking out of the back of it.\n\n**It burns through SAM.** S-adenosylmethionine is the cell's universal methyl donor. It is what marks DNA and histones — the proteins your DNA is wound around — and those marks determine which genes are switched on. Every methylation reaction in your cell competes for the same SAM pool. An enzyme consuming SAM at high rates to dispose of vitamin B3 is spending a budget that gene regulation also draws on.\n\n**It competes with polyamine synthesis.** SAM also supplies propylamine for making polyamines — spermidine and spermine — which the paper notes have \"a major role in energy metabolism.\"\n\nSo one enzyme, three currencies. Inhibit it and all three should move at once. That is unusual, and it is why NNMT attracted interest as a target rather than as a curiosity.\n\n## The finding that started it\n\nThe 2014 Nature paper did not set out to study NNMT. It was looking at Glut4, the glucose transporter that fat cells lose in obesity and diabetes. Using gene arrays across mice engineered to lack or overexpress Glut4 in fat, the authors found \"that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene.\"\n\nMost strongly, out of the whole array. That is the kind of result that redirects a laboratory. Then: \"We report that NNMT expression is increased in WAT and liver of obese and diabetic mice.\"\n\nAnd the experiment that made it a drug target: \"Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure.\"\n\nNote the mechanism named in that sentence. Not reduced appetite — increased energy expenditure. The mice were not eating less; their cells were spending more.\n\nThe paper then traced the pathway all the way through, and this is why it is a genuinely strong piece of work rather than an association. \"NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue.\" So the SAM that was being spent on disposal became available, showed up as changed histone marks, and those marks turned up the enzymes that control polyamine flux.\n\nThen they confirmed it in urine: \"Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism.\"\n\nThat last step is what separates a mechanism from a story. They predicted a specific waste product should appear if their model was right, and it appeared.\n\nFinally, oxygen consumption — the direct measure of a cell burning fuel — rose, \"in an ODC-, SSAT- and PAO-dependent manner.\" Knock out the polyamine enzymes and the effect disappears, which demonstrates the pathway is the cause rather than a bystander.\n\nThe paper's own summary of what NNMT is: \"a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.\"\n\n## Where 5-amino-1MQ comes in\n\nThe 2014 work used genetic knockdown, which is not a drug. Turning it into one required a molecule that could get inside a cell, hit NNMT and not hit everything adjacent to it. That is the 2018 paper in *Biochemical Pharmacology*, and its title is the finding: \"Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice.\"\n\nThree words in that title carry the work. **Membrane-permeable**: NNMT is inside the cell, so an inhibitor that cannot cross the membrane is useless regardless of how well it binds. **Selective**: the compound has to leave alone the structurally similar methyltransferases and the NAD⁺ salvage enzymes, or the effect is not attributable to NNMT. **Reverse**: the mice were already obese when treatment began.\n\nThe authors describe testing exactly those properties: \"we investigated the permeability, selectivity, mechanistic, and physiological properties of a series of small molecule NNMT inhibitors. Membrane permeability of NNMT inhibitors was characterized using parallel artificial membrane permeability and Caco-2 cell assays. Selectivity was tested against structurally-related methyltransferases and nicotinamide adenine dinucleotide (NAD+) salvage pathway enzymes.\"\n\nThat is a careful drug-discovery paper rather than an enthusiastic one. Permeability measured two independent ways, selectivity measured against the enzymes most likely to confound the result.\n\nThe doses in that work were given by injection, several times daily, over days. That is the only dosing evidence that exists for this compound, and it is in mice.\n\n## Why the three currencies matter more than the fat loss\n\nIt is worth staying with the mechanism, because it is the reason this compound is discussed at all and it is almost always skipped in favour of the weight number.\n\n**NAD⁺.** Every reaction that extracts energy from food hands electrons to NAD⁺. It also feeds the sirtuins, a family of enzymes that strip acetyl marks off proteins and cannot work without it, and PARP enzymes that repair damaged DNA and consume it heavily. NAD⁺ falls with age, and the entire supplement industry built on nicotinamide riboside and NMN exists to push more precursor into the front of that pathway. NNMT sits at the other end, quietly disposing of the same precursor. Blocking a leak and opening a tap are different interventions with the same intended effect, and nobody has compared them in a person.\n\n**SAM.** Every methylation reaction in the cell — on DNA, on histones, on neurotransmitters, on phospholipids — draws from one shared pool of S-adenosylmethionine. That means these reactions compete. An enzyme spending SAM at high rates to throw away vitamin B3 is a competitor for the budget gene regulation uses, and the 2014 paper measured exactly that consequence: inhibiting NNMT changed histone H3 lysine 4 methylation in fat tissue. Gene expression shifted because a methyl budget was freed.\n\nThat is the part to sit with. This is not a drug that changes one number. It changes which genes are marked, in a tissue, by changing how a shared resource is spent. That is a powerful mechanism and it is precisely why the unstudied long-term consequences are not a formality.\n\n**Polyamines.** Spermidine and spermine are involved in cell growth, autophagy and energy metabolism, and their flux is controlled by the rate-limiting enzymes the paper names — ODC, SSAT and polyamine oxidase. The oxygen-consumption increase in treated adipocytes disappeared when those enzymes were blocked, which is the strongest single piece of evidence in the whole literature that the polyamine arm is doing the work rather than accompanying it.\n\n## What the mouse numbers are and are not\n\nThe figures that circulate for this compound — body weight down, white fat mass down, adipocytes smaller, cholesterol lower, food intake unchanged — come from the 2018 small-molecule work in diet-induced obese mice, given by injection several times daily over days.\n\nTwo things about them. The unchanged food intake is the load-bearing detail, because it means the effect was on expenditure rather than on appetite, which is what the mechanism predicts and what makes the result internally consistent. And the species gap for metabolic endpoints is the widest in pharmacology: a mouse runs its metabolism several times faster per unit of mass than you do, carries proportionally far more brown fat, and is mildly cold-stressed at ordinary laboratory temperature, all of which flatter interventions that raise energy expenditure. That is the specific reason a long list of compounds that transformed mice did nothing in people.\n\nSo the numbers are real measurements of a real effect in an animal whose energy metabolism does not work like yours. Enough to justify pursuing the target. Not enough to predict a person.\n\n## What a page selling this will not tell you\n\n**There are no human trials.** Not one. Not a phase I, not a safety study, not a pharmacokinetic run. Every number attached to 5-amino-1MQ came out of a mouse or a dish.\n\n**The core evidence is a knockdown, not the drug.** The Nature paper's mechanistic depth — the histone marks, the polyamine flux, the diacetylspermine in urine, the enzyme-dependency controls — is all from genetic knockdown of NNMT. The small-molecule paper shows a molecule can reproduce the physiological outcome. It does not re-establish the whole mechanism.\n\n**NNMT is not only in fat.** The 2014 paper reports NNMT elevated in white adipose tissue *and liver*. The enzyme is also expressed in other tissues and is studied heavily in cancer biology, where its role is not a simple one. Inhibiting a methyltransferase that influences histone methylation is not a local intervention, and the long-term consequences of shifting the SAM budget across tissues have not been studied in any species.\n\n**It is not a NAD⁺ booster, and it is not a peptide.** It is a small molecule that stops NAD⁺ precursor being thrown away. That is a different mechanism from supplying more precursor, and the two have never been compared head to head in a person. It is also constantly sold as a peptide. It is not one — no amino acid chain, no injection requirement from its chemistry.\n\n**The regulation runs on glucose.** A 2020 study found NNMT expression in adipocytes responds to glucose availability, with glucose deprivation increasing it. So the enzyme this compound blocks is itself under nutritional control, which means baseline diet is a variable in any effect and nobody has measured how large a one.\n\n## The interactions worth reasoning about, and why they cannot be listed\n\nNo drug-interaction work has been published for this compound. The enzymes that metabolise it, its half-life, its plasma protein binding — none of that exists in the literature, so anyone giving you a specific interaction list has written it rather than read it. What can be reasoned about is the mechanism, and three things follow from it.\n\n**Anything else acting on the NAD⁺ pool.** Nicotinamide riboside, NMN, plain nicotinamide and niacin all push precursor into the pathway NNMT drains. Combining them is not obviously harmful and it is entirely unstudied, and there is a specific reason to be curious rather than confident: plain nicotinamide at high doses is itself a substrate for NNMT, so the interaction is not simply additive. Nobody has measured which way it goes.\n\n**Anything competing for the SAM pool.** SAM-e as a supplement, methylfolate, methylcobalamin, betaine and choline all sit in the methylation economy, and so do the drugs that draw on it heavily — levodopa consumes SAM through COMT-mediated methylation, and so do several others. The whole premise of inhibiting NNMT is to change how a shared methyl budget is spent, which makes anything else spending from that budget a genuine unknown rather than a theoretical one.\n\n**Anything acting on polyamines or autophagy.** Spermidine supplementation is sold on the same shelf and acts on the arm of this mechanism the 2014 paper showed to be load-bearing. Pushing the same pathway from two directions with no human data on either is compounding an unknown.\n\nThe honest summary of the interaction section is that there is nothing to report and specific reasons to expect the interactions are not trivial. That is more useful than a confident list somebody invented.\n\n## What it is genuinely useful for thinking about\n\nThe reason to know about NNMT is not that 5-amino-1MQ works. It is that the enzyme is the clearest published example of a single node where energy metabolism, gene regulation and polyamine flux intersect — and the 2014 paper walked the whole chain, from gene array to histone mark to urinary metabolite to oxygen consumption, with the controls to show the pathway was load-bearing.\n\nWhat is unresolved is everything about the drug. Whether a person tolerates NNMT inhibition, at what dose, with what effect on the tissues where the enzyme does something other than dispose of vitamin B3, and whether the fat-loss effect survives translation out of an animal whose metabolic rate is several times yours. Those are not gaps in the reading. They are experiments that have not been run.\n\n## The name, and one thing it tells you\n\nThe name is a chemical description, and reading it is worth thirty seconds because it explains what the molecule is doing.\n\n1MQ is 1-methylquinolinium — a quinoline ring carrying a methyl group on its nitrogen, which gives the nitrogen a permanent positive charge. The \"5-amino\" is an amine group added at the fifth position on that ring.\n\nNow compare that to the enzyme's actual product. NNMT takes nicotinamide and methylates its ring nitrogen, producing 1-methylnicotinamide — a ring with a methylated, positively charged nitrogen. 5-amino-1MQ is a close structural imitation of that product, which is why it binds where it does. It is a product-mimicking inhibitor: the enzyme's own output, rebuilt in a form it cannot let go of.\n\nTwo practical things follow. It is a small aromatic molecule, not a peptide, whatever the shelf it is sold on says. And its permanent positive charge is precisely why the 2018 paper had to measure membrane permeability two separate ways — permanently charged molecules cross membranes poorly as a rule, and NNMT is inside the cell, so permeability was the real obstacle rather than binding. That the compound crosses at all is the actual achievement of that paper.\n\nEverything above is what the published record supports. None of it is medical advice, and 5-amino-1MQ is sold for research use only, not for human consumption.\n","claims":[{"id":"c9","text":"No human trial of 5-amino-1MQ has been published — no phase I, no safety study, no pharmacokinetic run — and the deepest mechanistic evidence comes from genetic knockdown rather than from the drug.","tier":"human","effective_weight":0.8,"source_ids":["s1","s6"]},{"id":"c1","text":"NNMT is a disposal enzyme: it methylates nicotinamide, vitamin B3, into a form the cell excretes and cannot recycle back into NAD+.","tier":"mechanistic","effective_weight":0.3,"source_ids":["s2"]},{"id":"c2","text":"One enzyme consumes three currencies at once — NAD+ precursor, the shared SAM methyl pool, and the propylamine that polyamine synthesis draws on — so blocking it moves all three together.","tier":"mechanistic","effective_weight":0.3,"source_ids":["s2"]},{"id":"c3","text":"NNMT emerged as the most strongly reciprocally regulated gene in a DNA array study that was investigating Glut4, not NNMT.","tier":"animal","effective_weight":0.1,"source_ids":["s5"]},{"id":"c4","text":"Genetic knockdown of Nnmt in white adipose tissue and liver protected mice from diet-induced obesity by increasing cellular energy expenditure, not by reducing food intake.","tier":"animal","effective_weight":0.1,"source_ids":["s1"]},{"id":"c5","text":"The 2014 pathway was traced end to end: freed SAM changed histone H3 lysine 4 methylation, which upregulated the polyamine enzymes ODC and SSAT.","tier":"animal","effective_weight":0.1,"source_ids":["s3"]},{"id":"c6","text":"The predicted polyamine metabolite diacetylspermine appeared in urine and adipocyte secretion, and the increase in oxygen consumption disappeared when the polyamine enzymes were blocked.","tier":"animal","effective_weight":0.1,"source_ids":["s4"]},{"id":"c7","text":"5-amino-1MQ was first tested as a molecule in living animals in 2018, in mice that were already obese, by injection over days.","tier":"animal","effective_weight":0.1,"source_ids":["s6"]},{"id":"c8","text":"Membrane permeability was the real obstacle rather than binding, because 5-amino-1MQ carries a permanent positive charge and NNMT is inside the cell; it was measured two independent ways.","tier":"in-vitro","effective_weight":0.1,"source_ids":["s7"]},{"id":"c10","text":"NNMT expression in adipocytes is itself regulated by glucose availability, with glucose deprivation raising it about twofold.","tier":"cell","effective_weight":0.1,"source_ids":["s8"]}],"sources":[{"id":"s1","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/24717514/","title":"Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity","summary":"Kraus et al., Nature 2014. The paper that made NNMT a target. Note the named mechanism: increased energy expenditure, not reduced appetite. This is genetic knockdown, not the drug.","quote":"Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure.","hash":"9d042c569bd8f77b"},{"id":"s2","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/24717514/","title":"Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity","summary":"The three currencies one enzyme consumes. Why blocking one disposal enzyme moves three things at once: NAD+ precursor stops being destroyed, the shared methyl budget stops being spent on disposal, and polyamine synthesis stops competing for it. This is the reason NNMT is interesting rather than incidental.","quote":"NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation.","hash":"1f2b86e9788cbef8"},{"id":"s3","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/24717514/","title":"Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity","summary":"The pathway traced from histone mark to urinary metabolite. The freed methyl budget showed up as changed histone marks, and those marks turned up the polyamine enzymes. This is the step that makes the paper a mechanism rather than an association — and the reason to take the unstudied long-term consequences seriously, since gene marking is what changed.","quote":"NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue.","hash":"e307d1913a0c6196"},{"id":"s4","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/24717514/","title":"Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity","summary":"The predicted waste product, found in urine. They predicted a specific metabolite should appear if the model was right, and it appeared. Oxygen consumption then rose in an ODC-, SSAT- and PAO-dependent manner, so blocking the polyamine enzymes abolished the effect — the pathway is load-bearing rather than incidental.","quote":"Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism.","hash":"7c36d242e640b091"},{"id":"s5","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/24717514/","title":"Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity","summary":"How the target was found — it was not being looked for. The study was about Glut4, the glucose transporter fat cells lose in obesity. NNMT came out of the array as the most strongly regulated gene of all, which is the kind of result that redirects a laboratory.","quote":"Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls.","hash":"c1948f6bc0442ac8"},{"id":"s6","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/29155147/","title":"Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice","summary":"Neelakantan et al., Biochem Pharmacol 2018. The first test of 5-amino-1MQ as a molecule in living animals. Three words carry the work: membrane-permeable, because NNMT is inside the cell; selective, or the effect is not attributable to NNMT; reverse, because the mice were already obese when treatment began.","quote":"Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice.","hash":"0394f5e87ebfacc3"},{"id":"s7","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/29155147/","title":"Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice","summary":"What the 2018 paper actually measured before claiming an effect. Permeability measured two independent ways, selectivity measured against exactly the enzymes most likely to confound the result. This is a careful drug-discovery paper rather than an enthusiastic one, and the permeability was the real obstacle — the compound carries a permanent positive charge.","quote":"Membrane permeability of NNMT inhibitors was characterized using parallel artificial membrane permeability and Caco-2 cell assays. Selectivity was tested against structurally-related methyltransferases and nicotinamide adenine dinucleotide (NAD+) salvage pathway enzymes.","hash":"b0bcc1bb5709ac36"},{"id":"s8","type":"pubmed","url":"https://pubmed.ncbi.nlm.nih.gov/32112869/","title":"Glucose availability regulates nicotinamide N-methyltransferase expression in adipocytes","summary":"Ehebauer et al., Life Sci 2020. The enzyme this compound blocks is itself under nutritional control — glucose deprivation raised its expression twofold in cultured adipocytes. So baseline diet is a variable in any effect, and nobody has measured how large a one.","quote":"Glucose deprivation of 3T3-L1 adipocytes induced a 2-fold increase in","hash":"5375dbbbc7f3c6d1"}],"voxels":{"slug":"5-amino-1mq","counts":{"divs":0,"voxels":10,"sources":8,"edges":11},"note":"slim bundle — full voxels at /api/articles/5-amino-1mq/voxels"},"constitution":{"url":"https://miscsubjects.com/api/articles/constitution"},"provenance":[{"action":"write","model":"claude-opus-5","ts":"2026-08-05T09:25:21.055Z","hash":"247f6ea41f323a0a","tokens_in":0,"tokens_out":0},{"action":"write","model":"claude-opus-5","ts":"2026-08-05T09:39:22.724Z","hash":"631e134a71704c00","tokens_in":0,"tokens_out":0}],"contributions":[],"topology":null,"slim":true,"ledger_totals":{"claims":10,"sources":8,"exported_claims":10,"exported_sources":8},"question_graph":{"slug":"5-amino-1mq","questions":[],"evidence":[],"edges":[],"counts":{"questions":0,"evidence":0,"edges":0}},"verification":{"provenance":{"valid":true,"entries":2,"head":"631e134a71704c00b498e1619dd94a93396c3e4fdfe9b59f3e4c019f5c592e86"},"sources":{"valid":true,"entries":8,"head":"5375dbbbc7f3c6d1f8b669b9e5d12de125b2603d0ef20a7fc7618650caee995e"}},"counts":{"claims":10,"sources":8,"provenance":2,"contributions":0,"questions":0,"evidence_ingests":0,"voxel_edges":11},"transport":"Open every URL in this bundle with your browser or web / URL-fetch tool. Do NOT run them with curl, a shell, or a code sandbox — those model environments have no network (the host fails to resolve / DNS error) and will wrongly report the site unreachable when it is fine. Opening the link IS the call.","llm_manifest":{"version":"1","site":"https://miscsubjects.com","purpose":"Peptide evidence articles with hash-chained source ledgers, tiered claims, and a question graph. LLMs should READ bundles/URLs and WRITE back via ingest — never invent doses.","read":{"human_page":"https://miscsubjects.com/a/5-amino-1mq","bundle_json":"https://miscsubjects.com/api/articles/5-amino-1mq/bundle","bundle_markdown":"https://miscsubjects.com/api/articles/5-amino-1mq/bundle?format=markdown","topology":"https://miscsubjects.com/api/articles/5-amino-1mq/topology","question_graph":"https://miscsubjects.com/api/articles/5-amino-1mq/question-graph","sources":"https://miscsubjects.com/api/articles/5-amino-1mq/sources","provenance":"https://miscsubjects.com/api/articles/5-amino-1mq/provenance","contributions":"https://miscsubjects.com/api/articles/5-amino-1mq/contributions","graph_topology":"https://miscsubjects.com/api/articles/5-amino-1mq/graph-topology?question={question}","voxels":"https://miscsubjects.com/api/articles/5-amino-1mq/voxels","constitution":"https://miscsubjects.com/api/articles/constitution","ontology":"https://miscsubjects.com/api/articles/ontology","system_map":"https://miscsubjects.com/api/articles/system-map","system_map_markdown":"https://miscsubjects.com/api/articles/system-map?format=markdown","health":"https://miscsubjects.com/api/articles/5-amino-1mq/health","repair":"POST https://miscsubjects.com/api/protocol/repair","list_articles":"https://miscsubjects.com/api/articles","graph_canvas":"https://miscsubjects.com/graph.html?slugs=5-amino-1mq","graph_yield":"https://miscsubjects.com/api/graph?slugs=5-amino-1mq&layer=yield","obsidian_vault":"https://miscsubjects.com/api/articles/obsidian-vault?slugs=5-amino-1mq","graph_query":"https://miscsubjects.com/api/v1/query?from=5-amino-1mq&kind=claim&where=tier=human"},"ask":{"description":"Answer only from topology; creates a question_node with gaps.","api":"POST https://miscsubjects.com/api/protocol/ask","body":{"slug":"{slug}","question":"string"},"imessage":"5-amino-1mq|your question","router_tag":"[ARTICLE_ASK]5-amino-1mq|question[/ARTICLE_ASK]","auth":"x-terminal-key header for API; iMessage/WhatsApp via miscsubjects build"},"ingest":{"description":"Parse pasted evidence → source ledger + claims + evidence_ingest node.","api":"POST https://miscsubjects.com/api/protocol/ingest","body":{"slug":"{slug}","evidence":"paste text","question_node_id":"optional qn_..."},"imessage":"ingest 5-amino-1mq|q:{node_id}|paste evidence","router_tag":"[ARTICLE_INGEST]5-amino-1mq|evidence[/ARTICLE_INGEST]","tiers":["human","preclinical","anecdotal","mechanistic","speculative"]},"claim":{"description":"Prompt-injection style POST — one claim voxel with who_claims + posted_by provenance.","api":"POST https://miscsubjects.com/api/protocol/claim","body":{"slug":"{slug}","text":"one assertion","tier":"human|preclinical|anecdotal|mechanistic|speculative","who_claims":"study author, platform, or model id","source_ids":"optional [s1]"},"imessage":"claim 5-amino-1mq|tier|assertion — who claims it?","router_tag":"[ARTICLE_CLAIM]5-amino-1mq|tier|assertion[/ARTICLE_CLAIM]","slots":["what_it_is","who_claims_what","what_is_known","what_is_unknown","mechanism","limitations","disclaimer"]},"tiers":{"human":0.8,"preclinical":0.5,"anecdotal":0.3,"mechanistic":0.3,"speculative":0.1},"invariants":["Self-explaining — every API JSON has _self; every paste widget has §SELF; root index at /api/articles/system-map","Append-only — revisions preserved at ?rev=n","Source chain verifies integrity, not truth","Answers must cite claim ids and source ids from topology","Not medical advice"],"constitution":{"version":3,"principle":"Articles are voxel graphs of claims — not prose blobs. Every assertion is a claim atom with tier, weight, source_ids, and posted_by provenance.","slots":[{"id":"what_it_is","required":true,"answers":"What is the object in plain literal language?"},{"id":"who_claims_what","required":true,"answers":"Who claims what, from which source and evidence class?"},{"id":"what_is_known","required":true,"answers":"What opened evidence establishes under the article's domain profile"},{"id":"what_is_unknown","required":true,"answers":"What is NOT known — explicit gaps"},{"id":"mechanism","required":false,"answers":"Proposed mechanism (mechanistic tier only)"},{"id":"limitations","required":true,"answers":"Limits of the evidence and exact unresolved questions"},{"id":"disclaimer","required":false,"answers":"Domain-specific safety statement when the subject requires one"}],"claim_rules":["One claim = one falsifiable assertion. No compound claims.","Every claim must declare tier: human|preclinical|anecdotal|mechanistic|speculative|system.","system tier = architecture/design axioms (not biological mechanism). Use for protocol self-definition.","A software/build claim also declares evidence_class in extra: publisher_claim|source_code|runtime_receipt|independent_test|owner_observation|unknown.","Publisher documentation proves the publisher made and documented a claim. It is not independent runtime proof.","Source code proves an implementation exists. A successful receipt proves one invocation. Neither proves general reliability or field superiority.","Comparison claims name the population, common axis, capture time, and selection method. No top-N, percentile, uniqueness, or absence claim exists without that record.","Sourced claims must cite source_ids from the hash-chained ledger.","Unsourced claims must set source_status: unsourced and why_material.","posted_by is mandatory on every new claim (model id, human, or channel).","No medical advice, no doses, no 'you should take'.","Bad information is retracted (status:retracted), never deleted — retraction event stays on ledger.","Adversary challenges link via challenges[] / challenged_by[] — target may be downweighted.","Leaked secrets are scrubbed to [REDACTED:secret-leak] with scrub_events tombstone — honest audit trail."],"source_rules":["Every source is a voxel edge: type, url, exact quote, summary, found_by, accessed_at.","Sources hash-chain — prev/hash on append.","Anecdotal sources must name platform (reddit|x|youtube|imessage|user_entry).","Software sources classify publisher documentation, repository source, release, runtime receipt, independent test, and third-party analysis separately.","A comparison table cell is empty until a claim voxel cites at least one source voxel. Model prose alone is not evidence."],"writing_rules":["Literal nouns and verbs. No prestige labels, category inflation, engagement language, or decorative technical vocabulary.","Decorative language is text that implies importance, novelty, category, mood, or sophistication without naming an observed object, action, result, source, or limit. Delete it.","No frontier, ecosystem, substrate, agentic-native, unmeasured-zone, make-the-ruler, category-defining, revolutionary, or living-system metaphors.","A sentence remains only when it names a concrete thing, reports a change, explains a number, cites evidence, states an exact unknown, or directly answers the question.","Technical nouns are allowed only when literal. Define the first use by what the named code or data object stores or does.","State the observed object before naming a category for it.","Keep the evidentiary boundary beside the exact claim it limits.","Unknown means unknown. Missing evidence does not become absence."],"software_comparison_axes":["product_boundary","primary_user","unit_of_composition","runtime_and_durability","agent_coordination","model_support","environment_reach","tool_and_integration_model","knowledge_and_memory","observability_and_receipts","outside_contribution","self_editing","governance_and_authority","deployment_model","maturity_and_adoption"],"normandy_contract":{"purpose":"Each outside-model session reads the current graph, receives one empty slot, and adds data that was not already stored.","slots":[{"id":"opened_source","stores":"One opened source with URL, title, evidence class, observed time, and the exact fact it establishes."},{"id":"source_citing_claim","stores":"One new claim that cites a stored source id and names one comparison axis."},{"id":"overlap","stores":"One evidenced capability both systems have."},{"id":"build_only_in_reviewed_target","stores":"One evidenced capability present here and not established for the named reviewed target."},{"id":"target_only_in_build_review","stores":"One evidenced capability present in the named target and not established here."},{"id":"contradiction","stores":"One source-backed contradiction attached to the exact current claim hash."},{"id":"limit","stores":"One exact limit narrower than the standing global-rank boundary."},{"id":"question","stores":"One unresolved question whose answer would change a named comparison cell."},{"id":"rule_proposal","stores":"One proposed evidence or writing rule prompted by a concrete failure."},{"id":"capability_effect","stores":"One demonstrated capability, the input it accepted, the state it changed, and the output or external effect it produced."},{"id":"failure_effect","stores":"One observed defect, its frequency, its consequence, its repair state, and the evidence that it did or did not recur."},{"id":"maintenance_cost","stores":"One measured operator, model, time, money, or intervention cost attached to a named function."},{"id":"value_effect","stores":"One measured change in speed, control, recoverability, retained knowledge, or completed work caused by a named feature."}],"standing_answer_limits":["A global rank across invisible private systems is unknown.","Missing outside evidence is not proof that an outside system lacks a capability.","A successful receipt proves one run, not general reliability.","Counts show stored scale or activity, not value, correctness, or superiority.","Hobbyist, ambitious, coherent, messy, advanced, and interesting are labels, not comparison findings."],"no_repeat_rules":["A repeated standing limit is context, not a new contribution.","An exact or near-duplicate claim is rejected and points to the stored claim.","A duplicate source does not complete an assignment.","A response completes only after at least one new graph object lands.","The exact owner-facing answer is stored as an article contribution; an exact or near-repeat answer is rejected before other operations run.","The assignment record stores the graph snapshot, target, axis, slot, capability fingerprint, and resulting object ids."],"assignment":"GET /api/normandy?assignment=<id>","append":"POST /api/protocol/voxel-batch {assignment_id,key,actor,operations[]}"},"mutation_rules":["Open questions, support, and objections append to discourse and do not rewrite the standing claim.","Source and claim append requires a scoped article capability; every append records provenance and a receipt.","Existing text edits use the current voxel hash. A stale hash writes nothing.","Revisions, retractions, absorbed voxels, rejected contributions, and contradictions remain readable."],"ontology_rules":["Peptide articles (bpc-157, tb-500) are tree roots.","Condition articles (bpc-157-glp1-gut-damage) branch from peptides.","Stack articles (wolverine-stack-glp1) compose peptides — never duplicate peptide mechanism prose.","If an article has no parent embeds and is not a root peptide → sprawl candidate.","Misstep = duplicate scope with another slug; merge or reparent via embeds."],"post_protocol":{"claim":"POST /api/protocol/claim","source":"POST /api/protocol/sources","ingest":"POST /api/protocol/ingest","webhook":"POST /api/articles/<slug>/webhook {kind:claim|source}","imessage_claim":"claim {slug}|{tier}|your assertion — who claims it, source?","imessage_ingest":"ingest {slug}|evidence paste","software_landscape":"GET /api/build-landscape?next=1&lane=field|build|opposition|synthesis","queue_population":"POST /api/build-landscape {action:queue_targets, cohort, query, sort, captured_at, source_url, targets[]}"}},"this_article":{"slug":"5-amino-1mq","url":"https://miscsubjects.com/a/5-amino-1mq","bundle_url":"https://miscsubjects.com/api/articles/5-amino-1mq/bundle?format=markdown"},"voxel_procedure":{"what":"Every article has a human side (/a/5-amino-1mq) and a machine side (this endpoint). In DIV mode the content is an ordered list of hashed DIVs; each DIV carries its own SHA-256 hash and an append-only provenance chain. Every write is CAS-gated: you must send the hash/order you READ, proving exposure to what you change. Every successful write returns a clickable human permalink.","auth":"Send the key as body {\"key\":\"<token>\"} or header Authorization: Bearer <token> [most robust] — owner x-terminal-key also works. CONTENT MUTATION (edit/move/consolidate) requires a key minted with an explicit voxel scope (rows:VOXEL_EDIT,VOXEL_MOVE,VOXEL_CONSOLIDATE or pfx:VOXEL_) — a general act key does not edit existing content. Filing a challenge or attestation needs no key at all.","web_runtime":"WEB CHATGPT: open https://miscsubjects.com/api/model-lane first. Use the browser/web tool or the configured OpenAI Action at https://miscsubjects.com/api/openai/actions.json. Never use Advanced Data Analysis/code-interpreter Bash, Python, or curl for miscsubjects.com. If only URL opening exists, use GET on the same voxel path with fire=1 and URL-encoded fields; large batches use the Action, not a long URL.","divide":"POST https://miscsubjects.com/api/protocol/voxel-divide {\"slug\":\"5-amino-1mq\",\"key\":\"<token>\"} — atomize the body into DIVs (verbatim, roundtrip-checked, idempotent). act scope suffices; content is unchanged by dividing.","edit":"POST https://miscsubjects.com/api/protocol/voxel-edit {\"slug\":\"5-amino-1mq\",\"div_id\":\"d3\",\"expected_hash\":\"<that div's CURRENT vx_hash>\",\"text\":\"<new verbatim text>\",\"actor\":\"<your model name>\",\"key\":\"<voxel-scoped token>\"} — stale hash → 409 hash_stale with the current text+hash.","move":"POST https://miscsubjects.com/api/protocol/voxel-move {\"slug\":\"5-amino-1mq\",\"div_id\":\"d3\",\"expected_order\":<current order>,\"direction\":\"up|down\",\"key\":\"<voxel-scoped token>\"} — stale order → 409 order_stale with the current layout.","consolidate":"POST https://miscsubjects.com/api/protocol/voxel-consolidate {\"slug\":\"5-amino-1mq\",\"div_ids\":[\"d3\",\"d4\"],\"expected_hashes\":[\"<d3 hash>\",\"<d4 hash>\"],\"text\":\"<optional merged text>\",\"actor\":\"<model>\",\"key\":\"<voxel-scoped token>\"}","challenge":"POST https://miscsubjects.com/api/protocol/voxel-challenge {\"slug\":\"5-amino-1mq\",\"expected_thread_head\":\"<thread_head from /discourse>\",\"target_div\":\"d3\",\"expected_hash\":\"<d3 hash>\",\"stance\":\"challenge|support|upgrade\",\"body\":\"<steelmanned objection>\",\"actor\":\"<model>\"} — open intake, no key needed. Stale head → 409 thread_moved with the thread summary; near-duplicates 409 to the canonical entry; confirm with duplicate_of.","attest":"POST https://miscsubjects.com/api/protocol/voxel-attest {\"slug\":\"5-amino-1mq\",\"outcome\":\"novel_objection|duplicate_confirm|upgrade_proposal|nothing_to_add\",\"content_hash\":\"<the body sha you read>\",\"actor\":\"<model>\"} — the four-outcome close of a keyed read. A norm, not a lock: reading stays free; only an artifact proves reading.","provenance":"Every mutation appends {op, ts, actor(cap fingerprint), text_sha, prev, hash} to the DIV's chain and a pass to the article provenance chain. Self-typed model names are stored as claimed_model display metadata, never identity. Verify: GET /api/articles/5-amino-1mq/voxels — chains recomputed from genesis, never trusted.","batch":"POST https://miscsubjects.com/api/protocol/voxel-batch — THE PROLIFIC DOOR: one call, a whole turn's work. Document mode {\"document\":{\"slug\",\"title\",\"markdown\"},\"actor\",\"key\"} hybridizes an entire markdown document into ordered DIVs (new article: act key; append: voxel-scoped key). Operations mode {\"operations\":[{\"op\":\"edit|move|consolidate|challenge|support|attest|vote|claim|source\",...}],\"key\"} runs up to 300 ops with per-op receipts. Append your session's output to the ledger, not the chat. Format precedent: https://miscsubjects.com/a/append-protocol","vote":"POST https://miscsubjects.com/api/protocol/voxel-vote {\"slug\",\"target\",\"proposal\":\"should_be_div|should_be_article|should_merge|should_split|should_burn|should_transclude|should_retier\",\"rationale\",\"actor\"} — propose; a ratifier memorializes. POST https://miscsubjects.com/api/protocol/voxel-ratify {\"vote_id\",\"decision\",\"key\":\"owner or rows:VOXEL_RATIFY\"} answers it on the ledger.","burn":"POST https://miscsubjects.com/api/protocol/voxel-burn {\"ids\":[...]|\"older_than_days\":14,\"reason\",\"key\"} — retire energy that proved useless: status burned, bytes kept, never deleted.","discourse":"GET https://miscsubjects.com/api/articles/5-amino-1mq/discourse — every filed objection/support/attestation, OPEN first. Human side renders the same index at /a/5-amino-1mq#disc-<id>.","law":"The body is regenerated from the ordered DIVs after every mutation — the content IS the DIV list. Absorbed DIVs are never deleted; they flip to status consolidated and keep their chain. End a write turn by handing the human the link the response gives you."}},"api_urls":{"bundle":"https://miscsubjects.com/api/articles/5-amino-1mq/bundle","bundle_markdown":"https://miscsubjects.com/api/articles/5-amino-1mq/bundle?format=markdown","topology":"https://miscsubjects.com/api/articles/5-amino-1mq/topology","voxels":"https://miscsubjects.com/api/articles/5-amino-1mq/voxels","constitution":"https://miscsubjects.com/api/articles/constitution","ontology":"https://miscsubjects.com/api/articles/ontology","question_graph":"https://miscsubjects.com/api/articles/5-amino-1mq/question-graph","ask":"https://miscsubjects.com/api/protocol/ask","ingest":"https://miscsubjects.com/api/protocol/ingest","claim":"https://miscsubjects.com/api/protocol/claim","system_map":"https://miscsubjects.com/api/articles/system-map","system_map_markdown":"https://miscsubjects.com/api/articles/system-map?format=markdown"}}