[{"data":1,"prerenderedAt":160},["ShallowReactive",2],{"topic-research-science":3},{"articles":4,"guides":159},[5],{"id":6,"title":7,"author":8,"authorTitle":9,"body":10,"date":145,"description":146,"draft":147,"extension":148,"featured":149,"heroCredit":150,"heroImage":151,"meta":152,"navigation":149,"path":153,"readingTime":154,"seo":155,"stem":156,"topic":157,"__hash__":158},"articles\u002Farticles\u002Fwhat-we-mean-when-a-drug-works.md","What we mean when we say a drug \"works\"","Higher Place editors",null,{"type":11,"value":12,"toc":135},"minimark",[13,17,25,30,33,39,42,45,49,52,55,59,62,66,82,85,89,130],[14,15,16],"p",{},"Every few months a headline announces that a psychedelic compound has produced\n\"unprecedented\" results for depression, addiction or trauma. Some of those\nresults are real and important. They are also frequently misunderstood — by\nreaders, by reporters, and sometimes by the people running the studies.",[14,18,19,20,24],{},"This is not an argument that the research is weak. Much of it is careful, and\nthe field has matured quickly. It is an argument that ",[21,22,23],"em",{},"promising"," is a specific,\nlimited claim, and that learning to hear it precisely is the most useful skill a\ncurious person can bring to this subject.",[26,27,29],"h2",{"id":28},"a-result-is-a-sentence-with-hidden-clauses","A result is a sentence with hidden clauses",[14,31,32],{},"When a trial reports that a single dose \"significantly reduced depression at\nsix weeks\", several quieter facts travel underneath that sentence: how many\npeople were studied, who they were, what the comparison group received, how\nlong anyone was followed, how the outcome was measured, and how large the\ndifference actually was.",[34,35,36],"blockquote",{},[14,37,38],{},"A number without its denominator is a rumour with a decimal point.",[14,40,41],{},"Take the largest programme in the field. Compass Pathways ran two Phase 3\ntrials of a synthetic psilocybin formulation for treatment-resistant\ndepression. The first, with 258 participants, found that a single 25 mg dose\nbeat placebo at six weeks by a mean of 3.6 points on the MADRS, a 60-point\ndepression scale. The second, with 581 participants, found that two 25 mg doses\nbeat a 1 mg comparison dose by 3.8 points. Both results were statistically\nstrong. Both are also, in absolute terms, modest: a few points on a long scale,\nin the same neighbourhood as the average gap between a conventional\nantidepressant and placebo. That is not a criticism of the trials. It is what\n\"significant\" means, and it is a long way from \"cured\".",[14,43,44],{},"Smaller studies deserve even more caution. A 2021 trial comparing psilocybin to\nthe antidepressant escitalopram enrolled 59 people and, on its main outcome,\nfound no significant difference between the two. Early-phase studies exist to\ndetect whether an effect is plausible, not to measure it accurately. The honest\nreading of an exciting early result is not \"this works\" but \"this is worth the\nexpense and risk of finding out properly\".",[26,46,48],{"id":47},"the-unblinding-problem","The unblinding problem",[14,50,51],{},"Psychedelics present researchers with an awkward fact: people generally know\nwhether they have taken one. That breaks the blind that ordinary drug trials\nrely on, and expectation is a powerful medicine in its own right. Good teams now\ndesign around this — low-dose active comparators, independent raters, careful\nmeasurement of what participants believed they received — but a study that\nignores it should be read with that gap in mind.",[14,53,54],{},"This is not a theoretical worry. In 2024 the US Food and Drug Administration\ndeclined to approve MDMA-assisted therapy for post-traumatic stress disorder,\ndespite two positive Phase 3 trials, and the difficulty of blinding was among\nthe reasons its advisers gave. Regulators were not saying the treatment does not\nwork. They were saying the trials could not yet prove how much of the effect\nwas the drug.",[26,56,58],{"id":57},"durable-is-a-claim-about-a-denominator","\"Durable\" is a claim about a denominator",[14,60,61],{},"Durability is the whole question for a treatment given once or twice. So when\na company reports that benefit \"lasted six months\", ask: among whom? In the\nCompass trials, the six-month durability data were reported for participants\nwho had already responded at week six. That is a real and useful finding. It is\nalso a different, narrower claim than \"the treatment lasts six months\", because\nit leaves out everyone for whom it did not work in the first place.",[26,63,65],{"id":64},"what-good-evidence-will-look-like","What good evidence will look like",[67,68,69,73,76,79],"ul",{},[70,71,72],"li",{},"Larger samples that include the people clinicians actually treat, not only\nthe unusually well and unusually motivated.",[70,74,75],{},"Longer follow-up of everyone enrolled, not only responders.",[70,77,78],{},"Honest accounting of harms, including the difficult or destabilising\nexperiences that averages tend to hide.",[70,80,81],{},"Results reported in absolute terms — points on a scale, proportion of people\nin remission — rather than only as \"significant\".",[14,83,84],{},"None of this is a reason for despair, and none of it is a reason for hype. The\nfield is young and, for the first time, it has large trials to argue about. The\nmost respectful thing anyone can do for it, and for the people waiting on it,\nis to describe it accurately while it grows up.",[26,86,88],{"id":87},"sources-and-further-reading","Sources and further reading",[67,90,91,94,101,107,114,120,127],{},[70,92,93],{},"Compass Pathways, COMP005 topline results (June 2025), COMP006 topline\nresults (February 2026) and COMP006 26-week results (July 2026), company\nannouncements.",[70,95,96,97,100],{},"Goodwin GM et al. \"Single-dose psilocybin for a treatment-resistant episode of\nmajor depression.\" ",[21,98,99],{},"New England Journal of Medicine",", 2022.",[70,102,103,104,106],{},"Carhart-Harris R et al. \"Trial of psilocybin versus escitalopram for\ndepression.\" ",[21,105,99],{},", 2021.",[70,108,109,110,113],{},"Raison CL et al. \"Single-dose psilocybin treatment for major depressive\ndisorder: a randomized clinical trial.\" ",[21,111,112],{},"JAMA",", 2023.",[70,115,116,117,106],{},"Muthukumaraswamy SD, Forsyth A, Lumley T. \"Blinding and expectancy confounds\nin psychedelic randomized controlled trials.\" ",[21,118,119],{},"Expert Review of Clinical\nPharmacology",[70,121,122,123,126],{},"Aday JS et al. \"Great expectations: recommendations for improving the\nmethodological rigor of psychedelic clinical trials.\" ",[21,124,125],{},"Psychopharmacology",",\n2022.",[70,128,129],{},"US FDA, Psychopharmacologic Drugs Advisory Committee meeting on midomafetamine\n(MDMA) for PTSD, June 2024; complete response letter reported August 2024.",[14,131,132],{},[21,133,134],{},"This essay is general information, not medical advice. Trial results and\nregulatory status change; check current sources before relying on any figure\nhere.",{"title":136,"searchDepth":137,"depth":137,"links":138},"",3,[139,141,142,143,144],{"id":28,"depth":140,"text":29},2,{"id":47,"depth":140,"text":48},{"id":57,"depth":140,"text":58},{"id":64,"depth":140,"text":65},{"id":87,"depth":140,"text":88},"2026-05-12","Psychedelic trials report dramatic numbers. Understanding what those numbers measure — and what they quietly leave out — is the first step to reading them honestly.",false,"md",true,"Higher Place — original artwork","\u002Fimg\u002Fheroes\u002Fresearch-science.svg",{},"\u002Farticles\u002Fwhat-we-mean-when-a-drug-works",9,{"title":7,"description":146},"articles\u002Fwhat-we-mean-when-a-drug-works","research-science","Imw7cUqmXn37TBWU8b-tiNKmzjdOz3z_r-3qb-j2jV0",[],1791062477084]