{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T07:02:02Z","timestamp":1791529322041,"version":"4.3.4"},"reference-count":119,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The recent review of a new drug application for MDMA\u2010assisted therapy for posttraumatic stress disorder by the United States' Food and Drug Administration (FDA) highlighted epistemological and methodological challenges for evidence assessments. Similar challenges will also be faced in reviews of other compounds in early\u2010 and late\u2010stage development, like psilocybin for depression. The regulatory demand for two successful phase 3 randomized controlled trials (RCTs) seems problematic, given a current lack of agreement on what constitutes \u201csuccess\u201d, particularly when psychoactive drug administration is concomitant with (psycho)therapy. These complex arrangements challenge the internal validity of estimated average treatment effect through comparison with conventional control conditions. This paper reviews the assumptions behind RCTs' current \u201cgold\u2010standard\u201d status in the hierarchy of evidence\u2010based medicine (EBM). Recapitulating known epistemic limits of randomization and blinding, it emphasizes the urgent need to avoid the extrapolation fallacy. The resulting argument is that the degree of trustworthiness that efficacy\u2014reported in RCTs\u2014will reliably predict effectiveness\u2014in target populations outside RCTs\u2014depends on what type of psychedelic treatments will be regulated. If \u201cstand\u2010alone\u201d drugs for large\u2010scale prescription and consumption, trustworthiness should be graded low. On the other hand, for regulation of drug\u2010assisted (psycho) therapies, the degree of trustworthiness can be considered high. The reason being that these two treatment approaches are based on different causal claims with distinct external validities. Therefore, careful assessment of support factors in each is recommended to prevent detrimental consequences, from potential rejection of effective therapies up to medical reversal of eventually approved drugs.<\/jats:p>","DOI":"10.1002\/prp2.70097","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T03:06:06Z","timestamp":1744686366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["From Efficacy to Effectiveness: Evaluating Psychedelic Randomized Controlled Trials for Trustworthy Evidence\u2010Based Policy and Practice"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7111-9891","authenticated-orcid":false,"given":"Eduardo Ekman","family":"Schenberg","sequence":"first","affiliation":[{"name":"Instituto Phaneros  S\u00e3o Paulo Brazil"},{"name":"Project on Psychedelics Law and Regulation (POPLAR), Petrie\u2010Flom Center for Health Law Policy Biotechnology, and Bioethics at Harvard Law School  Cambridge Massachusetts USA"},{"name":"Language, Action and Brain Lab, Division of Psychology &amp; Language Sciences University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1057\/s41292\u2010022\u201000294\u20104"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l7069"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp1903305"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010021\u201001336\u20103"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010023\u201002565\u20104"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/2050324520974484"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2022.2546"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215\u20100366(20)30146\u20102"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2023.0099"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010021\u201001530\u20103"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2023.100727"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg1324"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2022.109165"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.14650"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.776"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpsc.2024.02.004"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/02698595.2011.574856"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010021\u201001524\u20101"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010021\u201001525\u20100"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/00048674221081763"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213\u2010022\u201006123\u20107"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1177\/20451253231198466"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2023.1968"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010022\u201000421\u20107"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1177\/02698811231180276"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213\u2010024\u201006598\u20106"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1089\/psymed.2023.0028"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.22r14518"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1080\/02791072.2023.2278586"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291722003191"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291723001289"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2021.1933434"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2023.2279736"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781444342673"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1353\/pbm.0.0040"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1353\/pbm.0.0080"},{"key":"e_1_2_8_38_1","volume-title":"Ending Medical Reversal: Improving Outcomes, Saving Lives","author":"Cifu A. 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