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Cited by 545Psychedelics and Drug StudiesTreatment of Major DepressionTranscranial Magnetic Stimulation Studies

Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial

Open access
Raison, Charles L., Sanacora, Gerard, Woolley, Joshua, Heinzerling, Keith, Dunlop, Boadie W., Brown, Randall T., Kakar, Rishi, Hassman, Michael +27 more·2023·JAMA
DOI 10.1001/jama.2023.14530PMC PMC10472268
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Abstract

Importance: Psilocybin shows promise as a treatment for major depressive disorder (MDD). Objective: To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. Design, Setting, and Participants: In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. Interventions: Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. Main Outcomes and Measures: The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. Results: A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. Conclusions and Relevance: Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03866174.

Integrity signals

Registry

Crossref · 10.1001/jama.2023.14530

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

18 of 30 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisenone given

    Psilocybin shows promise as a treatment for major depressive disorder (MDD).

    “Psilocybin shows promise as a treatment for major depressive disorder (MDD).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [6] 6. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30(12): 1181-1197. doi:10.1177/0269881116675513 source

      The Abstract reports substantial, sustained decreases in depressed mood after psilocybin, and Methods > Study participants says 18 of the 51 patients had an MDD diagnosis, including four also diagnosed with generalized anxiety disorder. But the results concern a mixed group of patients with life-threatening cancer and do not establish the effect specifically for MDD patients or for MDD more generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [7] 7. Agin-Liebes GI, Malone T, Yalch MM, et al. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. J Psychopharmacol. 2020;34(2):155-166. doi:10.1177/ 0269881119897615 source
    • cites [8] 8. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12): 1165-1180. doi:10.1177/0269881116675512 source

      The Discussion (Primary outcomes; page unavailable) reports sustained reductions in depression symptoms among patients with life-threatening cancer and cites a separate open-label study in treatment-resistant depression. This supports the cautious phrase “shows promise,” but this trial did not test psilocybin as a treatment for MDD specifically; its participants had cancer-related distress and anxiety-related diagnoses (Methods, Study sample and setting; page unavailable). (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The smaller placebo response in the current study may have inflated the placebo-adjusted effect size compared with studies of standard antidepressants in patients with MDD.

    “Nonetheless, placebo response rates in the current study are smaller than are typically observed with daily placebo pills, 34 which may have inflated the placebo-adjusted effect size compared with studies of standard antidepressants in patients with MDD.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] 34. Williams MT, Reed S, Aggarwal R. Culturally informed research design issues in a study of MDMA-assisted psychotherapy for posttraumatic stress disorder. J Psychedelic Stud. 2019;4(1):40-50. doi:10.1556/2054.2019.016 source

      The Introduction contrasts MDMA given 2–3 times with medications often taken daily, but it does not compare placebo response rates. Searches for daily placebo pills, MDD, and placebo-adjusted effect size found no passage addressing the cited claim that placebo responses were smaller than those typically observed with daily pills. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The 8% rate of severe adverse events in participants receiving psilocybin was similar to the 10% rate reported in the study by Goodwin et al in participants with TRD treated with a single 25-mg dose of psilocybin.

    “The 8% rate of severe adverse events in participants receiving psilocybin was similar to the 10% rate reported in the study by Goodwin et al in participants with TRD treated with a single 25-mg dose of psilocybin.14”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] 14. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022; 387(18):1637-1648. doi:10.1056/NEJMoa2206443 source

      The Safety section reports severe adverse events in 9% of the 25-mg group from day 2 through week 3, but does not report the claimed 10% rate. Table 3 also gives separate rates of 4% on day 1 and 3% after week 3; these interval-specific rates do not establish a 10% overall rate. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Interpretationreasoning

    It is likely that the acute psychoactive effects of psilocybin produced some degree of functional unblinding.

    “First, the success of allocation blinding was not assessed, and it is likely that the acute psychoactive effects of psilocybin produced some degree of functional unblinding that may have contributed to the observed effect in psilocybin-treated (psilocybin -niacin).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] 33. Michaels TI, Purdon J, Collins A, Williams MT. Inclusion of people of color in psychedelic-assisted psychotherapy: a review of the literature. BMC Psychiatry. 2018;18(1):245. doi:10.1186/s12888-018- 1824-6 source

      The Results > Study methodologies section says that finding a placebo that mimics psychedelics’ physiological effects is an important issue for double-blinded trials. That supports a general concern about blinding, but the paper does not say that psilocybin caused functional unblinding in the psilocybin–niacin comparison or that unblinding contributed to its observed effect. No page number is available in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Findingcitation

    Placebo response rates in the current study are smaller than are typically observed with daily placebo pills.

    “Nonetheless, placebo response rates in the current study are smaller than are typically observed with daily placebo pills, 34 which may have inflated the placebo-adjusted effect size compared with studies of standard antidepressants in patients with MDD.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] 34. Williams MT, Reed S, Aggarwal R. Culturally informed research design issues in a study of MDMA-assisted psychotherapy for posttraumatic stress disorder. J Psychedelic Stud. 2019;4(1):40-50. doi:10.1556/2054.2019.016 source

      The Introduction describes MDMA-assisted psychotherapy for PTSD and contrasts its dosing schedule with medications taken daily, but it does not compare placebo response rates. Searches of our copy for daily placebo pills and placebo-adjusted effects found no passage addressing the claimed comparison. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Recent critiques highlight notable limitations in many psilocybin studies, including small sample sizes, assessments by raters likely to be functionally unblinded, an open or waitlist comparator design, and an inadequate assessment of adverse events.

    “recent critiques highlight notable limitations in many of these studies, [16][17][18][19] including small sample sizes, assessments by raters likely to be functionally unblinded, an open or waitlist comparator design, and an inadequate assessment of adverse events (AEs).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [16] 16. Hall WD, Humphreys K. Is good science leading the way in the therapeutic use of psychedelic drugs? Psychol Med. 2022;52(14):2849-2851. doi: 10.1017/S0033291722003191 source

      In “Lowering of standards by major medical journals” (page unavailable), the paper describes a psilocybin trial with 30 and 29 patients in its two arms, calls it underpowered, and questions whether participants remained blinded. It does not say that outcome raters were functionally unblinded or that the studies used open or waitlist comparators or inadequately assessed adverse events. The trial it discusses used escitalopram as its comparator. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [17] 17. Breeksema JJ, Kuin BW, Kamphuis J, van den Brink W, Vermetten E, Schoevers RA. Adverse events in clinical treatments with serotonergic psychedelics and MDMA: a mixed-methods systematic review. J Psychopharmacol. 2022;36(10):1100-1117. doi:10. 1177/02698811221116926 source

      The Discussion > Limitations section (page unavailable) says the included studies were mostly small and that few assessed adverse events systematically. The Psilocybin section identifies open-label studies, and the Limitations section notes difficulty blinding participants. Our copy does not establish that outcome raters were functionally unblinded or that studies used waitlist comparators. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [18] 18. Yaden DB, Potash JB, Griffiths RR. Preparing for the bursting of the psychedelic hype bubble. JAMA Psychiatry. 2022;79(10):943-944. doi:10.1001/ jamapsychiatry.2022.2546 source

  • May combine two claims.

    Premisecitation

    Larger recent studies have addressed these issues to various degrees, but report primary end points of short duration, leaving open the question of the long-term clinical utility of psilocybin for an often chronic condition such as MDD.

    “Larger recent studies have addressed these issues to various degrees, but report primary end points of short duration, 14,15 leaving open the question of the long-term clinical utility of psilocybin for an often chronic condition such as MDD.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [14] 14. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022; 387(18):1637-1648. doi:10.1056/NEJMoa2206443 source
    • cites [15] 15. von Rotz R, Schindowski EM, Jungwirth J, et al. Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomised clinical trial. EClinicalMedicine. 2022;56:101809. doi:10.1016/j. eclinm.2022.101809 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent studies suggest that psilocybin engenders a rapid antidepressant response that far outlasts the presence of the drug in the body.

    “recent studies suggesting that psilocybin engenders a rapid antidepressant response that far outlasts the presence of the drug in the body.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [6] 6. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30(12): 1181-1197. doi:10.1177/0269881116675513 source

      The Results (Outcome measures; page unavailable) report a substantial antidepressant response in patients with life-threatening cancer at five weeks, sustained at six months. The Methods (Outcome measures; page unavailable) say the subjective drug effects had subsided by seven hours, supporting that the benefit outlasted the acute effects. But depression was first assessed five weeks after dosing, so this study does not establish how rapidly the antidepressant response began or when the drug left the body. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [7] 7. Agin-Liebes GI, Malone T, Yalch MM, et al. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. J Psychopharmacol. 2020;34(2):155-166. doi:10.1177/ 0269881119897615 source
    • cites [8] 8. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12): 1165-1180. doi:10.1177/0269881116675512 source

      The Discussion (Primary outcomes) reports immediate antidepressant effects lasting weeks to months after a single psilocybin dose, given with psychotherapy to patients with life-threatening cancer. The paper does not establish how long the drug remains in the body, so the comparison with its bodily presence is not directly supported. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    Functional unblinding may have contributed to the observed effect in psilocybin-treated participants and the increased dropout rate in niacin-treated participants.

    “First, the success of allocation blinding was not assessed, and it is likely that the acute psychoactive effects of psilocybin produced some degree of functional unblinding that may have contributed to the observed effect in psilocybin-treated (psilocybin -niacin).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] 33. Michaels TI, Purdon J, Collins A, Williams MT. Inclusion of people of color in psychedelic-assisted psychotherapy: a review of the literature. BMC Psychiatry. 2018;18(1):245. doi:10.1186/s12888-018- 1824-6 source

      The Results > Study methodologies section (page unavailable) says that a placebo must mimic psychedelic effects for a double-blinded trial, supporting the general concern about blinding. It does not report functional unblinding in a psilocybin–niacin comparison or link it to treatment effects or niacin-group dropout. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Niacin was used as an active placebo that produces an acute physiological response (flushing) thought to aid in blinding.

    “Niacin was used as an active placebo that produces an acute physiological response (flushing) thought to aid in blinding.8,22”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [8] 8. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12): 1165-1180. doi:10.1177/0269881116675512 source

      The Methods section (Study design and interventions; page unavailable) identifies niacin as the active control in a double-blind psilocybin trial. Our copy does not state that niacin caused flushing or that this physiological response was intended to aid blinding; the section refers readers to supplementary blinding procedures without describing them. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [22] 22. Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008;22(6):603-620. doi:10. 1177/0269881108093587 source

      The Preparation of volunteers section discusses blinding and an active placebo, but identifies that placebo as methylphenidate. Searches for niacin and flushing found no passage in our copy addressing niacin’s use, its physiological response, or whether it aided blinding. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Placebo response rates in the current study were equivalent to those seen in response to a low-dose psilocybin comparator in participants with TRD and larger than the effect of an inactive placebo in a recent study in participants with MDD.

    “Second, the use of niacin as active placebo may have increased believability of the comparator condition and enhanced the placebo response, given that placebo response rates in the current study were equivalent to those seen in response to a low-dose psilocybin comparator in participants with TRD and larger than the effect of an inactive placebo in a recent study in participants with MDD.14,15”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [14] 14. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022; 387(18):1637-1648. doi:10.1056/NEJMoa2206443 source
    • cites [15] 15. von Rotz R, Schindowski EM, Jungwirth J, et al. Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomised clinical trial. EClinicalMedicine. 2022;56:101809. doi:10.1016/j. eclinm.2022.101809 source
    • Rests on an assumption: Niacin 100 mg is an inactive placebo with no antidepressant effect.

  • May combine two claims.

    Findingcitation

    No serious TEAEs were reported in the current study; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs compared with niacin, with these severe AEs being known effects of psilocybin.

    “No serious TEAEs were reported in the current study; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs compared with niacin, with these severe AEs being known effects of psilocybin.17”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] 17. Breeksema JJ, Kuin BW, Kamphuis J, van den Brink W, Vermetten E, Schoevers RA. Adverse events in clinical treatments with serotonergic psychedelics and MDMA: a mixed-methods systematic review. J Psychopharmacol. 2022;36(10):1100-1117. doi:10. 1177/02698811221116926 source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Psychedelics may produce adverse events not captured by standard rating scales or may induce unrecognized new psychiatric conditions even as they improve target syndromes.

    “Moreover, psychedelics may produce AEs not captured by standard rating scales or may induce unrecognized new psychiatric conditions even as they improve target syndromes.32”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] 32. Jones BDM, Razza LB, Weissman CR, et al. Magnitude of the placebo response across treatment modalities used for treatment-resistant depression in adults: a systematic review and meta-analysis. JAMA Netw Open. 2021;4(9):e2125531. doi:10.1001/jamanetworkopen.2021.25531 source

      The Results (page not provided) list an ayahuasca trial and the depression rating scale it used, but do not discuss psychedelic adverse events or new psychiatric conditions. A search of our copy for those risks and for limitations of standard rating scales found no passage addressing the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationown data

    The use of niacin as active placebo may have increased believability of the comparator condition and enhanced the placebo response.

    “Second, the use of niacin as active placebo may have increased believability of the comparator condition and enhanced the placebo response, given that placebo response rates in the current study were equivalent to those seen in response to a low-dose psilocybin comparator in participants with TRD and larger than the effect of an inactive placebo in a recent study in participants with MDD.14,15”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [14] 14. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022; 387(18):1637-1648. doi:10.1056/NEJMoa2206443 source
    • cites [15] 15. von Rotz R, Schindowski EM, Jungwirth J, et al. Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomised clinical trial. EClinicalMedicine. 2022;56:101809. doi:10.1016/j. eclinm.2022.101809 source

  • May combine two claims.

    Findingown data

    Sustained depressive symptom remission rate appeared greater with psilocybin than niacin, but the difference was not statistically significant (12/48 [25%] vs 4/44 [9.1%]; adjusted absolute difference, 15.9 [95% CI, 1.0-30.8]; P = .05; OR, 3.4 [95% CI, 1.0-11.5]).

    “Sustained depressive symptom remission rate appeared greater with psilocybin, but the difference was not statistically significant (12/48 [25%] for psilocybin vs 4/44 [9.1%] for niacin; adjusted absolute difference, 15.9 [95% CI, 1.0-30.8];P = .05;OR, 3.4 [95% CI, 1.0-11.5])”
    • Also stated in: § Discussion · plain
      “The 15.9% difference in sustained remission rates between the groups was not significantly different.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Among 1529 potential participants who completed prescreening, 347 signed informed consent, 240 were excluded at screening, 3 were excluded prior to randomization, and 104 were randomized, received the study drug, and comprised the ITT population (51 in the psilocybin group and 53 in the niacin group).

    “Among 1529 potential participants who completed prescreening, 347 signed informed consent, 240 were excluded at screening, 3 were excluded prior to randomization, and 104 were randomized, received the study drug, and comprised the ITT population (51 in the psilocybin group and 53 in the niacin group)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Rates of mild and moderate drug-related TEAEs in the day 1-9 period were higher for psilocybin vs niacin (mild: difference, 35% [95% CI, 17.9%-52.9%]; RI, 1.8 [95% CI, 1.1-1.8]; moderate: difference, 18% [95% CI, 5.8%-30.8%]; RI, 2.3 [95% CI, 1.0-5.7]).

    “The rates of mild and moderate drug-related TEAEs in the same period were higher for psilocybin vs niacin (mild: difference, 35% [95% CI, 17.9%-52.9%];RI, 1.8 [95% CI, 1.1-1.8]);moderate: difference, 18% [95% CI, 5.8%-30.8%];RI, 2.3 [95% CI, 1.0-5.7]).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Visual perceptual effects were reported by 22/50 (44%) psilocybin participants on the day of dosing and by 3/50 (6%) after the dosing day, all resolved by study conclusion.

    “Visual perceptual effects (assessed following resolution of acute drug effects) were reported by 22/50 (44%) psilocybin participants on the day of dosing and by 3/50 (6%) after the dosing day, all resolved by study conclusion”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No suicidal or self-injurious behavior occurred during the trial and all instances of suicidal ideation were considered passive.

    “Based on C-SSRS or MADRS Item 10 scores and confirmed by clinical assessment, no suicidal or self-injurious behavior occurred during the trial and all instances of suicidal ideation were considered passive.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Psilocybin treatment was associated with improvements in various exploratory end points, including reductions in global disease severity, self-reported depressive and anxiety symptoms, and improvement in quality of life, while having no effect on emotional blunting.

    “Psilocybin treatment was associated with improvements in various exploratory end points, including reductions in global disease severity, self-reported depressive and anxiety symptoms, and improvement in quality of life, while having no effect on emotional blunting”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Three serious adverse events occurred between enrollment and randomization (nephrolithiasis; incisional hernia, obstructive; and appendicitis).

    “Three serious AEs occurred between enrollment and randomization (nephrolithiasis; incisional hernia, obstructive; and appendicitis; Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Severe solicited events were reported by 3 participants receiving psilocybin (2 headaches and 1 visual perceptual effects) and 1 headache was reported in a participant receiving niacin.

    “Severe solicited events were reported by 3 participants receiving psilocybin (2 headaches and 1 visual perceptual effects) and 1 headache was reported in a participant receiving niacin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    In contrast to prior psilocybin trials for depression, there was not a significant reduction in depressive symptoms or a psilocybin/placebo difference in depressive symptom status at the day 2 assessment.

    “In contrast to prior psilocybin trials for depression, 8,14,15 there was not a significant reduction in depressive symptoms or a psilocybin/ placebo difference in depressive symptom status at the day 2 assessment (ie, 1 day after dosing)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Randomization was administered centrally by the study's clinical research organization via the Advantage eClinical data system.

    “Randomization was administered centrally by the study's clinical research organization via the Advantage eClinical data system.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    One participant randomized to receive psilocybin received the incorrect treatment, resulting in 50 participants receiving psilocybin and 54 receiving niacin.

    “One participant randomized to receive psilocybin received the incorrect treatment, resulting in 50 participants receiving psilocybin and 54 receiving niacin.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The primary efficacy analysis was a de facto estimand conducted on the intent-to-treat (ITT) population that included all randomized participants analyzed according to randomized treatment group.

    “The primary efficacy analysis was a de facto estimand conducted on the intent-to-treat (ITT) population that included all randomized participants analyzed according to randomized treatment group.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    By 6 weeks, 1 participant in the psilocybin group and 9 in the niacin group had withdrawn or been lost to follow-up.

    “By 6 weeks, 1 participant in the psilocybin group and 9 in the niacin group had withdrawn or been lost to followup”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Psilocybin was generally well-tolerated, with most adverse events being of mild or moderate severity and generally limited to the acute dosing period.

    “Psilocybin was generally well-tolerated, with most AEs being of mild or moderate severity and generally limited to the acute dosing period.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    No procedure for α-level control was applied for exploratory end points, therefore P values reported for these outcomes should be considered nominal.

    “No procedure for α-level control was applied for exploratory end points, therefore P values reported for these outcomes in eTables 4-8 in Supplement 3 should be considered nominal (ie, not adjusted for multiple comparisons).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Participants, study sponsor, and study site personnel were blinded to treatment group until unblinding following data lock.

    “Participants, study sponsor, and study site personnel were blinded to treatment group until unblinding following data lock.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The current study does not allow inferences to be drawn regarding whether the antidepressant effect would have diminished over subsequent weeks or been maintained.

    “Similarly, the current study does not allow inferences to be drawn regarding whether the antidepressant effect would have diminished over subsequent weeks or been maintained”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    With 100 participants, the study had 92% power for the primary day 43 end point and 98% power for the key secondary day 8 end point.

    “a sample size of 100 participants resulted in 92% power for the primary day 43 end point and 98% power for the key secondary day 8 end point.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A minimal clinically important difference (MCID) in change in MADRS score was not prespecified, although depression trial literature supports a placebo-adjusted change in score as low as 2 and as high as 9 and an absolute change from pretreatment of 6 as clinically meaningful and a change of 12 as clinically substantial.

    “A minimal clinically important difference (MCID) in change in MADRS score was not prespecified, although depression trial literature supports a placebo-adjusted change in score as low as 2 and as high as 9 and an absolute change from pretreatment of 6 as clinically meaningful and a change of 12 as clinically substantial.25,26”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] 25. Hengartner MP, Plöderl M. Estimates of the minimal important difference to evaluate the clinical significance of antidepressants in the acute treatment of moderate-to-severe depression. BMJ Evid Based Med. 2022;27(2):69-73. doi:10.1136/ bmjebm-2020-111600 source
    • cites [26] 26. Kobak KA, Williams JB, Jeglic E, Salvucci D, Sharp IR. Face-to-face versus remote administration of the Montgomery-Asberg Depression Rating Scale using videoconference and telephone. Depress Anxiety. 2008;25(11):913-919. doi:10.1002/da.20392 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Participants were randomized in a 1:1 ratio using permuted blocks with random block sizes of 2, 4, and 6, with randomization stratified by site.

    “eligible participants were randomized in a 1:1 ratio using permuted blocks with random block sizes of 2, 4, and 6, with randomization stratified by site”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The current study used off-site centralized raters to reduce the potential impact of unblinding on the assessment of outcomes.

    “To help address this issue, the current study used off-site centralized raters to reduce the potential impact of unblinding on the assessment of outcomes.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A sequential significance testing procedure was used to control the overall α level at .05 for primary and secondary end points.

    “A sequential significance testing procedure was used to control the overall α level at .05 for primary and secondary end points.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Sensitivity analyses using multiple imputation methods were run for the primary and key secondary outcomes.

    “Sensitivity analyses using multiple imputation methods were run for the primary and key secondary outcomes.”
    Quote in the paperNot a substantial claim
32 of 32

  • The paper relies on this without support.

    Niacin 100 mg is an inactive placebo with no antidepressant effect.

    “compared with a 100-mg dose of niacin placebo administered under an identical protocol.”
    “the use of niacin as active placebo may have increased believability of the comparator condition and enhanced the placebo response”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In some instances, control groups consisted of waiting lists rather than active comparators, and therapeutic settings were sometimes not consistently provided.

    “In some instances, control groups consisted of waiting lists rather than active comparators, 60,73 and therapeutic settings were sometimes not consistently provided. 74,76”

    From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [76]

    The waiting-list statement is attributed to other citations, not this paper. The Limitations section (page unavailable) says psychological support followed an identical, fully protocolized program, but facilitator fidelity was not assessed, leaving possible differences in support between participants. It does not establish that therapeutic settings were inconsistently provided. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Blinding procedures were not consistently robust, and comparison with placebo or standard treatments was lacking in many studies.

    “Blinding procedures were not consistently robust, 26,32,60,72-76 and comparison with placebo or standard treatments was lacking in many studies. 25,26,31-33,39,57,60,72,73,75-81”

    From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [76]

    The Limitations section says this trial did not assess whether blinding succeeded and that psilocybin’s effects likely caused some functional unblinding. The Study Procedures section shows that the trial did use an active placebo (niacin), though it did not compare psilocybin with a standard treatment. This single trial does not establish that placebo or standard-treatment comparisons were lacking in many studies. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Research on MDD, anxiety and depressive symptoms associated with life-threatening cancer, and TRD showed the most robust evidence, supported by a non-randomized study and several RCTs.

    “Research on MDD, anxiety and depressive symptoms associated with life-threatening cancer, and TRD showed the most robust evidence, supported by a non-randomized study 72 and several RCTs. 26,31-33,60,73-77”

    From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [76]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Drug-related adverse-event confidence interval differs from the table

    Minor

    For drug-related adverse events through day 9, the Results text gives 41.3% as the upper confidence limit for the between-group difference, while Table 3 gives 54.6% for the same 38% difference.

1 of 1

Cites

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Related

Authors
Raison, C. L., Sanacora, G., Woolley, J., Heinzerling, K., Dunlop, B. W., Brown, R. T., Kakar, R., Hassman, M., Trivedi, R. P., Robison, R., Gukasyan, N., Nayak, S. M., Hu, X., O’Donnell, K. C., Kelmendi, B., Sloshower, J., Penn, A. D., Bradley, E., Kelly, D. F., Mletzko, T., Nicholas, C. R., Hutson, P. R., Tarpley, G., Utzinger, M., Lenoch, K., Warchol, K., Gapasin, T., Davis, M. C., Nelson-Douthit, C., Wilson, S., Brown, C., Linton, W., Johnson, M. W., Ross, S., & Griffiths, R. R.
Affiliations
  • Usona Institute (US)
  • Yale University (US)
  • San Francisco VA Medical Center (US)
  • Pacific Neuroscience Institute, Santa Monica, California
  • Emory University (US)
  • University of Wisconsin–Madison (US)
  • Center for Psychedelic Research, Segal Trials, Lauderhill, Florida
  • Hassman Research Institute (US)
  • Flourish Research, Chicago, Illinois
  • University of Utah (US)
  • Johns Hopkins University (US)
  • NYU Langone Health (US)
  • University of California, San Francisco (US)
  • Usona Institute, Fitchburg, Wisconsin
  • Emmes (United States) (US)
Corresponding author
Raison, Charles L.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2023-09-05
Volume
330
Issue
9
Pages
843
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2023.14530
PMC
PMC10472268
OpenAlex
W4386305655
Cited by
545
References
35
Citations by year
2026: 165 · 2025: 212 · 2024: 152 · 2023: 16
FWCI
158.26
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (UL1TR001863)
  • National Center for Advancing Translational Sciences
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords
psilocybin, major depressive disorder, antidepressant effects, psychological support, depression remission, sustained response, adverse events, antidepressant safety, psychedelic therapy, Sheehan Disability Scale, Montgomery-Asberg Depression Rating Scale, treatment durability
MeSH terms
Adult, Major Depressive Disorder, Female, Hallucinogens, Humans, Male, Mental Health, Niacin, Psilocybin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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