Blinding and expectancy confounds in psychedelic randomized controlled trials

References

• Grinspoon L. Psychedelic drugs reconsidered/Lester Grinspoon & James B. Bakalar. Bakalar JB, editor. New York: Basic Books; 1979.
   Google Scholar
• Grof S. My ketamine journeys, or ketamine and the enchantment of other worlds. In: Wolfson P, Hartelius G, editors. The ketamine papers: science, therapy, and transformation. Multidisciplinary Association for Psychedelic Studies (MAPS). 2016.
   Google Scholar
• Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J Psychoactive Drugs. 1997 Apr-Jun;29(2):165–183.
   PubMed Web of Science ®Google Scholar
• Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci. 2010 Sep;11(9):642–651.
   PubMed Web of Science ®Google Scholar
• Peace KE, Chen D-G. Clinical trial methodology. Boca Raton, Fl: Chapman & Hall; 2010. ( (CRC Biostatistics Series)).
   Google Scholar
• Chow S-C, Liu JP. Design and analysis of clinical trials: concepts and methodologies. 3rd ed. Hoboken, New Jersey: John Wiley & Sons; 2014.
   Google Scholar
• Rubin DB. Estimating causal effects of treatments in randomized and nonrandomized studies. J Educ Psychol. 1974;66(5):688–701.
   Web of Science ®Google Scholar
• Holland PW. Statistics and Causal Inference. J Am Stat Assoc. 1986 Dec 01;81(396):945–960.
   Web of Science ®Google Scholar
• Deaton A, Cartwright N. Understanding and misunderstanding randomized controlled trials. Soc Sci Med. 2018 Aug;210:2–21.
   PubMed Web of Science ®Google Scholar
• Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?”. Lancet. 2005 Jan 1-7;365(9453):82–93.
   PubMed Web of Science ®Google Scholar
• Bothwell LE, Podolsky SH. The emergence of the randomized, controlled trial. N Engl J Med. 2016 Aug 11;375(6):501–504.
   PubMed Web of Science ®Google Scholar
• Podolsky SH, Jones DS, Kaptchuk TJ. Chapter 3 - From trials to trials: blinding, medicine, and honest adjudication. In: Kesselheim AS, Robertson CT, editors. Blinding as a solution to bias. San Diego: Academic Press; 2016. p. 45–58.
   Google Scholar
• Junod SW FDA and clinical drug trials: a short history.[cited 01 May 2021]. Available from: https://www.fda.gov/media/110437/download
   Google Scholar
• Hoffmann A. LSD: my problem child. Oxford: Oxford University Press; 2013.
   Google Scholar
• Krebs TS, Johansen PO. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol. 2012 Jul;26(7):994–1002.
   PubMed Web of Science ®Google Scholar
• Beecher HK. The powerful placebo. J Am Med Assoc. 1955 Dec 24;159(17):1602–1606.
   PubMed Web of Science ®Google Scholar
• Kaptchuk TJ. Powerful placebo: the dark side of the randomised controlled trial. Lancet. 1998;351(9117):1722–1725.
   PubMed Web of Science ®Google Scholar
• Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013;170(7):723–733.
   PubMed Web of Science ®Google Scholar
• Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? N Engl J Med. 2001;344(21):1594–1602.
   PubMed Web of Science ®Google Scholar
• Miller FG, Rosenstein DL. The nature and power of the placebo effect. J Clin Epidemiol. 2006 Apr 01;59(4):331–335.
   PubMed Web of Science ®Google Scholar
• Kirsch I, Scoboria A. Apples, oranges, and placebos: heterogeneity in a meta-analysis of placebo effects. Adv Mind Body Med. 2001 Fall;17(4): 307–9;discussion 312–8.
   PubMedGoogle Scholar
• Ader R. Much ado about nothing. Adv Mind Body Med. 2001 Fall;17(4): 293–5;discussion 312–8.
   PubMedGoogle Scholar
• Greene PJ, Wayne PM, Kerr CE, et al. The powerful placebo: doubting the doubters. Adv Mind Body Med. 2001 Fall;17(4):298–307;discussion 312–8.
   PubMedGoogle Scholar
• Benedetti F. Placebo effects: from the neurobiological paradigm to translational implications. Neuron. 2014 Nov 5;84(3):623–637.
   PubMed Web of Science ®Google Scholar
• Turner JA, Deyo RA, Loeser JD, et al. The importance of placebo effects in pain treatment and research. JAMA. 1994;271(20):1609–1614.
   PubMed Web of Science ®Google Scholar
• Glasziou P, Chalmers I, Rawlins M, et al. When are randomised trials unnecessary? Picking signal from noise. BMJ. 2007;334(7589):349.
   PubMed Web of Science ®Google Scholar
• Jamshidian F, Hubbard AE, Jewell NP. Accounting for perception, placebo and unmasking effects in estimating treatment effects in randomised clinical trials. Stat Methods Med Res. 2014 Jun;23(3):293–307.
   PubMed Web of Science ®Google Scholar
• Kaptchuk TJ. The double-blind, randomized, placebo-controlled trial: gold standard or golden calf? J Clin Epidemiol. 2001 Jun;54(6):541–549.
   PubMed Web of Science ®Google Scholar
• Dahan R, Caulin C, Figea L, et al. Does informed consent influence therapeutic outcome? A clinical trial of the hypnotic activity of placebo in patients admitted to hospital. Br Med J (Clin Res Ed). 1986;293(6543):363–364.
   PubMed Web of Science ®Google Scholar
• Bergmann JF, Chassany O, Gandiol J, et al. A randomised clinical trial of the effect of informed consent on the analgesic activity of placebo and naproxen in cancer pain. Clin Trials Metaanal. 1994 Apr;29(1):41–47.
   PubMedGoogle Scholar
• Kirsch I. Are drug and placebo effects in depression additive? Biol Psychiatry. 2000 Apr 15;47(8):733–735.
   PubMed Web of Science ®Google Scholar
• Kube T, Rief W. Are placebo and drug-specific effects additive? Questioning basic assumptions of double-blinded randomized clinical trials and presenting novel study designs. Drug Discov Today. 2017 Apr;22(4):729–735.
   PubMed Web of Science ®Google Scholar
• Hartogsohn I. Set and setting, psychedelics and the placebo response: an extra-pharmacological perspective on psychopharmacology. J Psychopharmacol. 2016 Dec;30(12):1259–1267.
   PubMed Web of Science ®Google Scholar
• Strassman R. The political correction of psychedelics. Part 3. Psychedelics as Super-Placebos 2017. [cited 01 May 2021]. Available from: https://www.rickstrassman.com/the-political-correction-of-psychedelics-part-3-psychedelics-as-super-placebos
   Google Scholar
• Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008 May 3;336(7651):999–1003.
   PubMed Web of Science ®Google Scholar
• Gukasyan N, Nayak S Psychedelics, placebo effects, and set and setting: insights from common factors theory of psychotherapy. Transcultural Psychiatry: Cultural Contexts and Ethical Issues in the Therapeutic Use of Psychedelics. 2020;in press.
   Google Scholar
• Carhart-Harris RL, Roseman L, Haijen E, et al. Psychedelics and the essential importance of context. J Psychopharmacol. 2018 Jul;32(7):725–731.
   PubMed Web of Science ®Google Scholar
• Kirsch I. Response expectancy and the placebo effect. Int Rev Neurobiol. 2018;138:81–93.
   PubMed Web of Science ®Google Scholar
• Zilcha-Mano S, Roose SP, Brown PJ, et al. Not just nonspecific factors: the roles of alliance and expectancy in treatment, and their neurobiological underpinnings. Front Behav Neurosci. 2019;12:293.
   PubMed Web of Science ®Google Scholar
• Rutherford BR, Sneed JR, Roose SP. Does study design influence outcome? The effects of placebo control and treatment duration in antidepressant trials. Psychother Psychosom. 2009;78(3):172–181.
   PubMed Web of Science ®Google Scholar
• Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2009 Jan;19(1):34–40.
   PubMed Web of Science ®Google Scholar
• Constantino MJ, Vîslă A, Coyne AE, et al. A meta-analysis of the association between patients’ early treatment outcome expectation and their posttreatment outcomes. Psychotherapy (Chic). 2018 Dec;55(4):473–485.
   PubMed Web of Science ®Google Scholar
• Kaertner LS, Steinborn MB, Kettner H, et al. Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing. Sci Rep. 2021 Jan 21;11(1):1941.
   PubMed Web of Science ®Google Scholar
• Borkovec TD, Nau SD. Credibility of analogue therapy rationales. J Behav Ther Exp Psychiatry. 1972 Jan 01;3(4):257–260.
   Web of Science ®Google Scholar
• Devilly GJ, Borkovec TD. Psychometric properties of the credibility/expectancy questionnaire. J Behav Ther Exp Psychiatry. 2000 Jun 01;31(2):73–86.
   PubMed Web of Science ®Google Scholar
• Rutherford BR, Marcus SM, Wang P, et al. A randomized, prospective pilot study of patient expectancy and antidepressant outcome. Psychol Med. 2013 May;43(5):975–982.
   PubMed Web of Science ®Google Scholar
• Rutherford BR, Wall MM, Brown PJ, et al. Patient expectancy as a mediator of placebo effects in antidepressant clinical trials. Am J Psychiatry. 2017;174(2):135–142.
   PubMed Web of Science ®Google Scholar
• Younger J, Gandhi V, Hubbard E, et al. Development of the Stanford Expectations of Treatment Scale (SETS): a tool for measuring patient outcome expectancy in clinical trials. Clin Trial. 2012 Dec 01;9(6):767–776.
   PubMed Web of Science ®Google Scholar
• Dore J, Turnipseed B, Dwyer S, et al. Ketamine Assisted Psychotherapy (KAP): patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoactive Drugs. 2019 Mar 15;51(2):189–198.
   PubMed Web of Science ®Google Scholar
• Flückiger C, Del Re AC, Wampold BE, et al. The alliance in adult psychotherapy: a meta-analytic synthesis. Psychotherapy (Chic). 2018 Dec;55(4):316–340.
   PubMed Web of Science ®Google Scholar
• Posternak MA, Zimmerman M. Therapeutic effect of follow-up assessments on antidepressant and placebo response rates in antidepressant efficacy trials: meta-analysis. Br J Psychiatry. 2007 Apr;190:287–292.
   PubMed Web of Science ®Google Scholar
• Rutherford BR, Tandler J, Brown PJ, et al. Clinic visits in late-life depression trials: effects on signal detection and therapeutic outcome. Am J Geriatr Psychiatry. 2014;22(12):1452–1461.
   PubMed Web of Science ®Google Scholar
• Furukawa TA, Cipriani A, Atkinson LZ, et al. Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies. Lancet Psychiatry. 2016 Nov;3(11):1059–1066.
   PubMed Web of Science ®Google Scholar
• ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. International conference on harmonisation E9 expert working group. Stat Med. 1999 Aug 15;18(15):1905–1942.
   PubMed Web of Science ®Google Scholar
• Sumner RL, McMillan R, Spriggs MJ, et al. Ketamine enhances visual sensory evoked potential long-term potentiation in patients with major depressive disorder. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Jan 01;5(1):45–55.
   PubMedGoogle Scholar
• Hróbjartsson A, Emanuelsson F, Skou Thomsen AS, et al. Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies. Int J Epidemiol. 2014;43(4):1272–1283.
   PubMed Web of Science ®Google Scholar
• Savovic J, Jones H, Altman D, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies. Health Technol Assess. 2012 Sep;16(35):1–82.
   PubMed Web of Science ®Google Scholar
• Nüesch E, Reichenbach S, Trelle S, et al. The importance of allocation concealment and patient blinding in osteoarthritis trials: a meta-epidemiologic study. Arthritis Care Res (Hoboken). 2009 Dec 15;61(12):1633–1641.
   Web of Science ®Google Scholar
• Higgins JPT, Savovic J, Page MJ, et al. Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). 2019.
   Google Scholar
• Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev. 2015 Sep;23(9):Cd011612.
   Google Scholar
• Moncrieff J, Wessely S, Hardy R Active placebos versus antidepressants for depression. Cochrane Database of Systematic Reviews. 2004 (1).
   Google Scholar
• Ney PG, Collins C, Spensor C. Double blind: double talk or are there ways to do better research. Med Hypotheses. 1986 Oct;21(2):119–126.
   PubMed Web of Science ®Google Scholar
• Howick J. The philosophy of evidence‐based medicine. Chicester, United Kingdom: BMJ books. WIley-Blackwell.; 2011.
   Google Scholar
• Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134–1142.
   PubMed Web of Science ®Google Scholar
• Sumner R, McMillan R, Spriggs M, et al. Ketamine enhances visual sensory evoked potential LTP in patients with major depressive disorder. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging 2019;In press.
   Google Scholar
• Jager KJ, Zoccali C, MacLeod A, et al. Confounding: what it is and how to deal with it. Kidney Int. 2008 Feb 01;73(3):256–260.
   PubMed Web of Science ®Google Scholar
• Straus SE, Glasziou P, Richardson WS, et al. Evidence-based medicine E-book: how to practice and teach EBM. Philadelphia, UNITED KINGDOM: Elsevier; 2018.
   Google Scholar
• Sumner RL, Chacko E, McMillan R, et al. A qualitative and quantitative account of patient’s experiences of ketamine and its antidepressant properties. J Psychopharmacol. 2021:0269881121998321.
   Web of Science ®Google Scholar
• Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010 Mar;23(340):c869.
   Web of Science ®Google Scholar
• Moher D, Schulz KF, Altman DG, et al. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann Intern Med. 2001 Apr 17;134(8):657–662.
   PubMed Web of Science ®Google Scholar
• Fergusson D, Glass KC, Waring D, et al. Turning a blind eye: the success of blinding reported in a random sample of randomised, placebo controlled trials. BMJ. 2004 Feb 21;328(7437):432.
   PubMed Web of Science ®Google Scholar
• Hrobjartsson A, Forfang E, Haahr MT, et al. Blinded trials taken to the test: an analysis of randomized clinical trials that report tests for the success of blinding. Int J Epidemiol. 2007 Jun;36(3):654–663.
   PubMed Web of Science ®Google Scholar
• Sackett DL. Turning a blind eye: why we don’t test for blindness at the end of our trials. BMJ (Clin Res Ed). 2004;328(7448):1136.
   PubMed Web of Science ®Google Scholar
• Sackett DL. Commentary: measuring the success of blinding in RCTs: don’t, must, can’t or needn’t? Int J Epidemiol. 2007 Jun;36(3):664–665.
   PubMed Web of Science ®Google Scholar
• Senn SJ. Turning a blind eye: authors have blinkered view of blinding. BMJ (Clin Res Ed). 2004;328(7448):1135–1136.
   PubMed Web of Science ®Google Scholar
• Bang H, Ni L, Davis CE. Assessment of blinding in clinical trials. Control Clin Trials. 2004 Apr;25(2):143–156.
   PubMedGoogle Scholar
• James KE, Bloch DA, Lee KK, et al. An index for assessing blindness in a multi-centre clinical trial: disulfiram for alcohol cessation–a VA cooperative study. Stat Med. 1996 Jul 15;15(13):1421–1434.
   PubMed Web of Science ®Google Scholar
• Rees JR, Wade TJ, Levy DA, et al. Changes in beliefs identify unblinding in randomized controlled trials: a method to meet CONSORT guidelines. Contemp Clin Trials. 2005 Dec 01;26(1):25–37.
   PubMed Web of Science ®Google Scholar
• Kolahi J, Bang H, Park J. Towards a proposal for assessment of blinding success in clinical trials: up-to-date review. Community Dent Oral Epidemiol. 2009 Dec;37(6):477–484.
   PubMed Web of Science ®Google Scholar
• Mathai DS, Meyer MJ, Storch EA, et al. The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: a systematic review. J Affect Disord. 2020 Mar 01;264:123–129.
   PubMed Web of Science ®Google Scholar
• Bahji A, Vazquez GH, Zarate CA. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021 Jan 01;278:542–555.
   PubMed Web of Science ®Google Scholar
• Arabzadeh S, Hakkikazazi E, Shahmansouri N, et al. Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial. J Affect Disord. 2018;235:236–241.
   PubMed Web of Science ®Google Scholar
• Berman R, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–354. .
   Web of Science ®Google Scholar
• Burger J, Capobianco M, Lovern R, et al. A double-blinded, randomized, placebo-controlled sub-dissociative dose ketamine pilot study in the treatment of acute depression and suicidality in a military emergency department setting. Mil Med. 2016;181(10):1195–1199.
   PubMed Web of Science ®Google Scholar
• Canuso C, Fu DJ, Ionescu DF, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in adult patients with major depressive disorder at imminent risk for suicide: results from the phase 3 program. Neuropsychopharmacology. 2019 December;44(Supplement 1):454–455.
   Web of Science ®Google Scholar
• Cao Z, Lin C, Ding W, et al. Identifying ketamine responses in treatment-resistant depression using a wearable forehead EEG. IEEE transactions on biomedical engineering. 2018;66(6):1668-1679.
   Google Scholar
• Chen MH, Li CT, Lin WC, et al. Persistent antidepressant effect of low-dose ketamine and activation in the supplementary motor area and anterior cingulate cortex in treatment-resistant depression: a randomized control study. J Affect Disord. 2018 Jan 01;225:709–714.
   PubMed Web of Science ®Google Scholar
• Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139–148.
   PubMed Web of Science ®Google Scholar
• Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793–802.
   PubMed Web of Science ®Google Scholar
• Domany Y, Shelton R, McCullumsmith C Ketamine for acute suicidal ideation. An emergency department intervention: a randomized, double-blind, placebo-controlled, proof-of-concept trial. Depression and anxiety. 2020 Mar;37(3):224-233.
   Google Scholar
• Downey D, Dutta A, McKie S, et al. Comparing the actions of lanicemine and ketamine in depression: key role of the anterior cingulate. European neuropsychopharmacology. 2016;26(6):994-1003.
   Google Scholar
• Fava M, Freeman M, Flynn M, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Molecular psychiatry. 2018;22(10):616-630.
   Google Scholar
• Fedgchin M, Trivedi M, Daly E, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616–630
   PubMed Web of Science ®Google Scholar
• Grunebaum MF, Galfalvy HC, Choo TH, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2018 Apr 01;175(4):327–335.
   PubMed Web of Science ®Google Scholar
• Hu Y, Xiang Y, Fang J, et al. Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. Psychol Med. 2016 Feb;46(3):623–635.
   PubMed Web of Science ®Google Scholar
• Ionescu DF, Bentley KH, Eikermann M, et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: a randomized, double blind, placebo controlled trial. J Affect Disord. 2019 January 15;243:516–524.
   PubMed Web of Science ®Google Scholar
• Ionescu DF, Fu D-J, Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a Phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol. 2020;24(1):22-31.
   PubMed Web of Science ®Google Scholar
• Jafarinia M, Afarideh M, Tafakhori A, et al. Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: a double-blind, randomized, controlled trial. J Affect Disord. 2016;204:1–8.
   PubMed Web of Science ®Google Scholar
• Lai R, Katalinic N, Glue P, et al. Pilot dose-response trial of i.v. ketamine in treatment-resistant depression. World J Biol Psychiatry. 2014;15(7):579–584.
   PubMed Web of Science ®Google Scholar
• Lapidus KA, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014 Dec 15;76(12):970–976.
   PubMed Web of Science ®Google Scholar
• Li CT, Chen MH, Lin WC, et al. The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: a randomized controlled study. Hum Brain Mapp. 2016 Mar 01;37(3):1080–1090.
   PubMed Web of Science ®Google Scholar
• Loo C, Galvez V, O’Keefe E, et al. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr Scand. 2016 Jul;134(1):48–56.
   PubMed Web of Science ®Google Scholar
• Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site, randomized, parallel-arm, midazolam-controlled, clinical trial. Neuropsychopharmacology. 2012;38:S151–S152.
   Google Scholar
• Murrough J, Soleimani L, DeWilde K, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med. 2015 Dec;45(16):3571–3580.
   PubMed Web of Science ®Google Scholar
• Nugent A, Ballard E, Gould T, et al. Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Molecular psychiatry. 2018;24(7):1040-1052
   Google Scholar
• Phillips JL, Norris S, Talbot J, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019 May 01;176(5):401–409.
   PubMed Web of Science ®Google Scholar
• Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019 Jun 01;176(6):428–438.
   PubMed Web of Science ®Google Scholar
• Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016 Aug 01;173(8):816–826.
   PubMed Web of Science ®Google Scholar
• Xu Y, Li Y, Huang X, et al. Single bolus low-dose of ketamine does not prevent postpartum depression: a randomized, double-blind, placebo-controlled, prospective clinical trial. Arch Gynecol Obstet. 2017 May 01;295(5):1167–1174.
   PubMed Web of Science ®Google Scholar
• Zarate JCA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856–864.
   PubMed Web of Science ®Google Scholar
• Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68(1):71–78.
   PubMed Web of Science ®Google Scholar
• Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655–663.
   PubMed Web of Science ®Google Scholar
• 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 Dec 01;30(12):1165–1180.
   PubMed Web of Science ®Google Scholar
• Bogenschutz MP, Forcehimes AA, Pommy JA, et al. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015;29(3):289–299.
   PubMed Web of Science ®Google Scholar
• Johnson MW, Garcia-Romeu A, Cosimano MP, et al. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 2014;28(11):983–992.
   PubMed Web of Science ®Google Scholar
• Osório F, Sanches RF, Macedo LR, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Braz J Psychiatry. 2015;37(1):13–20.
   PubMed Web of Science ®Google Scholar
• Sanches RF, De Lima Osório F, Dos Santos RG, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a SPECT study. J Clin Psychopharmacol. 2016;36(1):77–81.
   PubMed Web of Science ®Google Scholar
• Thomas G, Lucas P, Capler NR, et al. Ayahuasca-assisted therapy for addiction: results from a preliminary observational study in Canada. Curr Drug Abuse Rev. 2013;6(1):30–42.
   PubMedGoogle Scholar
• Nutt DJ, King LA, Nichols DE. Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nat Rev Neurosci. 2013 Aug;14(8):577–585.
   PubMed Web of Science ®Google Scholar
• Ballou S, Kaptchuk TJ, Hirsch W, et al. Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial. Trials. 2017 May 25;18(1):234.
   PubMed Web of Science ®Google Scholar
• Chambers CD, Forstmann B, Pruszynski JA. Science in flux: registered reports and beyond at the European journal of neuroscience. Eur J Neurosci. 2019 Jan 01;49(1):4–5.
   PubMed Web of Science ®Google Scholar
• Miller GA, Chapman JP. Misunderstanding analysis of covariance. J Abnorm Psychol. 2001 Feb;110(1):40–48.
   PubMed Web of Science ®Google Scholar
• Wilkinson ST, Farmer C, Ballard ED, et al. Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. Neuropsychopharmacology. 2019 Jun 01;44(7):1233–1238.
   PubMed Web of Science ®Google Scholar
• Doblin R. Pahnke’s “Good Friday experiment”: a long-term follow-up and methodological critique. J Transpersonal Psychol. 1991;23(1):1–28.
   Google Scholar
• Gasser P, Holstein D, Michel Y, et al. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis. 2014 Jul;202(7):513–520.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Moreno FA, Wiegand CB, Taitano EK, et al. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry. 2006;67(11):1735–1740.
   PubMed Web of Science ®Google Scholar
• London AJ. Equipoise in research: integrating ethics and science in human research. JAMA. 2017;317(5):525–526.
   PubMed Web of Science ®Google Scholar
• Walsh BT, Seidman SN, Sysko R, et al. Placebo response in studies of major depressionvariable, substantial, and growing. JAMA. 2002;287(14):1840–1847.
   PubMed Web of Science ®Google Scholar
• Li F, Nasir M, Olten B, et al. Meta-analysis of placebo response in adult antidepressant trials. CNS Drugs. 2019 Oct 01;33(10):971–980.
   PubMed Web of Science ®Google Scholar
• Faries DE, Heiligenstein JH, Tollefson GD, et al. The double-blind variable placebo lead-in period: results from two antidepressant clinical trials. J Clin Psychopharmacol. 2001;21(6):561–568.
   PubMed Web of Science ®Google Scholar
• Kaptchuk TJ, Kelley JM, Deykin A, et al. Do “placebo responders” exist? Contemp Clin Trials. 2008 Jul 01;29(4):587–595.
   PubMed Web of Science ®Google Scholar
• Fava M, Evins AE, Dorer DJ, et al. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother Psychosom. 2003 May-Jun;72(3):115–127.
   PubMed Web of Science ®Google Scholar
• Jones B, Kenward M. Design and analysis of cross-over trials. New York: Chapman and Hall/CRC.; 2015.
   Google Scholar
• Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2020;78(5):481-489
   Web of Science ®Google Scholar
• Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016 Jul;3(7):619–627.
   PubMed Web of Science ®Google Scholar
• Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018 Dec 01;175(12):1205–1215.
   PubMed Web of Science ®Google Scholar
• Anand A, Charney DS, Oren DA, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry. 2000;57(3):270–276.
   PubMed Web of Science ®Google Scholar
• Deakin JFW, Lees J, McKie S, et al. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco–magnetic resonance imaging study. Arch Gen Psychiatry. 2008;65(2):154–164.
   PubMed Web of Science ®Google Scholar
• Kraehenmann R, Pokorny D, Aicher H, et al. LSD increases primary process thinking via serotonin 2A receptor activation. Front Pharmacol. 2017;8:814.
   PubMed Web of Science ®Google Scholar
• Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Bäbler A, et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport. 1998;9(17):3897–3902.
   PubMed Web of Science ®Google Scholar
• Holze F, Vizeli P, Ley L, et al. Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology. 2020 Oct 15;46:537–544.
   Web of Science ®Google Scholar
• Carroll RJ, Stefanski LA. Approximate Quasi-likelihood estimation in models with surrogate predictors. J Am Stat Assoc. 1990;85(411):652–663.
   Web of Science ®Google Scholar
• Cartwright N, Hardie J. Evidence-based policy: a practical guide to doing it better. New York: Oxford Scholarship Online; 2015.
   Google Scholar