Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) Therapy for Patients With Advanced Cancer: A Randomized Controlled Trial

Summary

Phase II randomized controlled trial, followed by an open-label extension phase. In the main study, participants will receive either a single high-dose (25 mg) or low-dose (1 mg) of psilocybin in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy. Upon completion of main study, participants who received the low dose will be offered to receive a single high-dose of psilocybin (25 mg) in the context of PEARL therapy (Open label extension study).

Timeline

Start

2026-09-14

Primary completion

2028-12-30

Completion

2029-07-30

Publications

• Background Freidel N, Kreuder L, Rabinovitch BS, Chen FY, Huang RST, Lewis EC. Psychedelics, epilepsy, and seizures: a review. Front Pharmacol. 2024 Jan 12;14:1326815. doi: 10.3389/fphar.2023.1326815. eCollection 2023.
• Background Kelly DF, Heinzerling K, Sharma A, Gowrinathan S, Sergi K, Mallari RJ. Psychedelic-Assisted Therapy and Psychedelic Science: A Review and Perspective on Opportunities in Neurosurgery and Neuro-Oncology. Neurosurgery. 2023 Apr 1;92(4):680-694. doi: 10.1227/neu.0000000000002275. Epub 2022 Dec 8.
• Background Simonsson O, Goldberg SB, Chambers R, Osika W, Long DM, Hendricks PS. Prevalence and associations of classic psychedelic-related seizures in a population-based sample. Drug Alcohol Depend. 2022 Oct 1;239:109586. doi: 10.1016/j.drugalcdep.2022.109586. Epub 2022 Aug 11.
• Background Doyle MA, Ling S, Lui LMW, Fragnelli P, Teopiz KM, Ho R, Di Vincenzo JD, Rosenblat JD, Gillissie ES, Nogo D, Ceban F, Jawad MY, McIntyre RS. Hallucinogen persisting perceptual disorder: a scoping review covering frequency, risk factors, prevention, and treatment. Expert Opin Drug Saf. 2022 Jun;21(6):733-743. doi: 10.1080/14740338.2022.2063273. Epub 2022 May 3.
• Background Rosenblat JD, Meshkat S, Doyle Z, Kaczmarek E, Brudner RM, Kratiuk K, Mansur RB, Schulz-Quach C, Sethi R, Abate A, Ali S, Bawks J, Blainey MG, Brietzke E, Cronin V, Danilewitz J, Dhawan S, Di Fonzo A, Di Fonzo M, Drzadzewski P, Dunlop W, Fiszter H, Gomes FA, Grewal S, Leon-Carlyle M, McCallum M, Mofidi N, Offman H, Riva-Cambrin J, Schmidt J, Smolkin M, Quinn JM, Zumrova A, Marlborough M, McIntyre RS. Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin. Med. 2024 Mar 8;5(3):190-200.e5. doi: 10.1016/j.medj.2024.01.005. Epub 2024 Feb 14.
• Background Harris G, Jones S, Pinkham MB, Lion KM, Ownsworth T. Reliability and validity of the telephone-based version of the Montgomery-Asberg depression rating scale for assessing depression in individuals with primary brain tumour. Disabil Rehabil. 2024 Mar;46(6):1158-1166. doi: 10.1080/09638288.2023.2191015. Epub 2023 Apr 5.
• Background Eskelinen M, Selander T, Ollonen P, Korhonen R. Moderate/severe Depression (MADRS) Can Affect the Quality of Life and Outcome Among Patients Admitted to Breast Cancer Diagnosis Unit. Anticancer Res. 2017 May;37(5):2641-2647. doi: 10.21873/anticanres.11611.
• Background Li M, Fitzgerald P, Rodin G. Evidence-based treatment of depression in patients with cancer. J Clin Oncol. 2012 Apr 10;30(11):1187-96. doi: 10.1200/JCO.2011.39.7372. Epub 2012 Mar 12.
• Background Evans J, Robinson OC, Argyri EK, Suseelan S, Murphy-Beiner A, McAlpine R, Luke D, Michelle K, Prideaux E. Extended difficulties following the use of psychedelic drugs: A mixed methods study. PLoS One. 2023 Oct 24;18(10):e0293349. doi: 10.1371/journal.pone.0293349. eCollection 2023.
• Background Barrett FS, Bradstreet MP, Leoutsakos JS, Johnson MW, Griffiths RR. The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms. J Psychopharmacol. 2016 Dec;30(12):1279-1295. doi: 10.1177/0269881116678781. Epub 2016 Nov 17.
• Background Rosenblat JD, Li M. Is ketamine a litmus test for capacity in assisted dying with depression? Psychooncology. 2021 Mar;30(3):417-420. doi: 10.1002/pon.5586. Epub 2020 Nov 15. No abstract available.
• Background Lowe B, Unutzer J, Callahan CM, Perkins AJ, Kroenke K. Monitoring depression treatment outcomes with the patient health questionnaire-9. Med Care. 2004 Dec;42(12):1194-201. doi: 10.1097/00005650-200412000-00006.
• Background Borm GF, Fransen J, Lemmens WA. A simple sample size formula for analysis of covariance in randomized clinical trials. J Clin Epidemiol. 2007 Dec;60(12):1234-8. doi: 10.1016/j.jclinepi.2007.02.006. Epub 2007 Jun 6.
• Background O'Cathain A, Murphy E, Nicholl J. Three techniques for integrating data in mixed methods studies. BMJ. 2010 Sep 17;341:c4587. doi: 10.1136/bmj.c4587. No abstract available.
• Background Bowleg L. The problem with the phrase women and minorities: intersectionality-an important theoretical framework for public health. Am J Public Health. 2012 Jul;102(7):1267-73. doi: 10.2105/AJPH.2012.300750. Epub 2012 May 17.
• Background Hsieh HF, Shannon SE. Three approaches to qualitative content analysis. Qual Health Res. 2005 Nov;15(9):1277-88. doi: 10.1177/1049732305276687.
• Background Younger J, Gandhi V, Hubbard E, Mackey S. Development of the Stanford Expectations of Treatment Scale (SETS): a tool for measuring patient outcome expectancy in clinical trials. Clin Trials. 2012 Dec;9(6):767-76. doi: 10.1177/1740774512465064. Epub 2012 Nov 20.
• Background Barrett FS, Johnson MW, Griffiths RR. Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J Psychopharmacol. 2015 Nov;29(11):1182-90. doi: 10.1177/0269881115609019. Epub 2015 Oct 6.
• Background Watanabe SM, Nekolaichuk CL, Beaumont C. The Edmonton Symptom Assessment System, a proposed tool for distress screening in cancer patients: development and refinement. Psychooncology. 2012 Sep;21(9):977-85. doi: 10.1002/pon.1996. Epub 2011 Jun 13.
• Background Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care. 1991 Summer;7(2):6-9.
• Background Calder AE, Hasler G. Validation of the Swiss Psychedelic Side Effects Inventory: Standardized assessment of adverse effects in studies of psychedelics and MDMA. J Affect Disord. 2024 Nov 15;365:258-264. doi: 10.1016/j.jad.2024.08.091. Epub 2024 Aug 19.
• Background Albers G, Echteld MA, de Vet HC, Onwuteaka-Philipsen BD, van der Linden MH, Deliens L. Evaluation of quality-of-life measures for use in palliative care: a systematic review. Palliat Med. 2010 Jan;24(1):17-37. doi: 10.1177/0269216309346593. Epub 2009 Oct 20.
• Background Steinhauser KE, Clipp EC, Bosworth HB, McNeilly M, Christakis NA, Voils CI, Tulsky JA. Measuring quality of life at the end of life: validation of the QUAL-E. Palliat Support Care. 2004 Mar;2(1):3-14. doi: 10.1017/s1478951504040027.
• Background Morita T, Murata H, Kishi E, Miyashita M, Yamaguchi T, Uchitomi Y; Japanese Spiritual Care Task Force. Meaninglessness in terminally ill cancer patients: a randomized controlled study. J Pain Symptom Manage. 2009 Apr;37(4):649-58. doi: 10.1016/j.jpainsymman.2008.04.017. Epub 2008 Oct 1.
• Background Breitbart W, Rosenfeld B, Gibson C, Pessin H, Poppito S, Nelson C, Tomarken A, Timm AK, Berg A, Jacobson C, Sorger B, Abbey J, Olden M. Meaning-centered group psychotherapy for patients with advanced cancer: a pilot randomized controlled trial. Psychooncology. 2010 Jan;19(1):21-8. doi: 10.1002/pon.1556.
• Background Peterman AH, Fitchett G, Brady MJ, Hernandez L, Cella D. Measuring spiritual well-being in people with cancer: the functional assessment of chronic illness therapy--Spiritual Well-being Scale (FACIT-Sp). Ann Behav Med. 2002 Winter;24(1):49-58. doi: 10.1207/S15324796ABM2401_06.
• Background Kissane DW, Wein S, Love A, Lee XQ, Kee PL, Clarke DM. The Demoralization Scale: a report of its development and preliminary validation. J Palliat Care. 2004 Winter;20(4):269-76.
• Background Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006 May 22;166(10):1092-7. doi: 10.1001/archinte.166.10.1092.
• Background Smith KA, Harvath TA, Goy ER, Ganzini L. Predictors of pursuit of physician-assisted death. J Pain Symptom Manage. 2015 Mar;49(3):555-61. doi: 10.1016/j.jpainsymman.2014.06.010. Epub 2014 Aug 10.
• Background Muthukumaraswamy SD, Forsyth A, Lumley T. Blinding and expectancy confounds in psychedelic randomized controlled trials. Expert Rev Clin Pharmacol. 2021 Sep;14(9):1133-1152. doi: 10.1080/17512433.2021.1933434. Epub 2021 Aug 26.
• Background Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382.
• Background Agin-Liebes GI, Malone T, Yalch MM, Mennenga SE, Ponte KL, Guss J, Bossis AP, Grigsby J, Fischer S, Ross S. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. J Psychopharmacol. 2020 Feb;34(2):155-166. doi: 10.1177/0269881119897615. Epub 2020 Jan 9.
• Background Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl). 2006 Aug;187(3):268-83; discussion 284-92. doi: 10.1007/s00213-006-0457-5. Epub 2006 Jul 7.
• Background Kocarova R, Horacek J, Carhart-Harris R. Does Psychedelic Therapy Have a Transdiagnostic Action and Prophylactic Potential? Front Psychiatry. 2021 Jul 19;12:661233. doi: 10.3389/fpsyt.2021.661233. eCollection 2021.
• Background Beaussant Y, Sanders J, Sager Z, Tulsky JA, Braun IM, Blinderman CD, Bossis AP, Byock I. Defining the Roles and Research Priorities for Psychedelic-Assisted Therapies in Patients with Serious Illness: Expert Clinicians' and Investigators' Perspectives. J Palliat Med. 2020 Oct;23(10):1323-1334. doi: 10.1089/jpm.2019.0603. Epub 2020 Apr 1.
• Background Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, Greer GR. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011 Jan;68(1):71-8. doi: 10.1001/archgenpsychiatry.2010.116. Epub 2010 Sep 6.
• Background Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B, Passie T, Brenneisen R. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis. 2014 Jul;202(7):513-20. doi: 10.1097/NMD.0000000000000113.
• Background Carhart-Harris RL, Roseman L, Haijen E, Erritzoe D, Watts R, Branchi I, Kaelen M. Psychedelics and the essential importance of context. J Psychopharmacol. 2018 Jul;32(7):725-731. doi: 10.1177/0269881118754710. Epub 2018 Feb 15.
• Background Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. 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;30(12):1165-1180. doi: 10.1177/0269881116675512.
• Background Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-1197. doi: 10.1177/0269881116675513.
• Background Ross S, Agrawal M, Griffiths RR, Grob C, Berger A, Henningfield JE. Psychedelic-assisted psychotherapy to treat psychiatric and existential distress in life-threatening medical illnesses and palliative care. Neuropharmacology. 2022 Sep 15;216:109174. doi: 10.1016/j.neuropharm.2022.109174. Epub 2022 Jun 27.
• Background Ross S. Therapeutic use of classic psychedelics to treat cancer-related psychiatric distress. Int Rev Psychiatry. 2018 Aug;30(4):317-330. doi: 10.1080/09540261.2018.1482261. Epub 2018 Aug 13.
• Background Reiche S, Hermle L, Gutwinski S, Jungaberle H, Gasser P, Majic T. Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:1-10. doi: 10.1016/j.pnpbp.2017.09.012. Epub 2017 Sep 22.
• Background Madsen MK, Fisher PM, Burmester D, Dyssegaard A, Stenbaek DS, Kristiansen S, Johansen SS, Lehel S, Linnet K, Svarer C, Erritzoe D, Ozenne B, Knudsen GM. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology. 2019 Jun;44(7):1328-1334. doi: 10.1038/s41386-019-0324-9. Epub 2019 Jan 26.
• Background Roseman L, Haijen E, Idialu-Ikato K, Kaelen M, Watts R, Carhart-Harris R. Emotional breakthrough and psychedelics: Validation of the Emotional Breakthrough Inventory. J Psychopharmacol. 2019 Sep;33(9):1076-1087. doi: 10.1177/0269881119855974. Epub 2019 Jul 11.
• Background Carhart-Harris RL, Nutt DJ. Serotonin and brain function: a tale of two receptors. J Psychopharmacol. 2017 Sep;31(9):1091-1120. doi: 10.1177/0269881117725915. Epub 2017 Aug 31.
• Background Rodin G, Lo C, Rydall A, Shnall J, Malfitano C, Chiu A, Panday T, Watt S, An E, Nissim R, Li M, Zimmermann C, Hales S. Managing Cancer and Living Meaningfully (CALM): A Randomized Controlled Trial of a Psychological Intervention for Patients With Advanced Cancer. J Clin Oncol. 2018 Aug 10;36(23):2422-2432. doi: 10.1200/JCO.2017.77.1097. Epub 2018 Jun 29.
• Background Rodin, G. & Hales, S. Managing Cancer and Living Meaningfully: An Evidence-Based Intervention for Cancer Patients and Their Caregivers. (Oxford University Press, 2021).
• Background Grossman CH, Brooker J, Michael N, Kissane D. Death anxiety interventions in patients with advanced cancer: A systematic review. Palliat Med. 2018 Jan;32(1):172-184. doi: 10.1177/0269216317722123. Epub 2017 Aug 8.
• Background Fulton JJ, Newins AR, Porter LS, Ramos K. Psychotherapy Targeting Depression and Anxiety for Use in Palliative Care: A Meta-Analysis. J Palliat Med. 2018 Jul;21(7):1024-1037. doi: 10.1089/jpm.2017.0576. Epub 2018 Apr 20.
• Background Ostuzzi G, Matcham F, Dauchy S, Barbui C, Hotopf M. Antidepressants for the treatment of depression in people with cancer. Cochrane Database Syst Rev. 2018 Apr 23;4(4):CD011006. doi: 10.1002/14651858.CD011006.pub3.
• Background Kaasa S, Loge JH, Aapro M, Albreht T, Anderson R, Bruera E, Brunelli C, Caraceni A, Cervantes A, Currow DC, Deliens L, Fallon M, Gomez-Batiste X, Grotmol KS, Hannon B, Haugen DF, Higginson IJ, Hjermstad MJ, Hui D, Jordan K, Kurita GP, Larkin PJ, Miccinesi G, Nauck F, Pribakovic R, Rodin G, Sjogren P, Stone P, Zimmermann C, Lundeby T. Integration of oncology and palliative care: a Lancet Oncology Commission. Lancet Oncol. 2018 Nov;19(11):e588-e653. doi: 10.1016/S1470-2045(18)30415-7. Epub 2018 Oct 18.
• Background Zimmermann C, Swami N, Krzyzanowska M, Hannon B, Leighl N, Oza A, Moore M, Rydall A, Rodin G, Tannock I, Donner A, Lo C. Early palliative care for patients with advanced cancer: a cluster-randomised controlled trial. Lancet. 2014 May 17;383(9930):1721-30. doi: 10.1016/S0140-6736(13)62416-2. Epub 2014 Feb 19.
• Background Kavalieratos D, Corbelli J, Zhang D, Dionne-Odom JN, Ernecoff NC, Hanmer J, Hoydich ZP, Ikejiani DZ, Klein-Fedyshin M, Zimmermann C, Morton SC, Arnold RM, Heller L, Schenker Y. Association Between Palliative Care and Patient and Caregiver Outcomes: A Systematic Review and Meta-analysis. JAMA. 2016 Nov 22;316(20):2104-2114. doi: 10.1001/jama.2016.16840.
• Background Sullivan DR, Chan B, Lapidus JA, Ganzini L, Hansen L, Carney PA, Fromme EK, Marino M, Golden SE, Vranas KC, Slatore CG. Association of Early Palliative Care Use With Survival and Place of Death Among Patients With Advanced Lung Cancer Receiving Care in the Veterans Health Administration. JAMA Oncol. 2019 Dec 1;5(12):1702-1709. doi: 10.1001/jamaoncol.2019.3105.
• Background Vehling S, Philipp R. Existential distress and meaning-focused interventions in cancer survivorship. Curr Opin Support Palliat Care. 2018 Mar;12(1):46-51. doi: 10.1097/SPC.0000000000000324.
• Background Rodin G, Lo C, Mikulincer M, Donner A, Gagliese L, Zimmermann C. Pathways to distress: the multiple determinants of depression, hopelessness, and the desire for hastened death in metastatic cancer patients. Soc Sci Med. 2009 Feb;68(3):562-9. doi: 10.1016/j.socscimed.2008.10.037. Epub 2008 Dec 7.
• Background Lo C, Hales S, Zimmermann C, Gagliese L, Rydall A, Rodin G. Measuring death-related anxiety in advanced cancer: preliminary psychometrics of the Death and Dying Distress Scale. J Pediatr Hematol Oncol. 2011 Oct;33 Suppl 2:S140-5. doi: 10.1097/MPH.0b013e318230e1fd.

Drugs

Indications