Robin L Carhart-Harris, Leor Roseman, Eline Haijen, … First Published February 15, 2018 Research Article Find in PubMed https://doi.org/10.1177/0269881118754710

Abstract
Psychedelic drugs are making waves as modern trials support their therapeutic potential and various media continue to pique public interest. In this opinion piece, we draw attention to a long-recognised component of the psychedelic treatment model, namely ‘set’ and ‘setting’ – subsumed here under the umbrella term ‘context’. We highlight: (a) the pharmacological mechanisms of classic psychedelics (5-HT2A receptor agonism and associated plasticity) that we believe render their effects exceptionally sensitive to context, (b) a study design for testing assumptions regarding positive interactions between psychedelics and context, and (c) new findings from our group regarding contextual determinants of the quality of a psychedelic experience and how acute experience predicts subsequent long-term mental health outcomes. We hope that this article can: (a) inform on good practice in psychedelic research, (b) provide a roadmap for optimising treatment models, and (c) help tackle unhelpful stigma still surrounding these compounds, while developing an evidence base for long-held assumptions about the critical importance of context in relation to psychedelic use that can help minimise harms and maximise potential benefits.Keywords Psychedelics, psychotherapy, serotonin
References
Aixala, M (2017) Psychotherapeutic Intervention in Integration of Difficult Psychedelic Experiences: The ICEERS Support Service. Oakland, CA: Psychedelic Science. Available at: http://psychedelicscience.org/conference/interdisciplinary/psychotherapeutic-intervention-in-integration-of-difficult-psychedelic-experiences-the-iceers-support-service (accessed 20 January 2018). Google Scholar | |
Albarelli, HP (2009) A Terrible Mistake: The Murder of Frank Olson and the CIA’s Secret Cold War Experiments. Walterville, OR: Trine Day. Google Scholar | |
Alboni, S, van Dijk, RM, Poggini, S. (2017) Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment. Mol Psychiatry 22: 552–561. Google Scholar | Medline | |
Ashby, CR, Edwards, E, Wang, RY (1994) Electrophysiological
evidence for a functional interaction between 5-HT1A and 5-HT2A
receptors in the rat medial prefrontal cortex: An iontophoretic study. Synapse 17: 173–181. Google Scholar | Medline | ISI | |
Austin, P, Tudorie, V, Stone, R. (2017) What is the Third Wave of Psychedelics? Available at: https://thethirdwave.co/about/(accessed 20 January 2018). Google Scholar | |
Barrett, FS, Bradstreet, MP, Leoutsakos, JS. (2016) The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms. J Psychopharmacol 30: 1279–1295. Google Scholar | SAGE Journals | ISI | |
Bentall, RP (2009) Doctoring the Mind: Is Our Current Treatment of Mental Illness Really any Good? New York: New York University Press. Google Scholar | |
Branchi, I (2011) The
double edged sword of neural plasticity: Increasing serotonin levels
leads to both greater vulnerability to depression and improved capacity
to recover. Psychoneuroendocrinology 36: 339–351. Google Scholar | Medline | |
Carbonaro, TM, Bradstreet, MP, Barrett, FS. (2016) Survey
study of challenging experiences after ingesting psilocybin mushrooms:
Acute and enduring positive and negative consequences. J Psychopharmacol 30: 1268–1278. Google Scholar | SAGE Journals | ISI | |
Carhart-Harris, RL, Erritzoe, D, Haijen, E. (2018) Psychedelics and connectedness. Psychopharmacology (Berl) 235: 547–550. Google Scholar | Medline | |
Carhart-Harris, RL, Goodwin, GM (2017) The therapeutic potential of psychedelic drugs: Past, present and future. Neuropsychopharmacology 42: 2105–2113. Google Scholar | Medline | |
Carhart-Harris, RL, Kaelen, M, Bolstridge, M. (2016) The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychol Med 46: 1379–1390. Google Scholar | Medline | ISI | |
Carhart-Harris, RL, Kaelen, M, Whalley, MG. (2015) LSD enhances suggestibility in healthy volunteers. Psychopharmacology (Berl) 232: 785–794. Google Scholar | Medline | ISI | |
Carhart-Harris, RL, Leech, R, Williams, TM. (2012) Implications for psychedelic-assisted psychotherapy: Functional magnetic resonance imaging study with psilocybin. Br J Psychiatry 200: 238–244. Google Scholar | Medline | ISI | |
Carhart-Harris, RL, Nutt, DJ (2017) Serotonin and brain function: A tale of two receptors. J Psychopharmacol 31: 1091–1120. Google Scholar | SAGE Journals | ISI | |
Caspi, A, Hariri, AR, Holmes, A. (2010) Genetic
sensitivity to the environment: The case of the serotonin transporter
gene and its implications for studying complex diseases and traits. Am J Psychiatry 167: 509–527. Google Scholar | Medline | ISI | |
Chiarotti, F, Viglione, A, Giuliani, A. (2017) Citalopram amplifies the influence of living conditions on mood in depressed patients enrolled in the STAR*D study. Transl Psychiatry 7: e1066. Google Scholar | Medline | |
Cohen, S (1960) Lysergic acid diethylamide: Side effects and complications. J NervMent Dis 130: 30–40. Google Scholar | Medline | ISI | |
Demyttenaere, K (2016) Taking the depressed “person” into account before moving into personalized or precision medicine. World Psychiatry 15: 236–237. Google Scholar | Medline | |
Dobkin de Rios, M (2009) The Psychedelic Journey of Marlene Dobkin de Rios: 45 Years with Shamans, Ayahuasqueros, and Ethnobotanists. Rochester, VT: Park Street Press. Google Scholar | |
Erritzoe, D, Nutt, DJ, Carhart-Harris, R (2017) Concerns regarding conclusions made about LSD-treatments. Hist Psychiatry 28: 257–260. Google Scholar | SAGE Journals | |
Erritzoe, D, Richards, WA (2017) Lessons to be learned from early psychedelic therapy in Denmark. Nordic Journal of Psychiatry 71: 487–488. Google Scholar | Medline | |
Fadiman, J (2017) Microdosing: The Phenomenon, Research Results, and Startling Surprises. Available at: http://psychedelicscience.org/ (accessed 20 January 2018). Google Scholar | |
Feinberg, B (2017) Conflict and
Transformation in Mazatec and Outsiders’ Views of the Therapeutic Value
of Mushroom Use in Huautla. Available at: http://psychedelicscience.org/ (accessed 20 January 2018). Google Scholar | |
Garcia-Romeu, A, Griffiths, RR, Johnson, MW (2014) Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Curr Drug Abuse Rev 7: 157–164. Google Scholar | Medline | |
Goodwin, GM (2016) Psilocybin: Psychotherapy or drug? J Psychopharmacol 30: 1201–1202. Google Scholar | SAGE Journals | ISI | |
Griffiths, RR, Johnson, MW, Carducci, MA. (2016) Psilocybin
produces substantial and sustained decreases in depression and anxiety
in patients with life-threatening cancer: A randomized double-blind
trial. J Psychopharmacol 30: 1181–1197. Google Scholar | SAGE Journals | ISI | |
Griffiths, RR, Johnson, MW, Richards, WA. (2011) Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects. Psychopharmacology (Berl) 218: 649–665. Google Scholar | Medline | ISI | |
Griffiths, RR, Richards, WA, McCann, U. (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl) 187: 268–283; discussion 284–292. Google Scholar | Medline | ISI | |
Harmer, CJ, Cowen, PJ (2013) ‘It’s the way that you look at it’–a cognitive neuropsychological account of SSRI action in depression. Philos Trans R Soc Lond B Biol Sci 368: 20120407. Google Scholar | Medline | ISI | |
Hartogsohn, I (2015) The Psycho-Social Construction of LSD: How Set and Setting Shaped the American Psychedelic Experience 1950–1970. PhD dissertation. Israel: Bar Ilan University. Google Scholar | |
Hartogsohn, I (2016) Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology. J Psychopharmacol 30: 1259–1267. Google Scholar | SAGE Journals | ISI | |
Hartogsohn, I (2017) Constructing drug effects: A history of set and setting. Drug Sci Pol Law 3: 1–17. Available at: https://doi.org/10.1177/2050324516683325. Google Scholar | |
Hendricks, PS, Thorne, CB, Clark, CB. (2015) Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population. J Psychopharmacol 29: 280–288. Google Scholar | SAGE Journals | ISI | |
Hofmann, A (1980) LSD: My Problem Child. NY: McGraw-Hill. Google Scholar | |
Jack (2017) Magic Mushrooms Take a Trip into Clinical Trials. https://www.ft.com/content/16209090-9589-11e7-a652-cde3f882dd7b (accessed 10 September 2017). Google Scholar | |
Johansen, PØ, Krebs, TS (2015) Psychedelics not linked to mental health problems or suicidal behavior: A population study. J Psychopharmacol 29: 270–279. Google Scholar | SAGE Journals | ISI | |
Johnson, M, Richards, W, Griffiths, R (2008) Human hallucinogen research: Guidelines for safety. J Psychopharmacol 22: 603–620. Google Scholar | SAGE Journals | ISI | |
Jokela, M, Keltikangas-Jarvinen, L, Kivimaki, M. (2007) Serotonin receptor 2A gene and the influence of childhood maternal nurturance on adulthood depressive symptoms. Arch Gen Psychiatry 64: 356–360. Google Scholar | Medline | |
Jokela, M, Lehtimaki, T, Keltikangas-Jarvinen, L (2007a) The influence of urban/rural residency on depressive symptoms is moderated by the serotonin receptor 2A gene. Am J Med Genet B Neuropsychiatr Genet 144B: 918–922. Google Scholar | Medline | ISI | |
Jokela, M, Lehtimaki, T, Keltikangas-Jarvinen, L (2007b) The serotonin receptor 2A gene moderates the influence of parental socioeconomic status on adulthood harm avoidance. Behav Genet 37: 567–574. Google Scholar | Medline | |
Kaelen, M, Barrett, FS, Roseman, L. (2015) LSD enhances the emotional response to music. Psychopharmacology (Berl) 232: 3607–3614. Google Scholar | Medline | ISI | |
Kaelen, MG, Giribaldi, B, Raine, J. (2018) The hidden therapist: Evidence for a central role of music in psychedelic therapy. Psychopharmacology (Berl) 235: 505–519. Google Scholar | |
Kazdin, AE (2007) Mediators and mechanisms of change in psychotherapy research. Annu Rev Clin Psychol 3: 1–27. Google Scholar | Medline | ISI | |
Kirsch, I (2013) The placebo effect revisited: Lessons learned to date. Complement Ther Med 21: 102–104. Google Scholar | Medline | ISI | |
Krebs, TS, Johansen, PØ (2012) Lysergic acid diethylamide (LSD) for alcoholism: Meta-analysis of randomized controlled trials. J Psychopharmacol 26: 994–1002. Google Scholar | Abstract | |
Labate, BC (2014) Ayahuasca Shamanism in the Amazon and Beyond. Oxford, NY: Oxford University Press. Google Scholar | |
Labate, BC, Cavnar, C (2016) Peyote: History, Tradition, Politics, and Conservation. Santa Barbara, CA: Praeger. Google Scholar | |
Larsen, JK (2016) Neurotoxicity and LSD treatment: A follow-up study of 151 patients in Denmark. Hist Psychiatry 27: 172–189. Google Scholar | SAGE Journals | ISI | |
Leary, T, Litwin, GH, Metzner, R (1963) Reactions to Psilocybin Administered in a Supportive Environment. J Nerv Ment Dis 137: 561–573. Google Scholar | Medline | ISI | |
Lee, MA, Shlain, B (1985) Acid Dreams: The Complete Social History of LSD, the CIA, the Sixties and Beyond. London: Pan. Google Scholar | |
Lee, MA, Shlain, B (1992) Acid Dreams: The Complete Social History of LSD, the CIA, the Sixties and Beyond. New York: Grove Weidenfeld. Google Scholar | |
Loizaga-Velder, A, Verres, R (2014) Therapeutic effects of ritual ayahuasca use in the treatment of substance dependence–qualitative results. J Psychoactive Drugs 46: 63–72. Google Scholar | Medline | ISI | |
Luckenbaugh, DA, Niciu, MJ, Ionescu, DF. (2014) Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord 159: 56–61. Google Scholar | Medline | ISI | |
Ludwig, A, Levine, J, Stark, L. (1969) A clinical study of LSD treatment in alcoholism. Am J Psychiatry 126: 59–69. Google Scholar | Medline | ISI | |
MacLean, KA, Johnson, MW, Griffiths, RR (2011) Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol 25: 1453–1461. Google Scholar | SAGE Journals | ISI | |
Maslow, AH (1976) Religions, Values and Peak-experiences. Harmondsworth: Penguin. Google Scholar | |
Nettl, B (1956) Music in Primitive Culture. [With Musical Illustrations and a Bibliography.]. Cambridge: Harvard University Press. Google Scholar | |
Nour, MM, Evans, L, Nutt, D. (2016) Ego-dissolution and psychedelics: Validation of the ego-dissolution inventory (EDI). Front Hum Neurosci 10: 269. Google Scholar | Medline | ISI | |
Novak, SJ (1998) Second thoughts on psychedelic drugs. Endeavour 22: 21–23. Google Scholar | Medline | |
Oram, M (2014) Efficacy and enlightenment: LSD psychotherapy and the Drug Amendments of 1962. J Hist Med Allied Sci 69: 221–250. Google Scholar | Medline | |
Richards, WA (2015) Sacred Knowledge: Psychedelics and Religious Experiences. New York: Columbia University Press. Google Scholar | |
Roseman, L, Nutt DJ, Carhart-Harris, RL (2017) Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol 8: 974. Google Scholar | Medline | |
Ross, S, Bossis, A, Guss, J. (2016) Rapid
and sustained symptom reduction following psilocybin treatment for
anxiety and depression in patients with life-threatening cancer: A
randomized controlled trial. J Psychopharmacol 30: 1165–1180. Google Scholar | SAGE Journals | ISI | |
Rucker, JJ, Jelen, LA, Flynn, S. (2016) Psychedelics in the treatment of unipolar mood disorders: A systematic review. J Psychopharmacol 30: 1220–1229. Google Scholar | SAGE Journals | ISI | |
Schwartz, C (2017) Molly at the Marriott: Inside America’s Premier Psychedelics conference. The New York Times. Available at: https://www.nytimes.com/2017/05/06/style/psychedelic-drug-resurgence-daily-life.html (accessed 6 May 2017). Google Scholar | |
Sos, P, Klirova, M, Novak, T. (2013) Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett 34: 287–293. Google Scholar | Medline | ISI | |
Stevens, J (1987) Storming Heaven: LSD and the American Dream. New York: Atlantic Monthly Press. Google Scholar | |
Studerus, E, Gamma, A, Kometer, M. (2012) Prediction of psilocybin response in healthy volunteers. PLoS One 7: e30800. Google Scholar | Medline | ISI | |
Timmermann, C, Spriggs, MJ, Kaelen, M. (2017) LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm. Neuropharmacology. pii: S0028–3908(17)30506–3. Google Scholar | Medline | |
Tupper, KW, Labate, BC (2014) Ayahuasca, psychedelic studies and health sciences: The politics of knowledge and inquiry into an Amazonian plant brew. Curr Drug Abuse Rev 7: 71–80. Google Scholar | Medline | |
Waldman, A (2017) A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life. New York: Knopf. Google Scholar | |
Wallace, AF (1959) Cultural determinants of response to hallucinatory experince. AMA Arch Gen Psychiatry 1: 58–69. Google Scholar | Medline | |
Watts, R, Day, C, Krzanowski, J. (2017) Patients’ accounts of increased “connectedness” and “acceptance” after psilocybin for treatment-resistant depression. J Humanist Psychol 57: 520–564. Google Scholar | SAGE Journals | ISI | |
Winkelman, M (2005) Drug tourism or spiritual healing? Ayahuasca seekers in Amazonia. J Psychoactive Drugs 37: 209–218. Google Scholar | Medline | ISI | |
Zinberg, NE (1984) Drug, Set, and Setting: The Basis for Controlled Intoxicant Use. New Haven; London: Yale University Press. Google Scholar |