Psychedelics and the essential importance of context

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

Article information

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

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	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
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	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
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	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
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	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
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	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
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	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
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	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
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