Psychedelics and the essential importance of context
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.
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The psychedelic experience comes with an increased sensitivity to internal and external stimuli.
“The psychedelic experience comes with an increased sensitivity to internal and external stimuli.”
The general context of psychedelic administration fundamentally shapes drug response, safety, and potentially therapeutic efficacy.
“It follows that the general context of psychedelic administration fundamentally shapes drug response and hence safety, as well as potentially therapeutic efficacy [9, 88].”
Patients may need particularly intensive supportive care during, as well as after, psychedelic experiences.
“This highlights the frequent clinical observation that patients may need particularly intensive supportive care during, as well as after psychedelic experiences (Carhart-Harris et al., 2018).”
From Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response (2024) · cites this paper as Carhart-Harris et al., 2018
Psychedelic experiences vary depending not only on individual characteristics, such as health status, but also on the type of preparation available, intentions agreed upon before the experience, and the environment in which the experience takes place.
“Psychedelic experiences vary depending not only on individual characteristics, such as health status, but also on the type of preparation available, intentions agreed upon before the experience, and the environment in which the experience takes place (Carhart-Harris et al., 2018; Golden et al., 2022).”
From Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response (2024) · cites this paper as Carhart-Harris et al., 2018
Both set and setting have the potential to greatly impact the outcomes of the psychedelic experience.
“It has long been recognised that both set (the mindset of the participant, including their expectations, assumptions and intentions for the psychedelic experience, as well as stable variables such as personality and the presence of psychopathology) and setting (the physical, social and cultural environment in which the experience occurs) have the potential to greatly impact the outcomes of the Psy”
From The psychological processes of classic psychedelics in the treatment of depression: a systematic review protocol (2022) · cites this paper as [43]
Contextual factors, such as the environment in which the experience takes place (setting), the mindset of the individual (set), and the support available after the experience (integration and setting), have a huge impact on the effects of psychedelics.
“Contextual factors, such as the environment in which the experience takes place (setting), the mindset of the individual (set), and the support available after the experience (integration and setting), have a huge impact on the effects of psychedelics (85–88).”
From Potential therapeutic effects of an ayahuasca-inspired N,N-DMT and harmine formulation: a controlled trial in healthy subjects (2024) · cites this paper as [85]
Differences in set and setting have been extensively shown to greatly influence the acute psychedelic experience.
“Differences in set and setting, which involve factors such as opportunity for preparation, guidance and integration by a trained guide, have been extensively shown to greatly influence the acute psychedelic experience (136, 137).”
From Examining the Potential Synergistic Effects Between Mindfulness Training and Psychedelic-Assisted Therapy (2021) · cites this paper as [136]
Changes in the ratings of subjective measures observed in the present study are not necessarily related to a pharmacological effect of 5-MeO-DMT, but could have resulted from uncontrolled variables such as response expectancy of the participants prior to and after the session or the set and setting of drug administration (Carhart-Harris et al. 2018; Hartogsohn 2016).
“Changes in the ratings of subjective measures that were observed in the present study are not necessarily related to a pharmacological effect of 5-MeO-DMT, but could have resulted from uncontrolled variables such as response expectancy of the participants prior to and after the session or the set and setting of drug administration (Carhart-Harris et al. 2018; Hartogsohn 2016).”
From Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment (2020) · cites this paper as Carhart-Harris et al. 2018
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Self-blinding citizen science to explore psychedelic microdosing
Szigeti, B., Kartner, L., Blemings, A., Rosas, F., Feilding, A., Nutt, D. J., Carhart-Harris, R. L., & Erritzoe, D. (2021) · eLife · doi:10.7554/elife.62878 · Cited by 192 · see citing works
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Self-citationTherapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials
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Psychedelic-Assisted Psychotherapy—A Systematic Review of Associated Psychological Interventions
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Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing
Kaertner, L. S., Steinborn, M. B., Kettner, H., Spriggs, M. J., Roseman, L., Buchborn, T., Balaet, M., Timmermann, C., Erritzoe, D., & Carhart-Harris, R. L. (2021) · Scientific Reports · doi:10.1038/s41598-021-81446-7 · Cited by 145 · see citing works
Tripping on nothing: placebo psychedelics and contextual factors
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A review of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy
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Taves, A. (2020) · Perspectives on Psychological Science · doi:10.1177/1745691619895047 · Cited by 140 · see citing works
Carhart-Harris, R. L. (2018) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000467 · Cited by 133 · see citing works
Self-citationMotives and Side-Effects of Microdosing With Psychedelics Among Users
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Self-citationTreatment with psychedelics is psychotherapy: beyond reductionism
Gründer, G., Brand, M., Mertens, L. J., Jungaberle, H., Kärtner, L., Scharf, D., Spangemacher, M., & Wolff, M. (2023) · The Lancet Psychiatry · doi:10.1016/s2215-0366(23)00363-2 · Cited by 119 · see citing works
Case analysis of long-term negative psychological responses to psychedelics
Bremler, R., Katati, N., Shergill, P., Erritzøe, D., & Carhart-Harris, R. L. (2023) · Scientific Reports · doi:10.1038/s41598-023-41145-x · Cited by 121 · see citing works
Self-citationZeifman, R. J., Wagner, A. C., Watts, R., Kettner, H., Mertens, L. J., & Carhart-Harris, R. L. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00782 · Cited by 106 · see citing works
Self-citationDavis, A. K., Agin-Liebes, G., España, M., Pilecki, B. C., & Luoma, J. B. (2021) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2021.1971343 · Cited by 104 · see citing works
Canalization and plasticity in psychopathology
Carhart-Harris, R. L., Chandaria, S., Erritzøe, D., Gazzaley, A. H., Girn, M., Kettner, H., Mediano, P. A. M., Nutt, D. J., Rosas, F. E., Roseman, L., et al. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109398 · Cited by 103 · see citing works
Self-citationExpectancy in placebo-controlled trials of psychedelics: if so, so what?
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“The subjective experience of intoxication with psychoactive substances has been shown to be extremely sensitive to both individual expectation of what the trip will be like (the set) as well as environmental factors (the setting) (Carhart-Harris et al. 2018).”
BackgroundVan Court, R. C., Wiseman, M. S., Meyer, K. W., Ballhorn, D. J., Amses, K. R., Slot, J. C., Dentinger, B. T. M., Garibay-Orijel, R., & Uehling, J. K. (2022) · Fungal Biology · doi:10.1016/j.funbio.2022.01.003 · Cited by 94 · see citing works
Does Psychedelic Therapy Have a Transdiagnostic Action and Prophylactic Potential?
Kočárová, R., Horáček, J., & Carhart-Harris, R. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.661233 · Cited by 96 · see citing works
Self-citationVarley, T. F., Carhart-Harris, R. L., Roseman, L., Menon, D. K., & Stamatakis, E. A. (2020) · NeuroImage · doi:10.1016/j.neuroimage.2020.117049 · Cited by 88 · see citing works
Self-citationThe acute effects of classic psychedelics on memory in humans
Healy, C. J. (2021) · Psychopharmacology · doi:10.1007/s00213-020-05756-w · Cited by 95 · see citing works
Greenway, K. T., Garel, N., Jerome, L., & Feduccia, A. A. (2020) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2020.1772054 · Cited by 94 · see citing works
Brennan, W., & Belser, A. B. (2022) · Frontiers in Psychology · doi:10.3389/fpsyg.2022.866018 · Cited by 90 · see citing works
Bender, D., & Hellerstein, D. J. (2022) · Psychopharmacology · doi:10.1007/s00213-021-06049-6 · Cited by 88 · see citing works
Psychedelics, Sociality, and Human Evolution
Rodríguez Arce, J. M., & Winkelman, M. J. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.729425 · Cited by 86 · see citing works
Leptourgos, P., Fortier, M., Carhart-Harris, R. L., Corlett, P. R., Dupuis, D., Halberstadt, A. L., Kometer, M., Kozáková, E., Larøi, F., Noorani, T. N., et al. (2020) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaa117 · Cited by 87 · see citing works
Self-citationEffects of External Stimulation on Psychedelic State Neurodynamics
Mediano, P. A. M., Rosas, F. E., Timmermann, C., Roseman, L., Nutt, D., Feilding, A., Kaelen, M., Kringelbach, M. L., Barrett, A. B., Seth, A. K., et al. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00289 · Cited by 84 · see citing works
Self-citationNeural Mechanisms and Psychology of Psychedelic Ego Dissolution
Stoliker, D., Egan, G. F., Friston, K. J., & Razi, A. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000508 · Cited by 89 · see citing works
Dupuis, D. (2022) · Transcultural Psychiatry · doi:10.1177/13634615211036388 · Cited by 99 · see citing works
More Realistic Forecasting of Future Life Events After Psilocybin for Treatment-Resistant Depression
Lyons, T., & Carhart-Harris, R. L. (2018) · Frontiers in Psychology · doi:10.3389/fpsyg.2018.01721 · Cited by 77 · see citing works
Self-citationOna, G., Kohek, M., Massaguer, T., Gomariz, A., Jiménez, D. F., Dos Santos, R. G., Hallak, J. E. C., Alcázar-Córcoles, M. Á., & Bouso, J. C. (2019) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2019.1567961 · Cited by 76 · see citing works
Moreton, S. G., Szalla, L., Menzies, R. E., & Arena, A. F. A. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05391-0 · Cited by 77 · see citing works
Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings
Pallavicini, C., Cavanna, F., Zamberlán, F., de la Fuente, L. A., Ilksoy, Y. A., Perl, Y. S., Arias, M., Romero, C., Carhart-Harris, R. L., Timmermann, C., et al. (2021) · Journal of Psychopharmacology · doi:10.1177/0269881120981384 · Cited by 83 · see citing works
Self-citationPsychedelics as a treatment for disorders of consciousness
Scott, G., & Carhart-Harris, R. L. (2019) · Neuroscience of Consciousness · doi:10.1093/nc/niz003 · Cited by 74 · see citing works
Self-citationKopra, E. I., Ferris, J., Winstock, A., Young, A., & Rucker, J. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221084063 · Cited by 69 · see citing works
Antidepressant effects of a psychedelic experience in a large prospective naturalistic sample
Nygart, V. A., Pommerencke, L. M., Haijen, E. C. H. M., Kettner, H., Kaelen, M., Mortensen, E. L., Nutt, D. J., Carhart-Harris, R. L., & Erritzøe, D. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221101061 · Cited by 74 · see citing works
Self-citationSumner, R. L., Chacko, E., McMillan, R. L., Spriggs, M. J., Anderson, C., Chen, J., French, A., Jung, S., Rajan, A., Malpas, G. A., et al. (2021) · Journal of Psychopharmacology · doi:10.1177/0269881121998321 · Cited by 75 · see citing works
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Therapeutic mechanisms of psychedelics and entactogens
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Psychedelic therapy's transdiagnostic effects: A research domain criteria (RDoC) perspective
Kelly, J. R., Gillan, C. M., Prenderville, J., Kelly, C., Harkin, A., Clarke, G., & O'Keane, V. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.800072 · Cited by 69 · see citing works
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Right-Wing Psychedelia: Case Studies in Cultural Plasticity and Political Pluripotency
Pace, B. A., & Devenot, N. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.733185 · Cited by 67 · see citing works
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Ancient Roots of Today’s Emerging Renaissance in Psychedelic Medicine
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A unified model of ketamine’s dissociative and psychedelic properties
Marguilho, M., Figueiredo, I., & Castro-Rodrigues, P. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221140011 · Cited by 65 · see citing works
Gandy, S., Forstmann, M., Carhart-Harris, R. L., Timmermann, C., Luke, D. P., & Watts, R. (2020) · Health Psychology Open · doi:10.1177/2055102920978123 · Cited by 65 · see citing works
Self-citationOn the Relationship between Classic Psychedelics and Suicidality: A Systematic Review
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Brain-immune crosstalk in the treatment of major depressive disorder
Branchi, I., Poggini, S., Capuron, L., Benedetti, F., Poletti, S., Tamouza, R., Drexhage, H. A., Penninx, B. W. J. H., & Pariante, C. M. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.11.016 · Cited by 64 · see citing works
Self-citationRoberts, C., Sahakian, B. J., & Robbins, T. W. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.09.001 · Cited by 61 · see citing works
Mans, K., Kettner, H., Erritzøe, D., Haijen, E. C. H. M., Kaelen, M., & Carhart-Harris, R. L. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.647909 · Cited by 60 · see citing works
Self-citationZeifman, R. J., Wagner, A. C., Monson, C. M., & Carhart-Harris, R. L. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.04.105 · Cited by 65 · see citing works
Self-citationToward Synergies of Ketamine and Psychotherapy
Mathai, D. S., Mora, V., & Garcia‐Romeu, A. (2022) · Frontiers in Psychology · doi:10.3389/fpsyg.2022.868103 · Cited by 61 · see citing works
Psychiatric risks for worsened mental health after psychedelic use
Marrocu, A., Kettner, H., Weiss, B., Zeifman, R. J., Erritzoe, D., & Carhart-Harris, R. L. (2024) · Journal of Psychopharmacology · doi:10.1177/02698811241232548 · Cited by 60 · see citing works
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Effects of psilocybin versus escitalopram on rumination and thought suppression in depression
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Pattern breaking: a complex systems approach to psychedelic medicine
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Psychedelic-induced mystical experiences: An interdisciplinary discussion and critique
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Self-citationKetamine as a Treatment for Anorexia Nervosa: A Narrative Review
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Self-citationSet and Setting in the Santo Daime
Hartogsohn, I. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.651037 · Cited by 54 · see citing works
Psychosis and psychedelics: Historical entanglements and contemporary contrasts
Friesen, P. (2022) · Transcultural Psychiatry · doi:10.1177/13634615221129116 · Cited by 57 · see citing works
Prediction of MDMA response in healthy humans: a pooled analysis of placebo-controlled studies
Studerus, E., Vizeli, P., Harder, S., Ley, L., & Liechti, M. E. (2021) · Journal of Psychopharmacology · doi:10.1177/0269881121998322 · Cited by 53 · see citing works
- Authors
- Carhart-Harris, R. L., Roseman, L., Haijen, E., Erritzoe, D., Watts, R., Branchi, I., & Kaelen, M.
- Affiliations
- Imperial College London (GB)
- Psychedelic Research Group, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
- Istituto Superiore di Sanità (IT)
- Corresponding author
- Carhart-Harris, Robin L
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2018-02-15
- Volume
- 32
- Issue
- 7
- Pages
- 725-731
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- OpenAlex
- W2788854095
- Cited by
- 657
- References
- 62
- Citations by year
- 2026: 83 · 2025: 102 · 2024: 112 · 2023: 105 · 2022: 97 · 2021: 72 · 2020: 49 · 2019: 24 · 2018: 13
- FWCI
- 46.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute for Health and Care Research (ACF-2013-21-501)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Social Sciences › Health › Religion, Spirituality, and Psychology
- Keywords
- psychedelics, set and setting, context effects, 5-HT2A receptor agonism, neuroplasticity, long-term mental health outcomes, harm reduction
- MeSH terms
- Animals, Clinical Trials as Topic, Hallucinogens, Humans, Research Design, Serotonin 5-HT2 Receptor Agonists
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