Psychedelic medicine at a crossroads: Advancing an integrative approach to research and practice

Abstract

Psychedelics have been already used by human societies for more than 3000 years, mostly in religious and healing context. The renewed interest in the potential application of psychedelic compounds as novel therapeutics has led to promising preliminary evidence of clinical benefit in some psychiatric disorders. Despite these promising results, the potential for large-scale clinical application of these profoundly consciousness-altering substances, in isolation from the sociocultural contexts in which they were traditionally used, raises important concerns. These concerns stem from the recognition that the mechanisms of therapeutic action of psychedelics are not entirely dependent on neurobiology, but also on the psychological, social and spiritual processes for their efficacy. For these reasons, physicians or psychotherapists involved in psychedelic-assisted psychotherapy need training in ways to accompany patients through this experience to promote positive outcomes and address potential side effects. Psychedelic therapies may foster the emergence of a novel paradigm in psychiatry that integrates psychopharmacological, psychotherapeutic, and cultural interventions for patients with mental health issues.

Keywords

Psychedelics LSD psilocybin ketamine psychotherapy consciousness culture context

Mind-altering substances have been used in ceremonial and religious contexts for millennia (George et al., 2021; Guerra-Doce, 2015; Miller et al., 2019). However, it was only in the 20th century that psychedelic compounds (such as the serotoninergic N, N-Dimethyltryptamine, lysergic acid diethylamide-LSD and psilocybin), glutamatergic dissociative anesthetics (such as ketamine) and empathogenic compounds (such as 3,4-Methylenedioxymethamphetamine-MDMA) were isolated from mushrooms and herbs or chemically synthesized (Nichols & Walter, 2021). Following an initial wave of scientific interest in the 1950s and 60s, psychedelic substances were scheduled as illegal by the U.S. Drug Enforcement Agency, and the field of psychedelic research underwent an almost total hiatus of nearly 50 years (Carhart-Harris & Goodwin, 2017; Hall, 2022). The last 15 years have seen a resurgence of interest and biomedical research assessing their therapeutic potential (Sessa, 2012; Tupper et al., 2015). Although this reassessment is still at an early stage, there are already new treatments emerging with claims of unique efficacy. Esketamine, a ketamine-derived enantiomer, was recently approved by the FDA as a first-in-class antidepressant for treatment-resistant depression (Kim et al., 2019), and there is increasing evidence that MDMA-assisted psychotherapy can be a safe and efficacious treatment for PTSD (Mitchell et al., 2021). Two recent randomized trials with psilocybin reported large effect sizes in reducing symptoms of major depressive disorder (Davis et al., 2021), though one of these studies did not find superiority over conventional SSRI treatment on the primary outcome (Carhart-Harris et al., 2021).

Despite efforts to uncover neurobiological mechanisms, our understanding of the therapeutic action of psychedelics remains limited. Psychedelics have effects on neuroplasticity, neuroimmunomodulation, neurotransmission (especially a synergistic action between serotonergic and glutamatergic systems), and epigenetics- all of which could contribute to therapeutic efficacy (Inserra et al., 2022; Inserra, De Gregorio, & Gobbi, 2021; Vollenweider & Preller, 2020). Psychedelics differ from other psychotropic drugs in their capacity to profoundly alter the phenomenology of consciousness through effects on neural circuitry including thalamo-cortico-thalamic pathways, which are critical for integrating external and internal stimuli (Doss, Madden, et al., 2022; Inserra, De Gregorio, Rezai, et al., 2021; Müller et al., 2017). However other pathways may also be implicated in the alteration of consciousness induced by psychedelics such as the hippocampal-cortex loop and the cortico-claustro-cortical circuit (Doss, Madden, et al., 2022). Psychedelics have also been shown to generally increase the functional integration of large-scale brain systems, encouraging synchronization of disparate brain regions and networks that are typically less connected to each other (Carhart-Harris & Friston, 2019). Increases in global functional connectivity have been correlated with altered phenomenology under psychedelics, including reports of “ego-dissolution” on LSD (Tagliazucchi et al., 2016). With respect to therapeutic mechanisms, a recent analysis of two fMRI studies investigating psilocybin-assisted psychotherapy found that pre–post increases in global brain network integration reliably correlated with improvements in depressive symptoms, even if the interpretation of the results has been challenged (Daws et al., 2022; but see preprint from Doss, Barrett, & Corlett, 2022).

Psychedelics have potent effects on perception, cognition, self-awareness, and consciousness. These could be incidental to the therapeutic effects at the level of brain circuitry, but there is evidence that the actions of psychedelics also depend on compelling experiences and changes in outlook and sense of meaning that may be socially mediated (Carhart-Harris, Erritzoe, et al., 2018; Kettner et al., 2021; Lifshitz et al., 2018; Majić et al., 2015). A prominent model of psychedelic brain action proposes a mechanism by which the effects on neurobiology may operate synergistically with contextual factors to facilitate deep changes in experience and behaviour. This “anarchic brain model,” proposed by Carhart-Harris and Friston (2019), suggests that psychedelics may generally loosen habitual patterns of predictive processing that the brain uses to build up models of the self and the world in which it is embedded. By rendering the brain less rigid and more malleable in its predictions about the world, psychedelics may make people particularly sensitive to contextual factors such as social cues, expectations, and other kinds of symbolic meanings, suggestions and affordances in the environment (Carhart-Harris, Roseman, et al., 2018). For example, based on his ethnographic study of the use of Ayahuasca in a Westernized treatment centre and among Indigenous healers in the Peruvian Amazon, Dupuis (2022) argues that the cultural worldview and social milieu in which the experiences took place shaped the specific visual and auditory content of the psychedelic experiences, so that people came to see and hear the spirits that they expected to encounter. These sensory experiences of the presence of spirits were deeply meaningful to participants and helped them to concretize and embody their cultural worldview and ontology (i.e., a world in which spirits can help guide human action) in ways that they often described as therapeutic.

In Western contexts, psychedelics drugs are often said to produce “mystical” experiences—sometimes described as episodes of ego-dissolution (Nour et al., 2016)—that many individuals report to be “life changing” or “transformational”. These experiences seem to allow people to take on fresh perspectives and reinterpret past negative experiences and traumas, potentially providing relief from suffering, depression, and distress (Griffiths et al., 2011) by enhancing acceptance, compassion, and a new perspective on past experiences including traumatic events. The prominence of experiences described as spiritual or self-transcendent was already reported in the well-known Marsh’s Chapel experiment with psilocybin in the 1960s, where mystical-type experiences were observed in healthy volunteers, many of whom reported never having experienced such states before (Doblin, 1991). Building on these early studies, several modern clinical trials with more rigorous methodology have replicated the finding that psychedelics can engender mystical-like states and, in some instances, have linked such experiences to therapeutic benefits (Griffiths et al., 2018; Johnson et al., 2019). A recent post-hoc analysis of a landmark clinical trial comparing psilocybin to escitalopram showed that having a psychedelic-induced mystical experience in the second session of the psychotherapy mediated reductions in depression symptoms (Murphy et al., 2022). This study also found that having an emotional breakthrough in the first session mediated depression outcomes, and that both mystical experiences and emotional breakthroughs were predicted by the strength of the therapeutic alliance reported by the patient.

The evidence of the importance of context and relationship in the efficacy of psychedelics points to a fundamental issue: psychedelics differ from the way other psychiatric medications are used, in that they are typically understood to act as catalysts for psychotherapeutic processes, rather than as standalone therapies. As recent trials have pointed out, social and psychological support are likely critical to maximizing the benefits and reducing potential psychological harms of psychedelic experiences (Carhart-Harris, Roseman, et al., 2018; Watts & Luoma, 2020). Research on psychedelics thus underscores the need to advance an integrated approach to therapeutics in mental health that emphasizes the interconnections between neurobiology, psychology, social-cultural context, and meaning-making.

Outside medical settings, psychedelic use has traditionally been embedded in ritual and ceremonial practices (Metzner, 1998). In some countries, such as the USA and Canada, psychedelic plant preparations such as Ayahuasca or peyote are legally permitted for sacramental use by Indigenous and syncretic religious communities. The disembedding of these substances from ceremonial settings raises questions about whether beneficial effects will be maintained and whether, in the absence of skilled guidance, the altered psychological states induced by psychedelics pose potential safety risks. Importantly, the traditional dispensers of these compounds, who often undergo extensive training before being “qualified”, usually have a well-defined role in accompanying the participant throughout the experience, and are well-acquainted with strategies to help participants navigate states of psychological or physical distress. This raises a critical issue for implementing this novel approach in psychiatry, suggesting that practitioners administering psychedelics should receive specific training that encompasses not only the clinical pharmacology of these compounds, but also the complex ways in which changes in neural functioning interact with patients’ personal, psychological, and cultural backgrounds (Penn et al., 2021; Phelps, 2017; Phelps & Henry, 2021). As psychedelics may amplify both beneficial and harmful psychological and interpersonal processes, their use requires close clinical attention and expertise, particularly when administered to individuals already suffering from significant mental health problems, including but not limited to, trauma, addiction, and depression. A growing number of organizations have begun developing programs to train practitioners in the skills necessary to navigate the complex and intense psychological processes catalyzed by psychedelics, including the processing of traumatic life events, the integration of new insights, and changes in one’s sense of self (Timmerman et al., 2022). Given the resource-intensive nature of psychedelic therapies, many questions remain about how such training can be delivered at scale. These questions are important and timely because, without adequate support and guidance, the same processes that may promote rapid healing, could instead cause significant harm.

In general, there is evidence that the casual, recreational or ceremonial use of psychedelic drugs is not associated with an increased prevalence of mental health problems (Argento et al., 2017; Barbosa et al., 2012; Hendricks et al., 2015; Schlag et al., 2022; St. Arnaud & Sharpe, 2022; Zeifman et al., 2022). Despite this preliminary evidence of physical and psychological safety, there are also reasons for caution. Psychedelics have varied pharmacology and our understanding of potential health effects and abuse liability remains limited. There is, therefore, legitimate concern that both acute and chronic use of psychedelics can have negative effects on mental health:
Although no association has been found between lifetime psychedelic use and psychosis in epidemiological studies or controlled trials (Hendricks et al., 2015; Johansen & Krebs, 2015), there is anecdotal evidence that psychedelics may trigger psychotic episodes, including paranoid, manic or depressive states, especially in vulnerable individuals with a family history of schizophrenia or bipolar disorder (for a review see: Dos Santos et al., 2017).

While psychedelics are currently being explored as treatment for post-traumatic stress disorder, there is still some concern that psychedelics can trigger or intensify the recollection of traumatic memories or give rise to a traumatic experience in their own right (Rossi et al., 2022).

Chronic hallucinogen use may be associated with persistent symptoms, including perceptual distortions in vision, hearing, touch, changes in sense of self and time perception, paranoia, mood changes (depression or mania) (Martinotti et al., 2018).
More epidemiological research is needed to assess the incidence of adverse effects and potential neurotoxicity arising from exposure to the different classes of psychedelic and empathogenic compounds during adolescence and adulthood, especially after repeated doses. Understanding the physiological mechanisms involved with specific psychedelic substances and identifying individuals at risk for negative effects remains an important research priority.

Several regulatory agencies and jurisdictions have already or are considering decriminalizing or even legalizing the possession and use of psychedelic compounds for personal use or self-medication (Smith & Appelbaum, 2021). If MDMA-assisted psychotherapy for PTSD receives FDA approval in the next several years, as is expected, this would mark the first time that a U.S. regulatory agency specifically approves a drug–psychotherapy combination. In Canada, the Special Access Program implemented in late 2021 permits emergency access to psychedelics such as psilocybin and MDMA for various conditions, including mental health disorders, when other therapies have failed, are unsuitable, or are not available in Canada (Government of Canada, 2022).

If psychedelics are legalized, adequate support should be provided by the government and health institutions to avoid potentially negative outcomes which could result in backlash and a renewed relegation of these promising interventions to the status of “illicit drugs” with no clinical utility. Developing such support would benefit from a comprehensive assessment to identify effective harm reduction strategies (such as access to psychological support or safe spaces in which to consume the substances). Guidelines and appropriate training and implementation resources, which take into account the issues raised here, should be carefully designed and established, before legalization. A plethora of new pharmaceutical companies are developing therapeutic uses of psychedelics for neuropsychiatric disorders; others are searching for novel psychedelic-based medicines without hallucinogenic effects or cardiac toxicity that might be further developed and approved by regulatory agencies.

The renewed interest in psychedelic treatments has created an opportunity for advances in pharmacotherapy in psychiatry, at a time when innovation has been lagging. However, many questions crucial to the future of any therapeutic use remain unanswered. The neurobiological mechanisms of psychedelic effects on cognition and experience are an important focus of current research. In addition to the putative neurobiological mechanisms, to what extent are the experiential changes induced by psychedelics (e.g., alterations in perception, mood and self-awareness) essential for their therapeutic effects? What is the incidence of negative, deleterious or psychopathological effects? What are the clinical predictors of therapeutic benefit or potential harm? Most importantly, given the likelihood that psychedelics work best in the context of psychological therapy and/or social accompaniment, we need to know more about the essential elements and dynamics of this relational context (Timmermann et al., 2022).

Future directions for research needed to guide clinical applications of psychedelics include : i) studies of the mediating role of cultural meaning and practices on the therapeutic effects of psychedelics; ii) identification of social, psychological, and biological predictors of positive and negative treatment outcome; iii) implementation of large-scale clinical trials to further elucidate safety, effectiveness, and mechanisms of therapeutic action; iv) the development of non-psychedelic analogues to maintain therapeutic effects; and v) studies of the long-term benefits and potential side effects of psychedelics. Together, these research efforts could lead to a better understanding of the complex interactions of neurobiology, mind, culture, and spirituality.

Despite many open questions, psychedelic therapies are undoubtedly encouraging mental health practitioners to consider novel paradigms of integrated neurobiological-psycho-social treatment and care. The history and ethnography of cultural practices associated with these compounds strongly suggests that their clinical use should be understood in terms of processes of psychological transformation that consider human beings as persons, integrating brain, mind, social, cultural, and spiritual meaning and values. Psychedelic research is thus bringing psychiatry to a crossroads: we either think through our uses of these substances in supportive psychological and spiritual contexts by well-trained clinicians and expert guides or follow naïve enthusiasms that may create yet another drug crisis built on the exaggerated—though perhaps lucrative—hope and false promise of a quick fix.

Footnotes

Declaration of conflicting interests

Dr Gobbi is the inventor of a pending patent on the method-of-use of LSD. The other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr Gobbi received grants from the Canadian Institutes of Health Research, MITACS and Diamond Therapeutics Inc. for research on psychedelics. Dr Inserra received Postdoctoral fellowships from the Canadian Institutes of Health Research, The Fonds de Recherche Santé du Québec, and The Québec Autism Research Training program for research on autism spectrum disorder and psychedelics. Dr Greenway has received grant support from The Quebec Network on Suicide, Mood Disorders and Associated Disorders, and stipends for preparing educational materials from Psychedelic.support.

ORCID iDs

Gabriella Gobbi

Kyle T. Greenway

Michael Lifshitz

Laurence J. Kirmayer

Gabriella Gobbi, MD, PhD, is a Professor of Psychiatry at McGill University, psychiatrist at the McGill University Health Center (MUHC), neuroscientist, and head of a laboratory in psychopharmacology (Neurobiological Psychiatry Unit). She holds the Canada Research Chair in Therapeutics for Mental Health. Her translational research focuses on discovering novel medicines for mental health, specifically depression, anxiety, insomnia, pain, and autism. Dr Gobbi’s main contributions to psychopharmacology are in the field of the cannabinoid system, melatonin receptors and psychedelics.

Antonio Inserra, MSc, PhD, is a Postdoctoral Research Fellow at the Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, where he studies the neurobiological and electrophysiological mechanisms underlying therapeutic improvements elicited by serotonergic psychedelics in translational models of autism spectrum disorder, depression, and anxiety. He holds a Canadian Institutes of Health Research postdoctoral fellowship to investigate the therapeutic potential of serotonin 2A receptor modulation in preclinical models of autism spectrum disorder.

Kyle T. Greenway, MD, MSc, is an R5 in psychiatry at McGill University and member of the Clinical Investigator Program. He conducts clinical research in psychopharmacology, particularly exploring integrative mind–body approaches to the use of ketamine for treatment-resistant depression and novel psychotherapeutic approaches to psilocybin-assisted psychotherapy.

Michael Lifshitz, PhD, is Assistant Professor in the Division of Social and Transcultural Psychiatry at McGill University and an Investigator at the Lady Davis Institute for Medical Research in Montreal, Canada. He completed his PhD in Neuroscience at McGill and then a postdoctoral fellowship in Anthropology at Stanford. His work investigates practices that aim to transform subjective experience—from meditation and hypnosis to placebos, prayer, and psychedelics. He combines neuroimaging, phenomenology, and ethnography to study how these practices modulate fundamental aspects of consciousness including the sense of self.

Laurence J. Kirmayer, MD, FRCPC, FCAHS, FRSC is James McGill Professor and Director, Division of Social and Transcultural Psychiatry, Department of Psychiatry, McGill University. He is Editor-in-Chief of Transcultural Psychiatry, a Senior Investigator at the Lady Davis Institute, and Director of the Culture & Mental Health Research Unit at the Institute of Community and Family Psychiatry, Jewish General Hospital in Montreal, where he conducts research on culturally responsive mental health services, the mental health of Indigenous peoples, the integration of culture in global mental health, and the anthropology and philosophy of psychiatry. He is a Fellow of the Canadian Academy of Health Sciences and the Royal Society of Canada (Academy of Social Sciences).

References

Argento

Strathdee

S. A.

Tupper

Braschel

Wood

Shannon

(2017). Does psychedelic drug use reduce risk of suicidality? Evidence from a longitudinal community-based cohort of marginalised women in a Canadian setting. BMJ Open, 7(9), Article e016025. https://doi.org/10.1136/bmjopen-2017-016025

Barbosa

P. C.

Mizumoto

Bogenschutz

M. P.

Strassman

R. J.

(2012). Health status of ayahuasca users. Drug Testing and Analysis, 4(7–8), 601–609. https://doi.org/10.1002/dta.1383

Carhart-Harris

R. L.

Erritzoe

Haijen

Kaelen

Watts

(2018). Psychedelics and connectedness. Psychopharmacology (Berl), 235(2), 547–550. https://doi.org/10.1007/s00213-017-4701-y

Carhart-Harris

R. L.

Friston

(2019). REBUS And the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacological Reviews, 71(3), 316–344. https://doi.org/10.1124/pr.118.017160

Carhart-Harris

Giribaldi

Watts

Baker-Jones

Murphy-Beiner

Murphy

Martell

Blemings

Erritzoe

Nutt

D. J.

(2021). Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine, 384(15), 1402–1411. https://doi.org/10.1056/NEJMoa2032994

Carhart-Harris

R. L.

Goodwin

G. M.

(2017). The therapeutic potential of psychedelic drugs: Past, present, and future. Neuropsychopharmacology, 42(11), 2105–2113. https://doi.org/10.1038/npp.2017.84

Carhart-Harris

R. L.

Roseman

Haijen

Erritzoe

Watts

Branchi

Kaelen

(2018). Psychedelics and the essential importance of context. Journal of Psychopharmacology, 32(7), 725–731. https://doi.org/10.1177/0269881118754710

Davis

A. K.

Barrett

F. S.

May

D. G.

Cosimano

M. P.

Sepeda

N. D.

Johnson

M. W.

Finan

P. H.

Griffiths

R. R.

(2021). Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry, 78(5), 481–489. https://doi.org/10.1001/jamapsychiatry.2020.3285

Daws

R. E.

Timmermann

Giribaldi

Sexton

J. D.

Wall

M. B.

Erritzoe

, … Carhart-Harris

(2022). Increased global integration in the brain after psilocybin therapy for depression. Nature Medicine, 28(4), 844–851. https://doi.org/10.1038/s41591-022-01744-z

10.

Doblin

(1991). Pahnke’s “Good Friday experiment”: A long-term follow-up and methodological critique. Journal of Transpersonal Psychology, 23(1), 1–28. http://www.psilosophy.info/resources/mushrooms_journal2.pdf

11.

Dos Santos

R. G.

Bouso

J. C.

Hallak

J. E. C.

(2017). Ayahuasca, dimethyltryptamine, and psychosis: A systematic review of human studies. Therapeutic Advances in Psychopharmacology, 7(4), 141–157. https://doi.org/10.1177/2045125316689030

12.

Doss

M. K.

Barrett

F. S.

Corlett

P. R.

(2022). Skepticism about recent evidence that psilocybin opens depressed minds. PsyArXiV. https://doi.org/10.31234/osf.io/a25wb

13.

Doss

M. K.

Madden

M. B.

Gaddis

Nebel

M. B.

Griffiths

R. R.

Mathur

B. N.

Barrett

F. S.

(2022). Models of psychedelic drug action: Modulation of cortical-subcortical circuits. Brain, 145(2), 441–456. https://doi.org/10.1093/brain/awab406

14.

Dupuis

(2022). The socialization of hallucinations: Cultural priors, social interactions, and contextual factors in the use of psychedelics. Transcultural Psychiatry, 59(3), https://doi.org/10.1177/13634615211036388

15.

George

D. R.

Hanson

Wilkinson

Garcia-Romeu

(2021). Ancient roots of today’s emerging renaissance in psychedelic medicine. Culture, Medicine, and Psychiatry. https://doi.org/10.1007/s11013-021-09749-y

16.

Government of Canada. (2022). Regulations amending certain regulations relating to restricted drugs (Special access program): SOR/2021-271. Canada Gazette, Part II, 156(1). https://www.gazette.gc.ca/rp-pr/p2/2022/2022-01-05/html/sor-dors271-eng.html

17.

Griffiths

R. R.

Johnson

M. W.

Richards

W. A.

Richards

B. D.

Jesse

MacLean

K. A.

Barrett

F. S.

Cosimano

M. P.

Klinedinst

M. A.

(2018). Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. Journal of Psychopharmacology, 32(1), 49–69. https://doi.org/10.1177/0269881117731279

18.

Griffiths

R. R.

Johnson

M. W.

Richards

W. A.

Richards

B. D.

McCann

Jesse

(2011). Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects. Psychopharmacology (Berl), 218(4), 649–665. https://doi.org/10.1007/s00213-011-2358-5

19.

Guerra-Doce

(2015). Psychoactive substances in prehistoric times: Examining the archaeological evidence. Time and Mind, 8(1), 91–112. https://doi.org/10.1080/1751696X.2014.993244

20.

Hall

(2022). Why was early therapeutic research on psychedelic drugs abandoned? Psychological Medicine, 52(1), 26–31. https://doi.org/10.1017/S0033291721004207

21.

Hendricks

P. S.

Thorne

C. B.

Clark

C. B.

Coombs

D. W.

Johnson

M. W.

(2015). Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population. Journal of Psychopharmacology, 29(3), 280–288. https://doi.org/10.1177/0269881114565653

22.

Inserra

Campanale

Cheishvili

Dymov

Wong

Marcal

Gobbi

(2022). Modulation of DNA methylation and protein expression in the prefrontal cortex by repeated administration of D-lysergic acid diethylamide (LSD): Impact on neurotropic, neurotrophic, and neuroplasticity signaling. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 119, 110594.

23.

Inserra

De Gregorio

Gobbi

(2021). Psychedelics in psychiatry: Neuroplastic, immunomodulatory, and neurotransmitter mechanisms. Pharmacological Reviews, 73(1), 202–277. https://doi.org/10.1124/pharmrev.120.000056

24.

Inserra

De Gregorio

Rezai

Lopez-Canul

M. G.

Comai

Gobbi

(2021). Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice. Journal of Psychopharmacology, 35(4), 469–482. https://doi.org/10.1177/0269881121991569

25.

Johansen

Krebs

T. S.

(2015). Psychedelics not linked to mental health problems or suicidal behavior: A population study. Journal of Psychopharmacology, 29(3), 270–279. https://doi.org/10.1177/0269881114568039

26.

Johnson

M. W.

Hendricks

P. S.

Barrett

F. S.

Griffiths

R. R.

(2019). Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacology & Therapeutics, 197, 83–102. https://doi.org/10.1016/j.pharmthera.2018.11.010

27.

Kettner

Rosas

F. E.

Timmermann

Kärtner

Carhart-Harris

R. L.

Roseman

(2021). Psychedelic communitas: Intersubjective experience during psychedelic group sessions predicts enduring changes in psychological wellbeing and social connectedness. Frontiers in Pharmacology, 234. https://doi.org/10.3389/fphar.2021.623985

28.

Kim

Farchione

Potter

Chen

Temple

(2019). Esketamine for treatment-resistant depression: First FDA-approved antidepressant in a new class. New England Journal of Medicine, 381(1), 1–4. https://doi.org/10.1056/NEJMp1903305

29.

Lifshitz

Sheiner

Kirmayer

L. J.

(2018). Cultural neurophenomenology of psychedelic thought: Guiding the “unconstrained” mind through ritual context. In K. C.

Fox

Christoff

(Eds.), The Oxford handbook of spontaneous thought: Mind-wandering, creativity, and dreaming (pp. 573–594). Oxford University Press.

30.

Majić

Schmidt

T. T.

Gallinat

(2015). Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences? Journal of Psychopharmacology, 29(3), 241–253. https://doi.org/10.1177/0269881114568040

31.

Martinotti

Santacroce

Pettorruso

Montemitro

Spano

M. C.

Lorusso

di Giannantonio

Lerner

A. G.

(2018). Hallucinogen persisting perception disorder: Etiology, clinical features, and therapeutic perspectives. Brain Sciences, 8(3), Article 47. https://doi.org/10.3390/brainsci8030047

32.

Metzner

(1998). Hallucinogenic drugs and plants in psychotherapy and shamanism. Journal of Psychoactive Drugs, 30(4), 333–341. https://doi.org/10.1080/02791072.1998.10399709

33.

Miller

M. J.

Albarracin-Jordan

Moore

Capriles

J. M.

(2019). Chemical evidence for the use of multiple psychotropic plants in a 1,000-year-old ritual bundle from South America. Proceedings of the National Academy of Sciences of the United States of America, 116(23), 11207–11212. https://doi.org/10.1073/pnas.1902174116

34.

Mitchell

J. M.

Bogenschutz

Lilienstein

Harrison

Kleiman

Parker-Guilbert

Ot’alora G.

Garas

Paleos

Gorman

Nicholas

Mithoefer

Carlin

Poulter

Mithoefer

Quevedo

Wells

Klaire

S. S.

van der Kolk

, … Doblin

(2021). MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine, 27(6), 1025–1033. https://doi.org/10.1038/s41591-021-01336-3

35.

Müller

Lenz

Dolder

Lang

Schmidt

Liechti

Borgwardt

(2017). Increased thalamic resting-state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatrica Scandinavica, 136(6), 648–657. https://doi.org/10.1111/acps.12818

36.

Murphy

Kettner

Zeifman

Giribaldi

Kartner

Martell

Read

Murphy-Beiner

Baker-Jones

Nutt

Erritzoe

Watts

Carhart-Harris

(2022). Therapeutic alliance and rapport modulate responses to psilocybin assisted therapy for depression. Frontiers in Pharmacology, 12, Article 788155. https://doi.org/10.3389/fphar.2021.788155

37.

Nichols

D. E.

Walter

(2021). The history of psychedelics in psychiatry. Pharmacopsychiatry, 54(4), 151–166. https://doi.org/10.1055/a-1310-3990

38.

Nour

M. M.

Evans

Nutt

Carhart-Harris

R. L.

(2016). Ego-Dissolution and psychedelics: Validation of the ego-dissolution inventory (EDI). Frontiers in Human Neuroscience, 10. https://doi.org/10.3389/fnhum.2016.00269

39.

Penn

A. D.

Phelps

Rosa

W. E.

Watson

(2021). Psychedelic-assisted psychotherapy practices and human caring science: Toward a care-informed model of treatment. Journal of Humanistic Psychology. https://doi.org/10.1177/00221678211011013

40.

Phelps

(2017). Developing guidelines and competencies for the training of psychedelic therapists. Journal of Humanistic Psychology, 57(5), 450–487. https://doi.org/10.1177/0022167817711304

41.

Phelps

Henry

(2021). Foundations for training psychedelic therapists. Current Topics in Behavioral Neurosciences, 2021. Advance online publication. https://doi.org/10.1007/7854_2021_266

42.

Rossi

G. N.

Hallak

J. E.

Bouso Saiz

J. C.

Dos Santos

R. G.

(2022). Safety issues of psilocybin and LSD as potential rapid acting antidepressants and potential challenges. Expert Opinion on Drug Safety, 21(6), 761–776. https://doi.org/10.1080/14740338.2022.2066650

43.

Schlag

A. K.

Aday

Salam

Neill

J. C.

Nutt

D. J.

(2022). Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. Journal of Psychopharmacology, 36(3), 258–272. https://doi.org/10.1177/02698811211069100

44.

Sessa

(2012). The psychedelic renaissance: Reassessing the role of psychedelic drugs in 21st century psychiatry and society. Muswell Hill Press.

45.

Smith

W. R.

Appelbaum

P. S.

(2021). Two models of legalization of psychedelic substances: Reasons for concern. Journal of the American Medical Association, 326(8), 697–698. https://doi.org/10.1001/jama.2021.12481

46.

St. Arnaud

K. O.

Sharpe

(2022). Contextual parameters associated with positive and negative mental health in recreational psychedelic users. Journal of Psychoactive Drugs, 1–10. https://doi.org/10.1080/02791072.2022.2039815

47.

Tagliazucchi

Roseman

Kaelen

Orban

Muthukumaraswamy

S. D.

Murphy

Laufs

Leech

McGonigle

Crossley

Bullmore

Williams

Bolstridge

Feilding

Nutt

Carhart-Harris

(2016). Increased global functional connectivity correlates with LSD-induced ego dissolution. Current Biology, 26(8), 1043–1050. https://doi.org/10.1016/j.cub.2016.02.010

48.

Timmermann

Watts

Dupuis

(2022). Towards psychedelic apprenticeship: Developing a gentle touch for the mediation and validation of psychedelic-induced insights and revelations. Transcultural Psychiatry. https://doi.org/10.1177/13634615221082796

49.

Tupper

K. W.

Wood

Yensen

Johnson

M. W.

(2015). Psychedelic medicine: A re-emerging therapeutic paradigm. Canadian Medical Association Journal, 187(14), 1054–1059. https://doi.org/10.1503/cmaj.141124

50.

Vollenweider

F. X.

Preller

K. H.

(2020). Psychedelic drugs: Neurobiology and potential for treatment of psychiatric disorders. Nature Reviews Neuroscience, 21(11), 611–624. https://doi.org/10.1038/s41583-020-0367-2

51.

Watts

Luoma

J. B.

(2020). The use of the psychological flexibility model to support psychedelic assisted therapy. Journal of Contextual Behavioral Science, 15, 92–102. https://doi.org/10.1016/j.jcbs.2019.12.004

52.

Zeifman

R. J.

Singhal

Wang

Nayak

S. M.

Weissman

C. R.

(2022). Decreases in suicidality following psychedelic therapy: A meta-analysis of individual patient data across clinical trials. The Journal of Clinical Psychiatry, 83(2), Article 39235. https://doi.org/10.4088/JCP.21r14057