This excellent, well-argued, book is required reading for anyone with interests in philosophy of mind, philosophy of psychology, and philosophy of psychiatry. It presents the first book-length argument for the effectiveness of psychedelic therapy and provides an account of how this effectiveness may be understood from within cognitive neuroscience. Everyone should read this book!
Richard Brown, Humanities Department, LaGuardia Community College,
CUNY & M.S. program in Cognitive Neuroscience at the Graduate Center, CUNY
Philosophy of Psychedelics is really two books in one. It provides an easily understood, scholarly and detailed review of psychedelic science, spanning phenomenology, psychology, neuroscience, and medical therapeutics. But setting this book apart from other recent books in this rapidly emerging field of inquiry, Chris Letheby takes his philosopher's scalpel to addressing intriguing philosophical implications of psychedelic research including the unsettling question of whether the claimed benefits from psychedelic experiences require the induction of delusional beliefs. This very readable volume should be of interest to scientists, philosophers, as well as those simply curious about recent the renaissance in psychedelic science and therapeutics.
Roland R. Griffiths, Ph.D. Director, Center for Psychedelic and Consciousness Research, Professor, Departments of Psychiatry and Neuroscience, Johns Hopkins University School of Medicine
Philosophy of Psychedelics is a terrific, intellectually meticulous study of the nature, meaning, and effects of psychedelic experiences. The discussion ranges over the mind-brain relation, transformative experiences, the ethics of psychedelic therapy, and whether psychedelics help us to see the nature of things as they really are or just produce uplifting and therapeutically positive hallucinations. Chris Letheby is a wise and careful guide to the current state of psychedelic therapy and sets very high standards for philosophers who want to follow him in thinking responsibly about this intriguing area of research.
Owen Flanagan is James B. Duke, Professor of Philosophy at Duke University, and the author of
*How to Do Things with Emotions* Princeton 2021. Philosophy of Psychedelics
INTERNATIONAL PERSPECTIVES IN PHILOSOPHY AND PSYCHIATRY
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Volumes in the series: Recovery of People with Mental Illness: Philosophical and Related Perspectives
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Values and Psychiatric Diagnosis
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The Oxford Handbook of Psychiatric Ethics
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Madness and Modernism: Insanity in the Light of Modern Art, Literature, and Thought
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Disembodied Spirits and Deanimated Bodies: The Psychopathology of Common Sense
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Lost in Dialogue: Anthropology, Psychopathology, and Care
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Essential Philosophy of Psychiatry
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Empirical Ethics in Psychiatry
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Alternate Perspectives on Psychiatric Validation: DSM, ICD, RDoC, and Beyond
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Philosophy of Psychedelics
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Acknowledgements
My deepest thanks are due to Philip Gerrans, Gerard O’Brien, and Jon Opie, without whom this book would not have been written. I am also indebted to Lisa Bortolotti and Thomas Metzinger for timely advice, encouragement, and assistance.
I am extremely grateful to Miri Albahari and Roland Griffiths for their generosity in reading the entire manuscript and providing detailed comments. For reading and commenting on sections of the manuscript, I would like to thank Sam Baron, Sascha Fink, Owen Flanagan, Remco Heesen, Nin Kirkham, Aidan Lyon, Michael Rubin, and Clas Weber. Needless to say, any errors that remain are my responsibility.
Finally, and with apologies to anyone I have forgotten, I would like to thank my stellar editorial team at Oxford University Press: Martin Baum, Janine Fisher, and Charlotte Holloway.
This research was partially supported by the Australian Government through the Australian Research Council’s Discovery Projects funding scheme (project DP190101451). The views expressed herein are those of the author and are not necessarily those of the Australian Government or Australian Research Council.
PMIR Phenomenal model of the intentionality relation
PP predictive processing
PSM phenomenal self-model
RCT randomised controlled trial
REBUS RElaxed Beliefs Under pSychedelics
RSC retrosplenial cortex
SN Salience Network
SSRI selective serotonin reuptake inhibitor
TPJ temporoparietal junction
TPN task-positive network
TRD treatment-resistant depression
vmPFC ventromedial prefrontal cortex
Introduction
The unacceptability of psychedelic therapy . . . stems in part at least from this fundamental empirical fact: Through the psychedelic experience persons tend to accept beliefs which are at variance with the usual conception of the ‘scientific world view’.
Willis Harman, ‘The issue of the consciousness expanding drugs’.
Something very strange is happening in psychiatry. Clinicians and researchers are becoming increasingly interested in a ‘new’ experimental treatment, with some suggesting it might herald a ‘new paradigm’ in the treatment of disorders such as anxiety, depression, and addiction (Nichols et al. 2017, Schenberg 2018). If promising initial results are borne out, this new treatment may significantly outperform existing pharmacological and psychological therapies in terms of rapidity and efficacy. And yet this treatment has a number of properties that, from the standpoint of mainstream philosophy and science, can only be described as extremely weird.
First, although it is a drug treatment, there is no daily dosing regimen of the kind familiar from existing antidepressant and antipsychotic medications. Patients receive one dose (or very few doses) of the drug—albeit with considerable interpersonal support and preparation—and then, in successful cases, their symptoms dramatically decrease for many months; no re-dosing required. Second, although it is in some sense a drug treatment, it’s far from clear that the drug itself is the direct cause of clinical improvement. Rather, it seems that the drug is merely a catalyst for a brief but intense conscious experience, and it is this experience that causes therapeutic effects. Third, and most weirdly, the kind of experience that seems to lead to the best outcomes is one that patients describe as ‘mystical’ or ‘spiritual’. Many patients given this treatment report transcendent experiences of ‘oneness’, ‘cosmic’ consciousness, or ‘ego dissolution’, and evidence suggests that these patients show the greatest clinical improvement.
I am referring, of course, to psychedelic therapy: the treatment of psychiatric disorder by the supervised administration of ‘hallucinogenic’ serotonin-2a agonist substances such as lysergic acid diethylamide (LSD), psilocybin (the active ingredient in ‘magic’ mushrooms), and N,N-dimethyltryptamine (DMT; a key psychoactive constituent of the Amazonian beverage ayahuasca). Given their widespread reputation as psychotomimetic (psychosis-mimicking) or psychotogenic (psychosis-generating) chemicals, the very idea of using psychedelics to treat mental illness may seem absurd
(Osmond 1957, Carhart-Harris et al. 2016a). However, these drugs were studied and prescribed as experimental psychiatric treatments in the 1950s and 1960s, prior to the public controversy surrounding their use by the hippie counterculture. Promising results were reported from this line of research, which was curtailed prematurely due to the crackdown on psychedelics and the subsequent ‘War on Drugs’. For decades, virtually no human psychedelic research was conducted.
Since the 1990s, this research has been slowly but steadily resuming, and the results to date are intriguing. Although it is still relatively early days, there is now sufficient evidence to take seriously the claims of earlier researchers. Supervised psychedelic sessions may, after all, have an acceptable safety profile (dos Santos et al. 2018a) coupled with significant and lasting psychological benefits for psychiatric patients (dos Santos and Hallak 2020) and even for healthy volunteers (Gandy 2019). Meanwhile, neuroimaging studies of the psychedelic state are providing tantalising clues about the biological bases of consciousness and self-awareness (dos Santos et al. 2016b). If these preliminary findings are replicated, then psychedelics may well find a place in twentyfirst-century psychiatry (Sessa 2005, 2012, 2018). But many questions remain. The transformative mechanisms of psychedelic experience are incompletely understood, and this strikingly novel type of therapeutic intervention raises many fascinating and puzzling issues, both scientific and philosophical.
This book is organised around one specific philosophical question that relates to the role of the mystical experience in psychedelic therapy. Patients and subjects who show the greatest psychological benefit from psychedelic experiences tend to be those who report a mystical experience, as defined by widely used psychometric questionnaires, and often the degree of mystical experience predicts the degree of benefit. A mystical experience is sometimes described as an overwhelmingly powerful apparent encounter with ‘ultimate reality’. Space, time, and the sense of individual selfhood fade away, to be replaced by a sense of union with ‘another Reality that puts this one in the shade’ (Smith 2000, p. 133). In some cases, this Reality is experienced as a divine or cosmic consciousness that underlies and unifies the entire manifest universe, evoking philosophical doctrines such as idealism and pantheism (Shanon 2002, p. 162). The apparent centrality of the mystical experience has led researcher Charles Grob to describe psychedelic therapy as an ‘existential medicine’ (Grob 2007, p. 213).
But this picture of psychedelic therapy raises an obvious worry: what if the divine universal consciousness is not real? Many philosophers and scientists today subscribe to a broadly naturalist, materialist, or physicalist world view, according to which mind and consciousness are not fundamental in the universe but are relatively recent products of complex evolution. From this perspective, the mystical apprehensions of psychedelic subjects look like ‘metaphysical hallucinations’ (Flanagan and Graham 2017, p. 294)—subjectively compelling but ultimately misleading by-products of aberrant brain activity, on a par with psychedelic subjects’ visions of walls ‘breathing’ or kaleidoscopic fractals (cf. Roche 2010). And there seems to be something seriously questionable about a treatment or enhancement modality that works by inducing metaphysical hallucinations. The journalist Michael Pollan, discussing the use of
psychedelics to treat psychological distress in terminally ill patients, puts the point forcefully: ‘Is psychedelic therapy simply foisting a comforting delusion on the sick and dying?’ (Pollan 2015). The worry is that psychedelics bring about their salutary psychosocial effects by a deceptive, epistemically (and therefore ethically) bad mechanism.
Call this the ‘Comforting Delusion Objection’ to psychedelic therapy. There are three popular responses. The first is that there’s no problem because the mystical experience is veridical. Far from inducing metaphysical hallucinations, psychedelics afford subjects a direct and transformative apprehension of ultimate reality (Smith 2000, Richards 2015). The second response is that the epistemic status of psychedelic experiences is relatively unimportant: what is more important is that they help people live better lives (Flanagan and Graham 2017). The third response is that the epistemic status of psychedelic experiences is very important, but also poor: we should be wary of permitting or prescribing psychedelic therapy because it does in fact work by the objectionable induction of comforting delusions (Lavazza 2017).
In this book, I present a fourth, relatively unexplored response to the Comforting Delusion Objection. My central thesis is that the Objection fails. My strategy is to start by assuming that (a) the naturalist worldview is true, so no cosmic consciousness exists, and (b) the epistemic status of psychedelic therapy is very important. This is the worst-case scenario for someone seeking to answer this objection. Clearly, if a cosmic consciousness or divine Reality exists, the objection fails (the first response above); and, clearly, if the epistemic status of psychedelic therapy is relatively unimportant, the objection fails (the second response above). Here I aim to show that the objection fails even if neither of these conditions holds—and this will show that the objection fails, whatever is the case.
My grounds for concluding that the Comforting Delusion Objection fails, even given assumptions (a) and (b) above, are twofold. First, the epistemic risks of psychedelic therapy, from a naturalistic standpoint, are less than one might suppose. Despite first appearances, psychedelic therapy does not work by instilling comforting metaphysical beliefs in a divine Reality. Such beliefs are sometimes acquired, but they are not necessary for therapeutic benefits, nor do they always accompany such benefits. The construct of a ‘mystical-type experience’, which mediates clinical outcomes, sometimes reflects experiences as of a cosmic consciousness or divine Reality. However, it sometimes reflects more naturalistic experiences of ‘ego dissolution’, connectedness, emotional catharsis, and psychological insight. Psychedelics promote well-being by temporarily disrupting the sense of self, allowing patients to access new ways of seeing themselves and their lives. Such existentially significant changes to self-awareness do not depend on changes to metaphysical beliefs about the ultimate nature of reality.
Second, psychedelic therapy is epistemically innocent, in the technical sense defined by Lisa Bortolotti (2015). Bortolotti defines epistemically innocent imperfect cognitions as those that have real epistemic flaws but also offer significant epistemic benefits that are unavailable by any other means. This is the status of psychedelic therapy, given naturalism. Psychedelic experiences can lead to knowledge acquisition, both
directly and indirectly—even if naturalism is true and the cosmic consciousness experience is a metaphysical hallucination. In the course of defending these claims, I will deal with issues concerning the nature of conscious experience, the relations between psychology and neuroscience, and the theory and philosophy of self-awareness. The second main thesis of the book is that a sustained and detailed interaction between philosophy and psychedelic science can be mutually beneficial: I aim to show that psychedelic science reveals phenomena of serious philosophical interest, while philosophy offers valuable tools for clarifying and interpreting results from psychedelic science.
I begin in Chapter 2 by reviewing recent scientific evidence concerning the safety, and therapeutic and transformative efficacy, of carefully controlled psychedelic administration. The recent wave of clinical studies suggests that psychedelics can indeed be given safely and responsibly, without serious adverse effects, to carefully selected and prepared subjects in carefully controlled conditions. These studies also provide evidence for durable psychological benefits following one (or very few) psychedelic sessions conducted in this fashion. But they also provide evidence that these benefits are mediated, at least in part, by mystical experiences, giving rise to the Comforting Delusion Objection. I outline the objection and my proposed response to it in more detail. I suggest that what is needed is a natural philosophy of psychedelics: a synthetic, big-picture inquiry integrating multidisciplinary evidence to address philosophical issues in a manner continuous with science and consistent with naturalism.
In the spirit of such a natural philosophy, I begin with detailed attention to the phenomena under investigation. As such, Chapter 3 presents an overview of the phenomenology of psychedelic therapy, including patients’ own impressions of the therapeutic mechanisms. Psychedelic experiences are notoriously variable and often held to be ineffable. Nonetheless, significant progress has been made on identifying typical themes from quantitative and qualitative reports. Subjects often describe an expansion of consciousness, a heightening of emotional experience, strange visions and insights, and a blurring of boundaries between self and world. Many subjects interpret these experiences in non-naturalistic terms, but many do not, instead emphasising experiences of psychological insight, emotional catharsis, acceptance, and connectedness to various aspects of self and world (Carhart-Harris et al. 2018a, Breeksema et al. 2020). This provides our first major clue that psychedelic therapy is not a simple matter of inducing existentially comforting metaphysical beliefs.
Although they provide suggestive evidence, we cannot assume that subjects’ impressions of the therapeutic mechanisms are correct. To determine how psychedelic therapy works, we need to examine a broader range of evidence. In Chapter 4, I survey three different theories of how psychedelics cause lasting psychological benefits. The first ascribes these benefits to psychedelics’ direct effects on the molecular-level mechanisms of neuroplasticity. On this view, psychedelic therapy is an experienceindependent pharmacotherapy, and the remarkable phenomenology is a mere cluster of therapeutically epiphenomenal ‘psychotomimetic’ side effects. The second and third theories differ in detail, but both ascribe lasting benefits to non-naturalistic
metaphysical ideations—the transcendent vision of a ‘Joyous Cosmology’ (Watts 1962) supposedly encountered in the mystical experience.
I argue that all three theories are inadequate. The neuroplasticity theory struggles to account for the robust correlation between measures of mystical-type experience and lasting benefits. This correlation suggests that the psychedelic experience itself is causally relevant to those benefits. However, on closer examination, we find that some subjects satisfy psychometric criteria for a ‘mystical-type experience’ without having a transcendent vision of cosmic consciousness. These criteria are broad enough to capture more naturalistic experiences of ‘ego dissolution’ and connectedness as well. Not all mystical-type experiences in the psychometric sense are non-naturalistic metaphysical hallucinations. The conclusion is that the key causal factor in psychedelic therapy is genuinely psychological—an aspect of the experience itself—but is not essentially tied to non-naturalistic metaphysical ideations.
In Chapter 5, I argue that the relevant psychological factor is change to the sense of self. A few studies pinpoint experiences of psychological insight as strongly linked to lasting benefits, and the relevant insights are often autobiographical in character. Moreover, several studies have shown that psychedelics can induce lasting increases in ‘mindfulness-related capacities’ for taking an open, non-reactive stance toward one’s inner experience—a stance that intrinsically involves changes to the sense of self. These studies constitute an important experimental vindication of the old idea that there are deep commonalities between psychedelic and meditative states (e.g., Huxley 1954, Watts 1962, Leary et al. 1964). Finally, neuroimaging research has consistently implicated certain large-scale brain networks, the Default Mode and Salience networks, in psychedelics’ lasting benefits, and both networks are linked to selfrepresentation by considerable independent evidence.
At this point, a question arises: how exactly do neurobiological changes, such as modulation of the Default Mode and Salience networks, relate to psychological changes, such as autobiographical insights and increased mindfulness-related capacities? I propose that neurocognitive theory, which attributes computational or information-processing functions to neural structures, provides a vital explanatory bridge between biological and psychological accounts of the psychedelic state (cf. Gerrans 2014). If we can specify the cognitive functions performed by the neural systems that psychedelics target, then this will allow us to explain why modulating those networks should lead to transformative experiences of ego dissolution, connectedness, catharsis, and insight.
In Chapters 6 and 7, I outline such a theory: the predictive self-binding account of psychedelic therapy (Letheby and Gerrans 2017). According to this account, one function of the networks targeted by psychedelics is to maintain a hierarchical predictive model of the self. This predictive self-model acts as a ‘centre of representational gravity’: by parsing information into self-relevant and self-irrelevant, into ‘me’ and ‘not me’, it functions as an organising principle that governs and constrains cognitive processing. In pathological conditions, detrimental forms of self-modelling often become rigidly entrenched. By ‘unbinding’ the self-model, psychedelics facilitate
experiences of ego dissolution and psychological insight in which pathological selfmodels can be revised. On this view, psychedelic therapy has a two-factor structure: it involves (a) the induction of neural and psychological plasticity at multiple levels, and (b) the discovery and consolidation of new forms of self-modelling.
I conclude Chapter 7 with some brief remarks on philosophical questions about self and self-consciousness. I have argued elsewhere that psychedelic evidence supports two controversial philosophical claims: that the self does not exist (Letheby and Gerrans 2017), and that there can be conscious experiences lacking all forms of self-consciousness (Letheby 2020). However, both arguments face serious objections. For present purposes, I content myself with two weaker, but still significant, claims: (i) there can be conscious experiences lacking anything like the ordinary sense of self, and (ii) the kind of self that we automatically take ourselves to be does not exist. Theoretically and existentially, this is plenty to be getting on with.
The upshot of Chapters 4–7 is that the epistemic risks of psychedelic therapy, given naturalism, are surprisingly small. In Chapter 8, I argue that its epistemic benefits, given naturalism, are surprisingly large. The concept of ‘epistemic innocence’ (Bortolotti 2015, 2020) encapsulates the overall epistemic status of psychedelic therapy, given naturalism: this intervention carries non-trivial epistemic risks, insofar as some subjects do acquire strong beliefs in a cosmic consciousness or spirit world, but these risks are offset by the fact that it also offers significant, often unique, epistemic benefits. I survey the major proposals about psychedelic-induced knowledge gain that are consistent with naturalism, and argue that psychedelics offer what philosophers call ‘knowledge by acquaintance’ with various often unrevealed aspects of the human mind, including its potential for diverse and beneficial modes of attention and cognition. This has connections with philosophical discussions of Frank Jackson’s (1982, 1986) famous thought experiment about Mary the super-neuroscientist. It also justifies the increasing use of the appellation ‘psychedelic’, meaning ‘mindmanifesting’ or ‘mind-revealing’ (Osmond 1957), in preference to the many available alternatives.
At later times, subjects can re-evoke these beneficial modes of attention and cognition, at least to some extent. Therefore, psychedelics also make available ability knowledge, or knowledge-how. The question of factual or propositional knowledge is more vexed. It is highly likely that psychedelics facilitate genuine psychodynamic insights into previously unconscious or unattended mental states, but the possibility of ‘placebo insights’ (Jopling 2001)—spurious apparent insights with real therapeutic benefits—must be kept in mind. The only viable solution is for psychedelic-induced apparent epiphanies to be subjected to sober scrutiny during the post-session integration period. I argue that psychedelic experiences also facilitate the acquisition of new knowledge of old facts, allowing subjects to experience existing beliefs in more vivid and motivating ways. Finally, I argue that psychedelic experiences have indirect epistemic benefits consequent on their lasting psychological benefits (Letheby 2016).
In Chapter 9, I turn to the philosophical project of ‘naturalising spirituality’. I argue that psychedelic research vindicates the claim that there are transformative
experiences and practices that (a) can legitimately be called ‘spiritual’, and (b) are compatible with adherence to a naturalistic world view. The existential transformation afforded by some psychedelic experiences provides a paradigm for naturalistic spirituality: the temporary suspension of our default, self-referential mode of cognition, making available broader perspectives, experiences of connectedness, and feelings of wonder and awe. This has connections to Iris Murdoch’s (1970) notion of ‘unselfing’ (cf. Kähönen 2020). There is considerable convergence between typical features of psychedelic-induced spiritual experiences and themes common to multiple philosophical accounts of naturalistic spirituality (Stone 2012), which provides further support for the general approach.
Finally, in Chapter 10, I summarise the discussion and make some suggestions for future research. My account makes several testable predictions—for instance, psychedelic-induced changes to the activity of specific brain networks should correlate with distinct types of ego-dissolution experiences, and psychedelic-induced changes to metaphysical beliefs (e.g., about the mind–body relation) should account for relatively little variance in clinical outcomes. In closing, I reflect on the broader significance of my arguments. Psychedelic science is a fast-moving field, and this book will be out of date in some respects before it hits the shelves—which is a good thing. In the coming years, we are set to learn more than ever before about these controversial substances, their risks, benefits, and potential applications, and the mechanisms underlying their remarkable effects. The philosophical discussion of psychedelics, in particular, is in its infancy. But I think it is not premature to bet that, when psychedelics cause lasting therapeutic benefits, these benefits are not brought about mainly by the induction of comforting delusions. Psychedelics can, as many have insisted, facilitate genuine insights and spiritual experiences—and this is a claim that even a philosophical naturalist should endorse.
On the need for a natural philosophy of psychedelics
Central to the entire LSD controversy is: ‘With how much credence should the chemical experience be accepted?’ Should it be totally accepted as the real reality, or is it preferable to attempt to study the state, sorting out the veridical from the illusory? Evidently, a choice must be made. The state must be either taken on faith without examination or it must be subjected to sorting and analysis. The overgullible will be easily persuaded, the overcritical will analyse it out of existence. Perhaps a third approach is possible––an attempt to measure without changing, to evaluate without destroying.
Sidney Cohen, Drugs of Hallucination.
2.1 Introduction
In this chapter, I review the history of psychedelics in science and psychiatry, recent evidence for their safety and therapeutic and transformative efficacy, and the facts about them that give rise to the Comforting Delusion Objection. I describe the main extant responses to the Objection, introduce my response, and outline my plan for defending it in the subsequent chapters. Psychedelics have struck many researchers as raising significant philosophical questions (Smythies 1953, Smith 1964, Shanon 2001), yet until recently have been largely ignored in academic philosophy. I propose that what is needed in this age of interdisciplinarity is a natural philosophy of psychedelics: a trans-disciplinary synthesis that integrates empirical findings with theoretical and conceptual considerations, to address some of the fascinating and distinctively philosophical questions raised by these controversial substances.
2.2 The psychedelic renaissance
The term ‘psychedelic’, meaning, roughly, ‘mind-manifesting’ (Osmond 1957), has been applied to a wide variety of drugs that cause dramatic changes to perception, emotion, and cognition (Sessa 2012). Psychedelics, thus construed, form a pharmacologically heterogeneous class: the Mexican psychoactive sage, Salvia Divinorum (or
its active principle, Salvinorin A), acts by agonism of the kappa opioid receptor in the brain, for instance (Roth et al. 2002), while dissociative anaesthetics such as ketamine produce psychedelic effects at low doses by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors (Krystal et al. 1994).
However, the term is sometimes reserved for a more restricted class: the ‘classic’ psychedelics, such as lysergic acid diethylamide (LSD), psilocybin (found in ‘magic’ mushrooms), mescaline (found in various cacti), and N,N-dimethyltryptamine (DMT, found in various plants and animals, and a key ingredient in the Amazonian beverage ayahuasca; Nichols 2016). These drugs, and others of this class, exert their psychoactive effects primarily by mimicking the action of the neurotransmitter serotonin (5-HT) at a specific receptor subtype: the serotonin-2a (5-HT2A) receptor (Vollenweider et al. 1998, Halberstadt 2015, Carhart-Harris 2019). It is these serotonergic (serotonin-acting) psychedelics that are my focus in this book, and I will reserve the word ‘psychedelic’ for them henceforth.1
Naturally occurring psychedelics have been used for religious, spiritual, and medicinal purposes for centuries, if not millennia, by various cultures around the world, especially in the Americas (Grinspoon and Bakalar 1979, Miller et al. 2019). Western scientists and intellectuals showed some interest in mescaline throughout the late nineteenth and early twentieth centuries (e.g., Mitchell 1896, Ellis 1897, Klüver 1926, Guttmann 1936). But the story of modern psychedelic science really begins with the Swiss chemist Albert Hofmann’s accidental discovery, in 1943, of the potent psychedelic effects of LSD (Hofmann 1980). Hofmann was originally investigating LSD and related compounds for purely medicinal purposes, but he and his colleagues were struck by the dramatic and bizarre alterations to consciousness that this new molecule produced at utterly minute doses. In subsequent years, the similarity between the effects of LSD and mescaline was recognised. Following this, the amateur mycologist R. Gordon Wasson (1957) confirmed that Psilocybe mushrooms were still in regular ceremonial use in Mexico. Hofmann identified psilocybin as the active ingredient and worked out how to synthesise it (Hofmann et al. 1958). Psychedelic science began in earnest.
Throughout the 1950s and 1960s, psychedelics were studied and used in many different ways (Grof 1975, pp. 1–4). Early researchers were impressed by the similarity between some psychedelic experiences and naturally occurring psychoses, leading to a conception of the drugs as ‘psychotomimetic’ (psychosis-mimicking) or ‘psychotogenic’ (psychosis-causing). This led to two major applications: the study of psychedelics’ mechanisms of action, in the hope of uncovering the biochemical bases of mental illness, and the controlled ingestion of psychedelics by psychiatrists, to increase their empathy with their psychotic patients (Osmond 1957). The discovery of
1 Note that the ‘entactogenic’ substance 3,4-methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) does not count as psychedelic on this definition: Although its effects are partly serotonergically mediated, it differs both pharmacologically and phenomenologically from the classic psychedelics (Nichols 1986, Roseman et al. 2014).
LSD’s serotonergic action was crucial in confirming that serotonin played a role in emotion and cognition. As such, it contributed to the ‘psychopharmacological revolution’ and the birth of modern biological psychiatry (Dyck 2010).
But stereotypically psychotic symptoms were not the only mental changes observed after psychedelic administration. Many subjects reported overwhelming experiences of a spiritual or religious nature: ineffable mystic union with the divine, direct experience of the primordial Good in existence, and transcendent visions of a ‘Joyous Cosmology’ (Watts 1962). Experiences of this type seemed to happen unbidden, even when expectations were quite different (Mangini 1998). Researchers who had thought that psychedelics might scare alcoholics sober by mimicking safely the terrifying symptoms of delirium tremens were surprised when many of their patients were moved to kick the bottle by powerful religious raptures. Experiences of this kind piqued the interest of intellectuals with a prior interest in mysticism, such as Aldous Huxley (1954) and Alan Watts (1960), whose writings laid the groundwork for the psychopharmacological spirituality of the 1960s counterculture.
Thus emerged a second, quite different conception of psychedelics, as agents of spiritual experience. Adherents of this approach looked to the drugs for clues about the nature of naturally occurring mystical states and even about the (pre-) historical genesis of religion. We can (anachronistically) dub this an ‘Entheogenic Conception’, using the neologism coined by Ruck et al. (1979) to foreground psychedelics’ spiritual and religious uses: generating the divine within. The most famous academic application of the Entheogenic Conception was Walter Pahnke’s (1963) ‘Good Friday Experiment’, in which psilocybin was administered to divinity students. While listening to a Good Friday service, one group of volunteers received psilocybin, and another an active placebo: those in the psilocybin group reported transcendent mystical experiences. Pahnke’s experiment had serious methodological flaws (Doblin 1991) but was nonetheless a milestone in establishing the potential of drugs in the study of religious experiences. A recent, more rigorous replication (Griffiths et al. 2006) is discussed further in section 2.3.3. Recent research has also documented numerous commonalities between psychedelic experiences and meditative states, vindicating the basic intuitions of pioneers such as Huxley and Watts (Millière et al. 2018, Smigielski et al. 2019a, 2019b, Heuschkel and Kuypers 2020).
The third, psychotherapeutic, conception of psychedelics is implicit in what I have said about their apparently transformative effects on alcoholics. Startled by the fact that ‘psychotomimetic’ drugs seemed able to catalyse lasting positive behavioural change, researchers noted that psychedelic subjects often experienced a seeming ‘upsurge’ (Sandison 1954) of previously unconscious material: repressed memories, desires, and fantasies. In line with the dominant psychoanalytical orientation of the day, some researchers concluded that psychedelics weakened the barriers of repression in a way that could facilitate therapeutic progress, by allowing access to the unconscious and enhancing the therapist–patient bond (Sandison et al. 1954, Eisner and
Cohen 1958). Hence the ‘psycholytic’ (mind-loosening) form of therapy practiced in Europe: repeated sessions of classical psychoanalysis enhanced by low doses of psychedelics (Leuner 1967).
Psychiatrists in the US tended rather to practice ‘psychedelic therapy’: the administration of one (or very few) high doses, with considerable preparation and interpersonal support, aimed at facilitating an overwhelming and transformative mystical or ‘peak’ experience (Faillace 1966). Positive results were reported from this method. Although much of the research was methodologically problematic, with over-reliance on anecdotal evidence and under-reliance on control groups (Smart and Storm 1964, Mangini 1998), a recent meta-analysis of six randomised controlled trials (RCTs) from the 1950s and 1960s found evidence for the efficacy of a single high dose of LSD in the treatment of alcoholism (Krebs and Johansen 2012).
Psychotomimetic, entheogenic, and psychotherapeutic investigations were three prominent strands of psychedelic research, but by no means the only ones. Some researchers were interested in psychedelics’ potential to enhance creativity (Harman et al. 1966; cf. Sessa 2008), others in their potential as a research tool for charting the human psyche (Osmond 1957). Aldous Huxley (1954) viewed the ‘antipodes of the mind’ disclosed in psychedelic experience as a promising region for disciplined scientific exploration. Later, Stanislav Grof famously compared psychedelics’ ‘potential significance for psychiatry and psychology to that of the microscope for medicine or the telescope for astronomy’ (Grof 1975, pp. 32–33). This approach has connections with the recent interdisciplinary enterprise of ‘philosophical psychopathology’, which uses observations from non-ordinary conditions as a basis for conclusions about the structure and function of the ordinary mind (Graham and Stephens 1994). This ‘telescopic’ conception has been one of the most prominent rationales for the use of psychedelics in recent cognitive neuroscience (e.g., Carhart-Harris et al. 2014).
In a seminal 1957 article that introduced the term ‘psychedelic’ to the scientific lexicon, Humphry Osmond summarised these various lines of investigation:
Nearly everyone who works with [psychedelics] and allied compounds agrees there is something special about them. Such words as ‘unforgettable’ and ‘indescribable’ abound in the literature. Few workers, however, have emphasised that the unique qualities of these substances must be investigated in many directions at the same time, a consideration that makes work in this field all the more difficult. I shall try to remedy this deficiency by citing several reasons for ascribing importance to them .
(1) The primary interest of these drugs for the psychiatrist lies in their capacity to mimic more or less closely some aspects of grave mental illnesses, particularly of schizophrenia. The fact that medical men have been preoccupied with transient states resembling mental illnesses that have been called model psychoses, however, does not mean that the only use for these compounds is in the study of pathological conditions . . .
(2) Psychiatrists have found that these agents have a place in psychotherapy. This practice may sound like carrying the idea of ‘a hair of the dog that bit you’ rather far, but it seems to be justified.
(3) Another potentiality of these substances is their use in training and in educating those who work in psychiatry and psychology, especially in understanding strange ways of the mind.
(4) These drugs are of value in exploring the normal mind under unusual circumstances.
(5) Last, but perhaps most important: there are social, philosophical, and religious implications in the discoveries made by means of these agents.
(Osmond 1957, pp. 419–420).
Despite this wealth of promising research programmes, the heyday of psychedelic science was short-lived. LSD, in particular, became the topic of intense socio-political controversy after its highly publicised adoption by the hippie counterculture, exemplified by Timothy Leary’s notorious exhortations to ‘turn on, tune in, and drop out’ (Pahnke 1967). Psychedelics’ real but relatively manageable risks (more on which shortly) were both increased by reckless recreational use and exaggerated by sensationalistic journalism (Masters and Houston 1966), inextricably linking psychedelics in the public imagination to fried brains, damaged chromosomes, and delusional leaps from rooftops (Dyck 2010). The net result was that psychedelics were prohibited and virtually all research into their effects on humans stopped. Funding dried up, and displaying an interest in the topic became tantamount to career suicide for any respectable scientist or psychiatrist (Sessa 2005).
Since the 1990s, in a changed socio-political climate, human research on psychedelics has resumed. This line of research is promising and has been aided by the many methodological, technological, and theoretical developments that have occurred in the mind and brain sciences since the 1970s. It is relatively early days, but the field has matured sufficiently that it is now commonplace to speak of a ‘psychedelic renaissance’ (Sessa 2018, Kelly et al. 2019, Holoyda 2020). Indeed, in the past few years, the expansion of the field has accelerated dramatically (Aday et al. 2019a, Doblin et al. 2019). A new generation of researchers—and even some first-generation psychedelic scientists (e.g., Richards 2015)—have picked up the loose ends described above: psychotomimetic, entheogenic, psychotherapeutic, and other potential applications of psychedelics are being probed with a multitude of methods. I will now review recent findings about the therapeutic and transformative potential—and, crucially, the safety profile—of carefully controlled psychedelic administration in human volunteers.
2.3 Evidence for safety and efficacy
2.3.1 Safety
One of the main reasons given for the prohibition of psychedelics in the 1960s was that these drugs were just too dangerous to be used safely. Political discourse and media coverage surrounding LSD, in particular, painted an alarming picture of a substance capable of causing instant and permanent insanity, genetic defects, and moral corruption (Masters and Houston 1966, Dyck 2010, Mangini 1998). This broad picture of psychedelics as far too hazardous to contemplate using still holds great sway in the public imagination today. Moreover, in most countries, these drugs are classified in the most restrictive legal categories, due to their having ‘high abuse potential’ and ‘no accepted medical use’ (Nutt et al. 2013, Krebs 2015). So how can psychedelic therapy even be a prospect worth discussing?
The fact is that, while they are no more risk-free than any other intervention, the dangers of psychedelics seem to have been greatly exaggerated (cf. dos Santos 2014). In a review of the literature, Rick Strassman (1984) found that adverse psychological reactions to psychedelics were relatively rare and. when they did occur, typically transient and manageable with interpersonal support. In the relatively few cases of prolonged psychosis following exposure to a psychedelic, there is often evidence of a pre-existing latent vulnerability, such as a family history of psychotic illness. The incidence of prolonged psychotic episodes when stringent exclusion criteria are applied seems to be very low.
Strassman’s findings have been borne out by the dozens of studies conducted since the early 1990s in which psychedelics have been administered to healthy subjects and to psychiatric patients. Hundreds, if not thousands, of volunteers have now been carefully screened, selected, prepared, dosed, and followed-up, in accordance with strict safety guidelines (dos Santos et al. 2018a). These guidelines recommend, among other things, the exclusion of anyone with a personal or immediate family history of psychotic illness, in order to minimise the probability of serious adverse effects (Johnson et al. 2008). Subjects receive the drug in a comfortable, quiet setting, with therapists present to provide reassurance. Often they are given a carefully curated playlist of music to guide the experience (Kaelen et al. 2018). Typically, there are several preparation sessions before the first drug session in which subjects can develop rapport and trust with the supervising therapists, and be educated about the range of possible drug effects and how best to handle these psychologically (e.g., with an attitude of openness and curiosity).
The results by now are clear: when such guidelines are followed, psychedelics have an excellent physiological and psychological safety profile (Nichols 2016, Sessa 2018, dos Santos et al. 2018a.) These substances are physically non-toxic and non-addictive2
2 Modak et al. (2019) provide an extremely rare, possibly unique, case report of apparent physical dependence on LSD. Stone et al. (2006) report findings concerning the existence of a ‘hallucinogen
at standard therapeutic and transformative doses. Human fatalities attributable to their direct action are virtually unknown, at least in the cases of LSD, psilocybin, mescaline, and DMT—barring a few massive overdoses at several hundred times the standard therapeutic dosage (Nichols and Grob 2018). They can acutely elevate heartrate and blood pressure, and thus are contraindicated for those with certain health conditions. Moreover, subjects sometimes report headaches in the days after the dosing session, but these are transient and relatively mild (Johnson et al. 2012). In a seminal paper that outlines safety guidelines for human psychedelic research, Johnson et al. summarise the drugs’ physiological safety profile as follows:
Hallucinogens generally possess relatively low physiological toxicity, and have not been shown to result in organ damage or neuropsychological deficits . . . Nonhuman animal studies have shown MDMA (structurally similar to some classical hallucinogens, but with a substantially different pharmacological mechanism of action) to have neurotoxic effects at high doses, although MDMA has been judged to be safe for human administration in the context of several therapeutic and basic human research studies. In contrast, there is no evidence of such potential neurotoxic effects with the prototypical classical hallucinogens (i.e., LSD, mescaline and psilocybin). Some physiological symptoms may occur during hallucinogen action, such as dizziness, weakness, tremors, nausea, drowsiness, paraesthesia, blurred vision, dilated pupils and increased tendon reflexes . . In addition, hallucinogens can moderately increase pulse and both systolic and diastolic blood pressure . . . However, these somatic effects vary and are relatively unimpressive even at doses yielding powerful psychological effects . . .
The physical adverse effects of these agents observed in cancer patients were manageable and similar to effects observed in physically healthy individuals. These researchers noted that any other symptoms experienced during sessions with cancer patients were symptoms already associated with their existing illness . . . Early clinical research also safely administered LSD to chronic alcoholics and cancer patients with considerable liver damage, suggesting hepatic concerns are ‘negligible unless the dysfunction is of a critical degree’ (Grof 1980, p. 164).
Participants and review committees may be concerned that LSD or other hallucinogens are associated with chromosomal damage. These concerns stem from an anti-LSD media campaign by the USA government in the late 1960s . . . However, many follow-up investigations soon squarely refuted the hypothesis that LSD use in humans was a significant risk for chromosomal damage or carcinogenic, mutagenic or teratogenic effects . . . (Johnson et al. 2008, pp. 606–607).
dependence syndrome’, in which physical dependence is not at issue, but rather problematic patterns of compulsive use. However, their definition of ‘hallucinogen’ includes substances other than classic psychedelics, such as MDMA and phencyclidine (PCP).
On the psychological front, subjects receiving high doses often experience considerable fear or anxiety during the dosing session (Griffiths et al. 2008), but this is managed with interpersonal support, and follow-ups in these studies have found no serious, lasting adverse effects (Garcia-Romeu et al. 2016). A recent study found that even quite high doses of psilocybin can be tolerated well by healthy volunteers (Nicholas et al. 2018). Writing in 2016, Ross et al. noted that over 2,000 doses of psilocybin had been administered in rigorous research trials during a 25-year period, with ‘no reports of any medical or psychiatric serious [adverse events], including no reported cases of prolonged psychosis or HPPD [hallucinogen persisting perception disorder]’ (Ross et al. 2016, p. 1176). In a more recent systematic review of psychedelics’ longterm effects, Aday et al. noted that ‘few subjects reported lasting negative side effects’, citing the finding of Studerus et al. (2011) that:
1/110 participants who received psilocybin reported experiences of anxiety and depression in the weeks following administration which warranted treatment. Additionally, ‘a few’ noted less severe emotional instability—but all adverse effects were resolved within a month.
(Aday et al. 2020, p. 184).
Aday et al. conclude:
All in all, limited harm has been reported in the new era of research which utilizes extensive safety protocols . . . and the drugs’ potential for dependency is low . . . In subjective accounts, [patients] with depression . . . and addiction . . . have noted the lack of long-term adverse side effects as being a considerable benefit over previous treatments they had attempted (e.g., antidepressants).
(Aday et al. 2020, p. 184).
In non-clinical settings, the risks are no doubt greater, but there is still evidence that they have been exaggerated. An oft-cited multicriteria decision analysis rated LSD and psilocybin among the least harmful of 20 commonly used recreational drugs, taking into account multiple types and dimensions of harm (Nutt et al. 2010). Researchers have extensively studied members of religious organisations, such as the Native American Church and Santo Daime, that routinely use psychedelics such as peyote and ayahuasca in their rituals. There is now a large body of evidence that members of these communities have good mental and physical health relative to the broader population (Halpern et al. 2005, 2008, Bouso et al. 2012, 2013, Barbosa et al. 2009, 2012, 2016, Ona et al. 2019; cf. Jiménez-Garrido et al. 2020).
Religious contexts aside, population-level studies have found lifetime use of psychedelics to be either un-associated or negatively correlated with various mental health problems such as psychosis, psychological distress, and suicidality (Hendricks et al. 2014, 2015a, 2015b, Krebs and Johansen 2013, Johansen and Krebs 2015, RougemontBücking et al. 2019). Similar studies have found psychedelic use to be associated with
