Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression

Psychedelic therapy may be more appropriately thought of as a distinct form of (drug-assisted) psychotherapy than as a pure pharmacotherapy. Psychedelic therapy involves a small number of high-dose psychedelic dosing sessions that are intended to facilitate a profound, potentially transformative psychological experience (Dyck, 2006; Majić et al., 2015). Psychedelic dosing sessions do not take place in isolation but rather are flanked by psychological preparation and integration. Preparation is intended to facilitate trust and rapport and a mind-set tuned toward emotional openness and “letting go” of psychological resistance (Richards, 2015; Russ and Elliott, 2017). Dosing sessions themselves typically take place in a welcoming environment, with dim lighting, eye-shades, calming and emotionally-directing music, with empathic support provided by trained therapists. The integration sessions subsequent to the dosing session(s) involve the same therapists (usually two) listening to the patient's narrative of their experience, which may include e.g., details of specific emotional insights.

A guiding principle of psychedelic psychotherapy is that the occurrence of a profound, potentially transformative psychological experience is critical to the treatment's efficacy. Evidence has shown that high-dose psychedelic sessions can reliably produce profound psychological experiences rated among the most “meaningful” of a person's life (Griffiths et al., 2006). A number of research teams have referred to these profound experiences and have applied relevant rating scales that have evolved out of studies of spontaneous and drug-induced “mystical,” “spiritual,” “peak” or “religious” experiences (Maslow, 1959; Stace, 1960; Pahnke and Richards, 1966; Maclean et al., 2012). Regardless of the terms chosen to define them, evidence suggests that profound psychological experiences can be predictive of subsequent psychological health, whether induced by psychedelics (O'Reilly and Funk, 1964; Klavetter and Mogar, 1967; Pahnke et al., 1970; Kurland et al., 1972; Richards et al., 1977; Maclean et al., 2011; Garcia-Romeu et al., 2014; Bogenschutz et al., 2015; Griffiths et al., 2016; Johnson et al., 2016; Ross et al., 2016), or other means (James, 1902; Maslow, 1959; Noyes Jr, 1980; Ludwig, 1985; Csikszentmihalyi and Csikszentmihalyi, 1992; Snell and Simmonds, 2015). Furthermore, some recent ketamine for depression studies have also found an association between the quality of acute experience (Sos et al., 2013; Luckenbaugh et al., 2014)—including the occurrence of mystical-type experiences (Dakwar et al., 2014)—subsequent positive clinical outcomes. Given the growing evidence favoring the therapeutic value of psychedelics (dos Santos et al., 2016; Rucker et al., 2016; Carhart-Harris and Goodwin, 2017), it is timely that we better understand their therapeutic mechanisms.

The so-called “mystical” experience has been a classic problem area for mainstream psychology—if not science more generally. The term “mystical” is particularly problematic, as it suggests associations with the supernatural that may be obstructive or even antithetical to scientific method and progress (Carhart-Harris and Goodwin, 2017). It is important to note that by using the term the mystical-type experience, we are referring only to the phenomenology of the experience and are keen not to endorse any associations between it and supernatural or metaphysical ideas. Readers interested in the phenomenology of mystical-type/peak experiences may wish to explore these classic texts (James, 1902; Stace, 1960; Maslow, 1964; Pahnke and Richards, 1966; Csikszentmihalyi and Csikszentmihalyi, 1992; Hood Jr et al., 2009; Richards, 2015).

In the late 1960s, William Richards and Walter Pahnke (former pupils of Abraham Maslow and Timothy Leary respectively) developed a measure of “peak” or “mystical-type” experience that was much inspired by the work of Stace (1960). Studying reports of “mystical-type” experiences occurring in a variety of different world religions, Stace identified a number of common or “universal” components that are largely independent of religious or cultural context (Stace, 1960). Based on this landmark work, Richards and Pahnke developed the “mystical experience questionnaire” (MEQ) designed to enquire whether related components featured in the psychedelic drug experience. The scale measured six components of experience: (1) sense of unity or oneness, (2) transcendence of time and space, (3) deeply felt positive mood, (4) sense of awesomeness, reverence and wonder, (5) meaningfulness of psychological or philosophical insight, (6) ineffability and paradoxicality (Pahnke and Richards, 1966; Pahnke et al., 1970). A similar questionnaire which is based on Stace (1960) is the “M scale” (Hood Jr, 1975). Both the MEQ and M scale have been found to be predictive of long-term positive therapeutic outcomes in trials of psilocybin for cancer-related distress (Griffiths et al., 2016; Ross et al., 2016), tobacco smoking (Garcia-Romeu et al., 2014; Johnson et al., 2016) and alcohol dependence (Bogenschutz et al., 2015).

Perhaps the most widely used subjective measure of altered states of consciousness, and particularly the psychedelic state, is the altered states of consciousness questionnaire (ASC) (Dittrich, 1998). We chose this scale over the MEQ as it measures a broader range of subjective phenomena, not just the “mystical-type experience.” Crucially, this enabled us to test the specificity of the relationship between mystical-type experiences (vs. e.g., perceptual changes) and subsequent therapeutic outcomes. One of the principal ASC factors is named “oceanic boundlessness” (OBN)—a term that has its origins in a conversation between Sigmund Freud and the French intellectual and “mystic” Romain Rolland (Freud, 1920) and makes reference to an “oceanic feeling” of boundlessness (Freud, 1929). Sharing a common intellectual background in Stace (1960) (Majić et al., 2015), items belonging to the OBN are closely related to those found in the MEQ. Previous factor analyses have parcellated the ASC into either 5 (Dittrich, 1998) or 11 dimensions (Studerus et al., 2010). As one of the original 5 ASC factors, OBN is explicitly linked to Stace's “mystical experience”, (Studerus et al., 2010) and 4 of the 11 revised ASC factors also relate to OBN. Explicitly, the 4 OBN sub-factors are named “insightfulness,” “blissful state,” “experience of unity” and “spiritual experience” (Studerus et al., 2010).

We recently completed an open-label clinical trial assessing the feasibility of treating 20 patients with treatment-resistant depression (TRD) with psilocybin (Carhart-Harris et al., 2017). Results were encouraging: 47% of patients showed a clinically significant response 5 weeks post treatment (≥50% reduction in depressive symptoms). The present study sought to extend on our previous reports on this trial, by specifically focusing on whether the quality of the acute psychedelic experience was predictive of longer-term clinical outcomes. Specifically, we asked whether psilocybin-induced OBN and Dread of Ego Dissolution (DED) (related to acute anxiety) were predictive of decreases in depression at a key endpoint, whether the relationship between OBN and decreased depression was significantly stronger than between psilocybin's more generic sensory perceptual effects and depression changes.

This trial received a favorable opinion from the National Research Ethics Service London—West London, was sponsored and approved by Imperial College London's Joint Research and Compliance Office (JRCO), and was adopted by the National Institute for Health Research Clinical Research Network. The National Institute for Health Research/Wellcome Trust Imperial Clinical Research Facility gave site-specific approval for the study. The study was reviewed and approved by the Medicines and Healthcare products Regulatory Agency (MHRA) and a Home Office Schedule One license was obtained for drug storage and administration. All participants provided written informed consent after receiving a complete description of the study.

Consistent with our prior hypothesis, psilocybin-induced high OBN (sharing features with mystical-type experience) and low DED (similar to anxiety) predicted positive long-term clinical outcomes in a clinical trial of psilocybin for TRD. This result replicates those of previous studies showing that psychedelic-induced peak or mystical-type experiences are predictive of positive long-term outcomes (O'Reilly and Funk, 1964; Klavetter and Mogar, 1967; Pahnke et al., 1970; Kurland et al., 1972; Richards et al., 1977; Maclean et al., 2011; Bogenschutz et al., 2015; Griffiths et al., 2016; Johnson et al., 2016; Ross et al., 2016). This relationship appears to be somewhat specific, in that OBN was significantly more predictive of positive clinical outcomes than altered visual and auditory perception—endorsing the moniker “psychedelic” (“mind-revealing”) over “hallucinogen” when referring to this class of drug—at least in the context of psychedelic therapy. It also suggests that the therapeutic effects of psilocybin are not a simple product of isolated pharmacological action but rather are experience dependent. We also found that greater DED (anxiety and impaired cognition) experienced during the drug session was predictive of less positive clinical outcomes.

One may naturally infer from these findings that the occurrence of OBN or mystical-type experience mediates long-term positive clinical outcomes (Griffiths et al., 2016; Ross et al., 2016) and while this assumption may be valid, we must exercise caution about ascribing too much to this relationship. It remains possible that as yet unmeasured and therefore unaccounted for components of psychedelic therapy play important roles in mediating long-term outcomes. There are several candidate factors in this regard, and the following should not be considered an exhaustive list: emotional insight/breakthrough or catharsis; priming and suggestibility; reliving of trauma/defining life events; insights about the self and relationships; the patients relationship to music heard; his/her success at “letting go”; the quality of therapeutic relationship; and the degree of “closure” attained during post-drug integration work (Frederking, 1955; Sandison, 1955; Abramson, 1956; Martin, 1957; Eisner and Cohen, 1958; Leuner, 1961; Jensen, 1963; Shagass and Bittle, 1967; Richards, 1978; Loizaga-Velder, 2013; Gasser et al., 2014; Belser et al., 2017; Russ and Elliott, 2017; Watts et al., 2017).

These factors may exert influence before, during and after the acute experience itself and may also be more or less dependent on particular psychological frameworks and their relevant vocabularies. For example, the psychoanalytic models of Freud and Jung were dominant in psychiatry in the mid-twentieth century and thus references to ego, repression and the unconscious are commonplace among the psychedelic research literature of this period. While the processes that underlie these constructs may indeed be operative in the context of psychedelics, little effort has been made to define, measure and quantify their contributions (Shagass and Bittle, 1967; Barr et al., 1972). The development of subjective (Nour et al., 2016), behavioral and biological measures (Carhart-Harris et al., 2012, 2016b; Lebedev et al., 2015; Tagliazucchi et al., 2016) relevant to these constructs, and more importantly, the processes that underlie them, would represent an important advance not just for psychedelic science but for the psychological frameworks themselves (Carhart-Harris et al., 2014). We should be conscious of not being too attached (or averse) to any specific theoretical frameworks however, and approaches that endeavor to access “framework-free” descriptions of phenomena may prove particularly useful in this regard (Varela, 1996; Petitmengin, 2006). Critically, it is our view that it is possible to work toward a secular, biologically-informed account of the mystical-type experience that does not resort to “explaining away” or “reducing down” the core phenomenology and depth psychology may be a useful bedfellow in this regard.

Returning to the present study's main findings, DED was found to negatively correlate with clinical outcome, yet, none of the patients showed a worsening of clinical symptoms at 5 weeks. Less DED combined with high OBN predicted 54% of the variance of clinical change at 5 weeks—a substantial contribution and one that helps justify the emphasis placed on minimizing anxiety and relinquishing psychological resistance in psychedelic therapy (Eisner and Cohen, 1958; Sherwood et al., 1962; Grof et al., 2008; Richards, 2015), as well as paying careful attention to preparation and “set and setting” (Hartogsohn, 2017; Carhart-Harris et al., in press). That anxiety arises in parallel with psychological struggle is resonant with principles of psychoanalytic theory (Sandison, 1961), as can be seen in the choice of terms for the “DED” and “OBN” factors of the ASC—both of which invoke constructs that can be traced to Freud (1929, 1962).

According to psychoanalytic theory, the overcoming of psychological resistance is required for emotional breakthrough and insight (Freud, 1920) and the occurrence of mystical-type/peak experiences (Jung, 2014). Consistently, writers on the mystical-type/peak experience have reliably identified loss of self or “ego-dissolution” as one of its basic pre-requisites and features (James, 1902; Stace, 1960; Maslow, 1964). Recent work has sought to develop and validate a measure that is sensitive to difficult or challenging psychedelic experiences (Barrett et al., 2016; Carbonaro et al., 2016) and there is some evidence that the intensity of such experiences is predictive of positive long-term outcomes, whereas the duration of struggle is predictive of negative outcomes (Carbonaro et al., 2016). This is presumably because the successful resolution of conflict brings with it, insight and relief, whereas the failure to breakthrough perpetuates suffering. ASC and other questionnaires such as the challenging experience questionnaire (CEQ) (Barrett et al., 2016) may be insensitive to whether or not successful resolution of psychological conflict has occurred. Therefore, the development of new scales specifically designed to focus on emotional breakthrough after struggle may add considerable value.

Improving our subjective measures of high-level human experiences such as the mystical-type/peak experience will enhance our ability to understand their psychology and underlying neural substrates. As touched on in the introduction, psychopharmacology is increasingly acknowledging the importance of “context” and particularly “environment” as a factor mediating the effects of both intrinsic neurobiological features (e.g., genotypes) and exogenous pharmacological inputs—such as drugs (Alexander et al., 1981; Caspi et al., 2010). For example, a recent popular model of the action of SSRIs incorporates “environment” and cognitive (re)appraisal (Harmer et al., 2017) as key determinants of therapeutic efficacy (see also Branchi, 2011; Belsky, 2016). Like SSRIs, classic psychedelic drugs also work on the serotonin system; however, unlike the SSRIs, they are direct agonists at the 5-HT2A receptor (Nichols, 2016). There is compelling evidence that the 5-HT2A receptor is psychedelics' key site of action (Nichols, 2016). Intriguingly, recent work has found that the phenotypic expression of 5-HT2AR genotypes is significantly dependent on the influence of “environment” (Jokela et al., 2007). These findings may imply that enhanced sensitivity to context is an important function of 5-HT2A receptor signaling (Carhart-Harris and Nutt, 2017).

Ascending from the pharmacological to the whole-brain systems level, increased cortical entropy has been found to be a reliable feature of the psychedelic state (Carhart-Harris et al., 2014), to relate to high-level subjective experiences such as “ego-dissolution” (Nour et al., 2016; Atasoy et al., 2017; Schartner et al., 2017) that are relevant to the mystical-type experience, and to be predictive of longer-term trait changes—such as increased “openness” (Lebedev et al., 2016). Recent work suggests that increased brain entropy under psychedelics is consistent with the brain being more closely tuned to “criticality” (Atasoy et al., 2017). Criticality refers to systems that reside in a functional “sweet spot”, critically poised between order and disorder—in which they can effectively retain information (by being sufficiently ordered) while being appropriately adaptive and sensitive to change (by being sufficiently disordered). Intriguingly, one of the signatures of a critical system is a sensitivity to perturbation (Bak, 1996). It follows that enhanced sensitivity to perturbation in a psychedelically-induced “entropic” and “critical” brain may account for the special sensitivity to “environment” that is characteristic of the psychedelic state (Hartogsohn, 2016; Carhart-Harris et al., in press).

Understanding the neurobiological mechanisms of OBN, mystical-type or peak experiences (Vollenweider, 2001) should enable us to better comprehend, define and study them. This is important, not least because they are proving to be important determinants of treatment success in psychedelic therapy (Richards et al., 1977; Bogenschutz et al., 2015; Griffiths et al., 2016; Johnson et al., 2016; Ross et al., 2016). Crucially, better understanding the biological basis of mystical-type/peak experiences and their longer-term impact on the mind and brain should help to demystify them, facilitating an easier conversation about them with mainstream psychology. Researchers in the mainstream have as much a responsibility as those in “the periphery” to facilitate this. Denying the relevance of these phenomena is as damaging to scientific progress as denying their physical basis. The prize for successfully integrating mystical-type experience into mainstream science may be their potential to have a substantial positive impact on medicine, education and society—which ironically, may, at least in part, explain why their integration into western society has proved so difficult to achieve (Stevens, 1987).

To summarize, the occurrence of high OBN (sharing features with mystical-type experience) and low DED (relating to anxiety and impaired cognition) under psilocybin predicted positive clinical outcomes in a trial of psilocybin for TRD. This relationship exhibited a degree of specificity, in that psilocybin-induced OBN was significantly more predictive of reduced depressive symptoms than the drug's more generic visual and auditory perceptual effects. Future work, with a larger sample size, is required to more comprehensively and systematically measure the influence of different potential predictive factors on the quality of acute psychedelic experiences (Gasser et al., 2014; Belser et al., 2017; Watts et al., 2017) and subsequent long-term outcomes (Carhart-Harris et al., in press). As psychedelic therapy gains influence and credibility (Carhart-Harris and Goodwin, 2017), it seems vital that appropriate consideration is paid to the importance of promoting a certain kind of experience, as the quality of that experience may be the critical determinant of therapeutic success.

LR analyzed the data and wrote the paper; DN sanctioned the research and approved an earlier draft of the manuscript; RC-H designed and conducted the research, and wrote the paper.