Characterization and prediction of acute and sustained response to psychedelic psilocybin in a mindfulness group retreat

A burgeoning interest in the phenomenology and neurobiology of psychedelic drugs has grown in recent years, motivated by rising evidence of their therapeutic potential for some psychiatric disorders^1,2. For example, psilocybin reduced symptoms of therapy-resistant depression³ and depression and anxiety in terminal cancer patients⁴ after administration of just one or two doses. Psilocybin and other classic psychedelics are partial serotonin-2A-receptor agonists⁵ that may produce transient, profound changes in self-consciousness, experienced as a dissolution of the ordinary sense of self and a breakdown of the perceived boundaries between the self and the world⁶. Empirical research has repeatedly reported that, in a supportive setting at medium-to-high doses (20–30 mg PO), psilocybin can trigger alterations of self-consciousness in association with feelings of bliss, unity, and insightfulness^7–10. Such experiences have been referred to as at least partially overlapping occurrences of self/ego dissolution^11,12, self-loss¹³, states of selflessness^14–16, mystical-type experiences^17,18, or non-dual awareness¹⁹. Although the experiential quality of psilocybin-induced alterations resemble the states of self-transcendence reported by various traditions of Eastern descent^20,21 and can occasionally occur during deep meditative practices^22,23, there are no experimental data that support this assumption.

The intensity and form of psychedelic experience, indexed as mystical-type experience or self-dissolution effect, seem to mediate beneficial therapeutic outcomes^24–26. Similarly, many meditation practices aim to reduce self-referential processing^27,28 and achieve a temporary dissolution of self-boundaries¹⁵, which may lead to an enduring reduction of self-focus or ego-centricity^14,29,30. Notably, meditation was found to alleviate symptoms of depression, anxiety, and stress and to promote lasting benevolent emotions and prosocial behavior³⁰ in clinical and non-clinical populations^31–33. Despite similarities between meditation- and psychedelic-induced temporary alterations in the sense of self, neither the phenomenological similarities and differences of such multifaceted experiences nor the impact of additional putative modulatory factors have yet been systematically investigated in a prospective study. The phenomenological differences between meditation- and psychedelic-induced self-dissolution may result in different long-term changes in psychosocial functions.

Many traditional meditative practices, and in particular mindfulness-based meditation such as Vipassana, Zen, and their secular forms³⁴, aim at maintaining attention on the present moment with a non-judgmental, accepting stance toward the enfolding experiences^15,35,36. This involves directing of attention, body awareness, and emotion regulation strategies to achieve an increased cognitive and emotional flexibility^35–37 This, in turn, is thought to reduce self-centered psychological functioning^15,30, which may culminate in states of selflessness^15,38. Meditation experiences arise along a spectrum of meditation depth³⁹ and are shaped by other factors, such as previous meditation experience, dispositional mindfulness, openness, and absorption^40,41. However, profound states of selflessness during meditation occur rarely and mostly in long-term meditators²². In contrast, psilocybin can induce a state of self-dissolution at a relatively high rate (up to 60%), particularly at higher doses^42,43, and along a perception-hallucination continuum with increasing emotional arousal.

Although the content and intensity of psychedelic experiences depend most critically on dosage⁴⁴, the same dose can induce a pleasurable state of self-dissolution or, under certain circumstances, a more distressing response associated with thought disturbances, fear of losing control, anxiety, or panic⁴⁵. The reactions to psychedelics and their subsequent interpretations are commonly shaped by the “set” (i.e., the subject’s expectation, personality traits, and current mood state) and “setting” (i.e., the physical and social environment in which the drug is taken)^46–49. Considering the role of set and setting in study designs resulted in more positive subjective effects and fewer dysphoric reactions^9,50 than in earlier experimental work that ignored these issues^51,52. Thus, a better understanding of non-pharmacological variables for the outcome of the psychedelic experience seems crucial, in consideration of their suggested therapeutic potential.

Taken together, both meditation and psilocybin can promote a spectrum of altered states of consciousness that are modulated by additional dispositional (trait) and state factors. In this prospective, matched-group study, we quantified the effects of meditation alone and meditation combined with psilocybin in expert meditators participating in a well-structured 5-day mindfulness-based meditation retreat. First, we explored whether state mindfulness and meditation depth increased across the retreat and whether psilocybin modulated these outcomes, in addition to direct pre-post trait-like mindfulness. Second, we compared the spectrum and extent of alterations of consciousness, indexed by the Altered States of Consciousness Rating Scale (5D-ASC), and mystical-type of experience, indexed by the Mysticism Scale (M-scale). Furthermore, we conducted a multiple regression analysis to explore whether a number of trait and state factors contributed to inter-individual differences in self-dissolution as measured by the 5D-ASC and M-Scale instruments. Specifically, we hypothesized that particular state and trait variables would influence self-dissolution, i.e., openness, extraversion, neuroticism^53,54, absorption^41,44, optimism about life⁵³, pre-experience with altered states⁵³, mood and emotion regulation strategies^36,44,53, trait and state mindfulness, and meditation depth the day before drug intake⁴¹. Additionally, we explored the possibility that the high cognitive and emotion regulation capacity of meditation experts^36,55–58 would buffer possible distressing aspects of psychedelic experiences, such as negative emotions, anxiety, disorientation, and fear of loss of control and self-identity (colloquially known as a “bad trip”)⁵⁹, which can arise with high doses of psilocybin. Because both the extent of psilocybin-induced alterations of self-consciousness, as indexed by mystical-type experience^4,26, and longer mindfulness-based meditation periods lead to persisting positive outcomes in healthy subjects^31,60 and patient populations^4,26,31,61, we explored whether the intensity of different sub-dimensions of the mystical-type experience predicted persisting changes in behavior and attitudes at a 4-month follow-up. We hypothesized that the combination of psilocybin and mindfulness meditation training would lead to larger changes than meditation alone.

In the present study, we investigated the synergistic effects of psilocybin and mindfulness as well as related state and trait predictors in experienced meditators during a 5-day group retreat. Given the importance of set and setting in shaping reactions to psychedelics, we hypothesized that mindfulness training may deepen psychedelic-induced experiences. We also investigated the possibility that it may buffer the emotional overload and anxiety that can arise with self-dissolution effects⁶⁷. We showed that state mindfulness and meditation depth gradually increased over the course of the retreat and that meditation depth was acutely increased by psilocybin administration (Fig. 1). These findings demonstrate that during acute drug effects, experienced meditators were able to remain engaged in their usual meditation practice and that psilocybin has the capacity to deepen meditative states. Interestingly, dispositional mindfulness measured 1 day after the completion of the retreat was higher among participants who had received psilocybin than among those who had received placebo (Fig. 2). This finding aligns well with the observed increase in mindfulness capacity 24 hours after administration of the psychedelic N,N-dimethyltryptamine to healthy volunteers in the form ayahuasca⁶⁸. Thus, the current findings corroborate the view that psychedelics may enhance mindfulness capacity⁶⁸ and that dispositional mindfulness may change over time with practice, suggesting putative neuroplasticity-related modulations of this trait^32,69,70.

The combination of psilocybin and meditation produced much stronger alterations of consciousness and a profound positively experienced self-dissolution (OB score) compared with meditation alone, and virtually without loss of cognitive control and anxiety (AED score), despite the relatively high dose of psilocybin that was used. However, the self-dissolution was accompanied by marked vivid imagery, ranging from elementary to complex scenery hallucinations (VR score). A comparison of the 5D-ASC results in the psilocybin group with those obtained in healthy, non-meditating participants who had conducted a simple neuropsychological task under the same psilocybin dose⁴⁴ revealed that meditation plus psilocybin resulted in substantially higher scores on the spiritual experience (66% vs. 22%), blissful state (86% vs. 48%), and feeling of unity (70% vs. 40%) subscales and lower scores on the AED and VIR scales than psilocybin alone, whereas the auditory and visual alterations did not differ⁴⁴ (SI Fig. 1). These findings support our view that mindfulness-related trait and state capabilities may foster and positively shape the experiential quality of self-dissolution and buffer psilocybin-induced anxiety and vigilance deficits. Interestingly, a 1–2 month preparatory training in meditation and spiritual practice bolstered the positive effects on self-dissolution in healthy individuals, as tested with similar doses of psilocybin⁷¹.

Three participants in the placebo group met the a priori criteria for a strong mystical-type experience (Fig. 5B). Exploration of M-scale subscales indicated that the mystical-type experience reported by these placebo participants was very similar to that reported by the psilocybin participants. These findings provide the first experimental evidence and corroborate the view⁷² that meditation and psilocybin can occasion phenomenologically overlapping mystical-type experiences. However, there are also some notable differences between meditation- and psilocybin-induced alterations of consciousness. Whereas the mystical-type experiences in the placebo group arose virtually without anxiety, cognitive impairments, audiovisual synesthesia, or vigilance reduction, and with relative few elementary imageries, in the psilocybin group they were associated with vivid visual alterations, pronounced audiovisual synesthesia, moderate cognitive impairments, and vigilance reduction (Fig. 6A,B). Consistent with previous work, such experiences occur in deep meditation unpredictably and at a very low rate^73,74, whereas psilocybin can occasion such positive mystical-type experiences in a supportive clinical setting at relatively high rates (≈60%)^10,42,44,75. Psilocybin also produced more intense mystical-type experiences than placebo in the seminal “Good Friday Experiment”, where participants attended a Christian service in a group setting at Harvard University’s Marsh Chapel¹⁰. In light of these observations, we suggest that the retreat setting in the present study reassured, through the presence of others and social bonding, a safe and supportive environment that may have contributed to the positive outcomes of psilocybin-induced self-dissolution.

Our analysis of putative predictors of the acute psychedelic experience highlights that psilocybin was the most important determinant. This is consistent with a previous pooled analysis of psilocybin experiments⁴⁴. In accordance with earlier studies^46,76,77, we also found that the personality trait “openness” (expressing the level of permeability to novel experience) and optimism toward life contributed to the experience of OB, as well as the three core dimensions of mysticism. The significant correlation between OB and these three dimensions further supports this finding. Openness is composed of active imagination, attentiveness to inner feelings, intellectual curiosity, preference for variety, adventurousness, and aesthetic sensitivity, clustering together in one dimension⁷⁸. This personality disposition not only predicted the positive outcome of psychedelic experiences^53,60, but also correlated with the prevalence of spontaneously occurring mystical-type experiences⁷⁹, and was associated with the meditation depth⁴¹. Consistent with previous work⁵³, visionary experience was associated with the personality trait extroversion, but unlike earlier reports it was not correlated with the participant’s absorption capacity⁴⁴. In regard to the core components of mindfulness meditation practice, we found that reappraisal of emotions was negatively related to the AED dimension of altered states of consciousness and introvertive mysticism, which also refers to loss of ego functioning, whereas the mindfulness trait acceptance of thoughts and emotions correlated positively with introvertive mysticism and the interpretation of mystical experience. Furthermore, meditation depth assessed the day before drug administration substantially contributed to the OB dimension of altered states of consciousness and interpretation of mystical experience, both of which depict positive emotions associated with self-dissolution. Relaxation the day before drug administration and age were predictors of positive self-dissolution in a previous study⁵³. In light of these observations, it is conceivable that mindfulness training may help to buffer the emotional distress and anxiety that may arise with the ego dissolution state. This may happen by promoting reappraisals, more flexible selection of interpretation of the experience, and redirection of emotional load. A better understanding of non-pharmacological variables could help stratify individuals and better predict specific responses to classical psychedelics.

The follow-up results highlight that changes in behaviors were significantly higher in the psilocybin group than in the placebo group for appreciation of life, self-acceptance, quest for meaning and sense of purpose, and appreciation of death (Fig. 7). The pattern of changes was similar although less pronounced than that obtained from an external observer (SI Fig. 3). This adds to the literature reporting transformational processes following psychedelic experiences. Comparable enduring positive changes in attitude and behavior after one or two doses of psilocybin have been reported to persist at least 14 months⁸⁰ or more⁸¹. Interestingly, although our participants were well-functioning individuals who scored high in life satisfaction at baseline, it appears that they could still greatly benefit from the psilocybin-facilitated experience.

Remarkably, despite the long engagement of our study participants in contemplative practices, the psilocybin experience was valued equivalent to their strongest lifetime mystical-type experience (Fig. 5A). Moreover, most participants in the psilocybin group attributed a high personal meaning to the psilocybin experience: 37% considered it one of the five, and 47% one of the ten most meaningful life experiences. However, this finding is somewhat less pronounced than that of a recent study in non-meditating psilocybin subjects^42,80. A possible explanation for this difference is that we administered a lower dose of psilocybin and the long-term meditation practice may support the cultivation of enduring happiness and well-being. Additionally, being open to moment-to-moment experiences, without the aim to judge them and create any attachments, may have contributed to these comparably less pronounced effects on personal meaning.

Our regression analysis of predictors of the long-term behavioral changes showed that the extent of self-dissolution and the drug administration substantially contributed to the global change in attitude and behavior. Moreover, the experience of unity as an index of reduced self-other boundaries and oneness with the surrounding predicted self-acceptance. This temporary loss of the ordinary ego/self and self-boundaries appears to diminish self-referential processing or ego-centricity and thus to foster an altered perspective toward oneself, others, and the environment. This interpretation is supported by recent findings demonstrating that psilocybin modulates neuronal activity in brain networks that mediate a sense of self^8,82. Furthermore, the sense of sacredness contributed to the change in appreciation of life, and sacredness and ineffability contributed to the change in quest for meaning/sense of purpose, across both groups independent of drug condition. These findings support the view that spiritual experiences, including sense of sacredness and ineffability, contribute to psychological well-being^83–85, and act through meaning-making mechanisms^86,87. In line with a recent large survey reporting that peak psychedelic experiences were linked to reduced fear of death⁷², we found that psilocybin alone predicted the change in appreciation of death. This is also consistent with recent studies demonstrating that the extent of psilocybin-occasioned mystical-type experience mediated the reduction of existential anxiety and depression in terminal cancer patients^4,26.

The perceptible effects of psychoactive drugs pose a methodological challenge in maintaining the integrity of blinding procedures. Therefore, a major limitation of this study was the use of an inert placebo and the possible recognition of the active and non-active conditions by participants. However, this choice was motivated by the objective to quantify the meditation-specific parameters without additional confounding factors, i.e., with respect to the inactive placebo. Nevertheless, we reduced the element of expectancy by including solely psychedelic-naïve volunteers (≈2/3 of the sample) and those with limited previous exposure to consciousness-altering drugs (≈1/3 of the sample). Furthermore, we obscured the experimental conditions (i.e., placebo versus psilocybin) through a highly structured silent retreat that limited interpersonal exchange within the group setting, with instructions emphasizing individual practice. Even though it remains possible that the observed effects reflect some expectancy, we argue based on previous results from our group and other researchers that they are likely attributable to the unique psychoactive profile of psilocybin.

In addition to the overall positive outcome of psilocybin administration found in this study, a few results compel further discussion. At the dose tested, psilocybin produced no adverse events (including physical discomfort, disorientation, severe anxiety, panic, or psychotic-like reactions) neither acutely during the trial session nor post-acutely during the retreat. Two participants reported in the postacute psychiatric investigation that they felt transiently emotionally overwhelmed during the peak effect of the drug, but did not value this as negative. No adverse events or persistent negative effects were reported at the 4-month follow-up. The low ratings on the 5D-ASC scale for “anxiety” (mean score, 3%; min–max range, 0–10%) are in accordance with and even smaller than those reported by previous studies, suggesting that even during peak effects psilocybin is well tolerated and rarely produces profound or psychotic anxiety in a controlled clinical setting in healthy human subjects⁶. However, it should be said that challenging psychological experiences may still occur as acute and durable effects of both meditation practice and psychedelic ingestion, including psychological distress or disorientation⁸⁸, psychotic episodes, panic attacks, depersonalization, or asociality⁸⁹. The incidence of adverse effects can be reduced by proper medical and psychological screening, a reassuring setting, and supervision.

The present study demonstrated that the combination of psilocybin and mindfulness training increased the incidence and intensity of alterations of consciousness characterized by profound states of self-dissolution and virtually no anxiety. Personality traits and core components of mindfulness-based meditation shaped the different facets of selflessness. The psilocybin-induced dissolution of self, either due to a perception of unity of all things and/or ego loss, mediated beneficial enduring changes in psychosocial functioning. The effect of psilocybin on meditation depth and trait mindfulness may increase the effective positive impact of meditation retreats on psychological outcome. Both meditation depth and higher levels of mindfulness have been linked to a wide range of well-being and mental health markers^31,90. The present results also suggest that the combination of mindfulness training and psychedelic-assisted intervention may offer potential for the further development of psychedelic-assisted applications to improve well-being and health in both therapeutic and non-therapeutic settings

The authors thank Vanja Palmers, Zen teacher, for guiding the retreat, Peter Gasser, Anke Röskamp, Juraj and Sonja Styk, Karim Tissira, and David Andel for psychological and medical supervision of the retreat, and Sara Romer, Anja Seidl, Brigitte Wicki, Niklas Bürgi, and Rahel Nicolet for organizational support and assistance with data collection. This study was supported by the Swiss Neuromatrix Foundation (2014-0101).

L.S. and M.K. designed the experiments. L.S., M.K., M.S., R.K., and T.H. performed the experiment. L.S. and F.X.V. analyzed the data and wrote the manuscript. All authors further edited the paper and approved the final version of this manuscript.

Data is available upon personal request.

The authors declare no competing interests.

Supplementary information accompanies this paper at 10.1038/s41598-019-50612-3.