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 trait32,69,70.

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 rate73,74, 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 studies46,76,77, 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 experiences53,60, 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 subjects42,80. 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 self8,82. 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-being83,84,85, and act through meaning-making mechanisms86,87. 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 patients4,26.

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 markers31,90. 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