GoKawiilEthics and clinical trial registration
The study protocol was approved by the Monash University Human Research Ethics Committee. The trial was registered with the Australian New Zealand Clinical Trials Registry under the registration number ACTRN12621001375842. The research was performed in accordance with all relevant guidelines and regulations, and written informed consent was obtained from all participants.
Study design
The PsiConnect study was open-label and included two imaging sessions: a baseline (no psilocybin) session and a session following the administration of a 19 mg dose of psilocybin. Both sessions involved MRI and EEG scans, with four conditions repeated in each: resting state, guided meditation, music listening and movie watching. In fMRI, conditions began approximately 80 min post-dose and followed a fixed order (rest → meditation → music → movie). The sequence progressed from low-stimulus to high-stimulus contexts to prioritize safety and experiential coherence for psychedelic-naive participants. The EEG session started after a room transfer and 20–40 min of setup (cap placement and impedance checks), with the movie presented first, followed by the three eyes-closed conditions (movie → rest → meditation → music). Discussion addressing expectancy, condition order and EEG timing is detailed in Supplementary Information.
In the resting-state condition (8 min MRI, 5 min EEG), participants were instructed to relax and keep their eyes closed while remaining still. During the guided meditation (6 min 30 s MRI, 5 min EEG), participants received meditation guidance via MRI-safe audio, with guiding prompts interspersed between silent periods of practice. For the music listening condition (11 min 24 s MRI, 7 min EEG), a curated playlist was designed to evoke emotional depth and resonance. In the naturalistic movie condition (6 min MRI, 5 min EEG), participants watched a video of moving clouds without audio. EEG blocks were intentionally shorter (total ≈ 22 min) to acquire all four contexts within the acute effects window and to minimize fatigue, motion and impedance drift; see the accompanying PsiConnect data descriptor89. These conditions were studied in both the baseline (no psilocybin) and psilocybin sessions and were repeated in both fMRI and EEG, allowing for comprehensive cross-modal and longitudinal analyses of brain activity and connectivity.
The eligible participants were stratified based on age and self-reported gender before allocation to the mindfulness meditation and control groups using a non-randomized, balanced procedure. No blinding was performed at any stage, including data analysis. Half of the participants were assigned to an 8-week mindfulness-based cognitive therapy programme, ‘Finding Peace in a Frantic World’, run by a trained and registered instructor, which involved weekly group meetings and daily independent practice; the other half were assigned to a control group with no intervention. Each participant was scanned at both baseline (no psilocybin) and under psilocybin. Engagement was consistent across the mindfulness-based cognitive therapy group: participants attended at least six of eight sessions and averaged 85 min of independent practice per week. Because no statistically significant differences were observed between meditators and non-meditators in connectivity or subjective effect measures under psilocybin, the two groups were pooled for all analyses reported here. Sample size was constrained by recruitment capacity and available imaging resources. No statistical methods were used to predetermine sample size.
Our decision to administer a standardized dose of 19 mg psilocybin rather than a body weight-adjusted dose was based on previous research showing no clear advantage of weight-adjusted dosing in terms of subjective effect intensity or predictable differences in response across individuals of varying body weight90. The dosage was administered as one oral capsule and selected in consultation with multiple collaborators who had previous psychedelic imaging experience. This dose was determined to be tolerable for the majority of healthy adults undergoing imaging procedures, while also sufficient to produce substantial subjective effects.
Several behavioural measures were collected before and during the baseline (no psilocybin) and psilocybin scans (see the section ‘Reported behavioural measures’). The follow-up conducted the day after psilocybin administration included semi-structured, open-ended questions and experience ratings. Further follow-up measures were administered 1 week and 1, 3, 6 and 12 months after psilocybin administration.
Participants
Sixty-five healthy adults 18–55 years of age (37.7 ± 10.7; 30 female and 35 male) with no psychedelic experience were recruited. Sex was recorded at imaging intake and is reported here; self-reported gender, which was used for stratification between meditators and non-meditators and is concordant with sex for all but one participant, is detailed in the Reporting Summary. Participants were required to have no formal meditation practice and limited previous exposure to meditation. They were first screened via short online survey and then detailed screening was performed by a suitably trained staff member for excluding any psychopathology using the long-form SCID-5 (ref. 91). Exclusion criteria included a history of psychiatric disorders or suicidality; a 5-year history of substance and/or alcohol use disorder; first-degree relatives with a diagnosed psychotic disorder; a history of major neurological disorders including stroke or epilepsy; formal meditation practice within the past 6 months or extensive previous exposure to mindfulness meditation; use of contraindicated medications; and any serotonergic psychedelic use within the past 6 months. Participants were also screened for magnetic resonance contraindications and provided informed consent. Although hallucinogen use was assessed via the SCID-5, exclusion was applied to serotonergic psychedelic use specifically. We operationally defined ‘no psychedelic experience’ as no previous serotonergic psychedelic use with subjective effects. During structured screening, three participants disclosed nominal or remote lifetime exposures without subjective effects: two reported ineffective microdoses, and one reported remote exposure over 20 years previously with minimal or no recall. These cases are detailed in Supplementary Table 6. The remaining 62 participants reported no lifetime serotonergic psychedelic use across online, phone and SCID checks. On the day of psilocybin administration, they were assisted by a study doctor, researchers, laboratory staff with relevant training, and volunteers from the community drug harm reduction support organization ‘DanceWize’. Psilocybin was generally well tolerated, although some adverse effects were reported, including reports of transient headaches during the night (n = 3). Three participants received follow-up support from a clinical psychologist familiar with psychedelic integration. These follow-up calls were conducted over the phone, and no further support was required. On no occasion was it deemed necessary by the study doctor to administer an anxiolytic.
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