Psychedelic replications in virtual reality and... — Research Summary & Context

Psychedelic replications in virtual reality and... — Research Summary & Context | Blossom

Abstract

Background

Recent research has shown promising results for the therapeutic benefits of psychedelics. One popular view claims that these benefits are mediated by the subjective experiences induced by these substances. Based on this, we designed a virtual reality experience, Psyrreal, that mimics the phenomenological components of psychedelic experiences.

Aims

We aimed to investigate the therapeutic efficacy of Psyrreal and psychedelic VR experiences in treating depressive symptoms as well as explore the effect of Psyrreal on subjective factors which have been suggested to mediate the therapeutic benefits of psychedelics.

Methods

In this open-label feasibility study, thirteen participants with mild-to-moderate depression underwent a 2-day therapeutic intervention implementing Psyrreal. Depressive symptoms were evaluated by the Emotional State Questionnaire (EST-Q2) at the start of the intervention and 2 weeks after. A thematic analysis of semi-structured interviews after Psyrreal was also conducted as an additional assessment of the method.

Results

A 2-day intervention implementing Psyrreal led to significant decreases in depressive symptoms at the 2-week follow-up (n = 10, p = 0.007, Hedges’ g = 1.046) measured by the Emotional State Questionnaire (EST-Q2). The analysis of semi-structured interviews suggests that Psyrreal could lead to insight and alterations in the sense of self in some people.

Conclusion

This work proposes a novel method using virtual reality to augment the treatment of psychological disorders as well as to precisely investigate the mediating subjective factors of the therapeutic effects of psychedelic substances. Our preliminary results suggest that VR experiences combined with psychological support show potential in treating depressive symptoms and further research into similar methods is warranted

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Research Summary of 'Psychedelic replications in virtual reality and their potential as a therapeutic instrument: an open-label feasibility study'

Introduction

Psychedelic-assisted therapies have seen a strong resurgence because of promising results across conditions such as depression, addiction and end-of-life distress. A central unresolved question in this literature is whether therapeutic benefit arises primarily from neurochemical action or from the subjective experiences psychedelics produce — for example mystical-type states, ego-dissolution and insight. If subjective phenomenology is a key mediator, then replicating those phenomenological elements without drugs might produce at least some therapeutic effects and offer a more accessible alternative for people who cannot, or prefer not to, take psychedelic compounds. Aday and colleagues designed a virtual reality (VR) experience called Psyrreal intended to mimic a broad set of audiovisual and narrative features of psychedelic, mystical and meditative states. This open-label feasibility study tested Psyrreal in a 2-day augmented therapeutic protocol for adults with mild-to-moderate depressive symptoms, with the main aim of assessing whether the intervention reduced depressive symptoms and whether psychedelic-like subjective factors (mystical experiences, ego-dissolution, insight) were elicited and measurable.

Methods

Study design and participants: The investigators conducted an open-label, one-group uncontrolled longitudinal feasibility study. Recruitment occurred via a public Estonian mental-health website between October and December 2021. Thirteen adults (8 women, 5 men), aged 20–58 (mean 33.8, SD 10.6), enrolled; exclusions included current depression therapy or medication, psychotic disorders, epilepsy, family history of schizophrenia, and hypersensitivity to motion sickness. After screening and re-evaluation on day 1, two participants were excluded (one on antidepressants, one whose depressive score fell below the inclusion cut-off), leaving a final analysed sample of 11; n = 10 for the primary depression follow-up measure because one participant missed the 2-week EST-Q2 questionnaire. Most participants (9/13) reported a prior diagnosis of depression. Intervention and hardware/software: Psyrreal is a purpose-built, somato-audiovisual VR application developed in Unreal Engine 4.27 and run on an HTC Vive Pro Eye headset. The experience comprises 19 distinct visual "levels" combining open-eye effects, closed-eye visuals (CEVs), large-scale vistas, and narrative elements, supported by a composed soundtrack designed to manipulate tempo and perceived time. The software is distributed on request under a Creative Commons Attribution-Non-Commercial licence. A small validation study with experienced psychedelic users (reportedly seven participants) rated similarity of some scenes and physical sensations to drug states. Procedure and psychological support: The protocol spanned two consecutive days. Day 1 comprised a 30–45 minute preparatory session with a clinical psychologist, a 15-minute demonstrative VR control (10 minutes guided meditation with eyes closed, then 5 minutes in a non-interactive living-room VR environment) and short discussion; questionnaires (EDI, PIQ, MEQ30) were administered referencing the 5-minute demo VR for baseline comparison. Day 2 began with a brief pre-session discussion, the same guided meditation, then a 45-minute Psyrreal session while the participant was seated; a psychologist was available nearby and a technician monitored equipment. After an integrative 20–30 minute session with the psychologist, EDI, PIQ and MEQ30 were re-administered. A follow-up EST-Q2 questionnaire was sent 2 weeks post-intervention. Participants were asked to abstain from alcohol/substances prior to sessions; informed consent and ethics approval (University of Tartu) were obtained. Measures and analysis: The primary symptom measure was the Emotional State Questionnaire (EST-Q2), with a depression subscale cut-off of ≥12 for inclusion. Secondary self-report measures included the Psychological Insight Questionnaire (PIQ), the Ego-Dissolution Inventory (EDI), and the Revised Mystical Experience Questionnaire (MEQ30). The Montgomery–Åsberg Depression Rating Scale (MADRS) was administered by the psychologist at baseline to validate depressive severity. Semi-structured integrative interviews were audio-recorded and thematically analysed. Quantitative before–after comparisons used paired-sample t-tests (two-tailed, α = 0.05); normality of difference scores was checked with Shapiro–Wilk. Analyses were performed in JASP. The authors also performed sensitivity analyses excluding two participants who reported seeking psychological counselling after the intervention, with results reported as similar in supplementary materials.

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INTRODUCTION

"I had profound and visionary encounters with nature, and this was long before I conducted my initial experiments with LSD [lysergic acid diethylamide]. Indeed, my first experiences with LSD were very reminiscent of these early mystical encounters I had had as a child in nature. So, you see that it is even possible to have these experiences without drugs." Albert Hoffman, cited in Grob. The last two decades have seen a massive resurgence of research into psychedelics largely due to their wide range of therapeutic benefits [e.g., addiction, depression, endof-life distress, suicidality, obsessive-compulsive disorder, migraine, phantom-limb pain, for reviews see]. This has elevated interest in substanceassisted therapies, where psychedelic sessions are included as a part of the therapeutic process. Preliminary results regarding the efficacy of such methods have been promisingand have even shown strong effects in patients whose ailment has not responded to conventional methods[see also]. However, it is currently unclear how psychedelic substances confer these benefits. One possibility is that the underlying mechanisms are strictly neurochemical. The alternative proposal is that subjective experiences hold the key to the success of psychedelic interventions. According to the latter view, therapeutic success is caused by the subjective experiences elicited by these substances, such as mystical, ego-dissolutionor insight experiences. If psychedelicinduced subjective experiences underlie their therapeutic effects, then it should be possible to achieve at least some of the benefits of psychedelic therapy without the substances themselvessimply by emulating specific aspects of psychedelic experiences. Furthermore, despite the many benefits of psychedelic therapy, there can also be some disadvantages to administering psychedelic substances (e.g., cost, legality, and contraindication) in certain population groupswhich highlights a necessity for finding more accessible alternatives. We propose a way to study this question by mimicking many of the wildly different subjective psychedelic experiences in virtual reality (VR), replicating the audiovisual phenomena reported during psychedelic, mystical and deep meditative experiences. The potential of virtual reality as a therapeutic device has become an increasingly researched topic. Different VR interventions have been used in the treatment of anxiety with promising results, while depression has only been investigated in a couple of studies. Recent developments in VR technology suggest that it could be possible to induce mystical experiencesand imitate parts of the phenomenology of the psychedelic state. Also, some recent studies have suggested that using psychedelic phenomenology in VR can lead to similar cognitiveand neuraleffects as seen under psychedelic substances. Thus, these recent works raise the intriguing possibility that perhaps the implementation of such phenomenology in VR could be used to confer similar therapeutic benefits to psychedelicaugmented therapy. In this work, we have created Psyrreal, a psychedelic-inspired virtual reality experience. While previous studiesimplementing psychedelic phenomenology in VR used visually relatively simple and unvarying environments, here we have incorporated a much larger set of visual effects and different environments as psychedelic experiences have massive inter-, and intraindividual variance. The participant is taken on an immersive journey through many surreal and vastly different virtual environments which aim to convey certain concepts and narratives often reported during psychedelic experiences [e.g., connectednessor ego-dissolution]. Following the example of Carhart-Harris et al., we conducted an open label feasibility study on healthy adults with mild to moderate depressive symptoms to guide further research into similar methods, and investigate the potential therapeutic effects of Psyrreal as well as the specific mechanisms of VR and psychedelic experiences that may confer these benefits. The primary expected outcome of the study was that a VR experience that simulates psychedelic phenomenology could, in

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Study Details

Study Type
individual
Population
humans
Characteristics
open labelfollow up
Journal
Frontiers in Psychiatry
Topics
Anxiety Disorders Depressive Disorders Substance Use Disorders (SUD)Palliative & End-of-Life Distress
APA Citation

Results

Sample and safety: All 13 registered participants completed the study procedures, but two were excluded from analyses as described above; the final analysed sample was 11 for most measures and 10 for the EST-Q2 follow-up. No serious adverse events were reported. Four participants (of the original 13) mentioned transient nausea during the VR session; otherwise participants were encouraged to report discomfort and none was recorded as a formal adverse event. Primary outcome — depressive symptoms: Baseline EST-Q2 depression subscale mean was 15.20 (SD = 2.66). At the 2-week follow-up (n = 10), EST-Q2 mean decreased to 11.00 (SD = 3.74). Paired-samples t-test indicated a statistically significant reduction: t(9) = 3.50, p = 0.007, Hedges' g = 1.046 (large effect). The response rate (≥50% reduction from baseline) was 18% and the remission rate (score below 12) was 60%. Baseline EST-Q2 scores correlated with clinician MADRS ratings (r = 0.66, p = 0.010). The authors note that the modest response but higher remission is partly explained by the mild-to-moderate baseline symptom levels. Secondary and subjective measures: Anxiety subscale scores of the EST-Q2 also decreased at follow-up, although baseline anxiety scores were generally low and only four participants had scores indicative of anxiety disorder (≥12). MEQ30 mean increased from 39.58 (SD = 19.57) after the demo VR to 42.73 (SD = 18.43) after Psyrreal; this change was not statistically significant, t(10) = 0.673, p = 0.520, g = 0.137. Changes in PIQ (insight) and EDI (ego-dissolution) likewise did not reach statistical significance. The authors emphasise high interindividual variability on these subjective questionnaires; one participant reported a complete mystical experience on day two, and another on day one only. Qualitative findings: Thematic analysis of integrative interviews identified several recurring themes. All participants reported some positive emotions during the experience: 55% reported calmness/peace and 55% reported joy/pleasure. Seven participants reported negative emotions (e.g., sadness, fear, anxiety), with four mentioning sadness. Forty-five per cent reported personally relevant thoughts during the session; examples included descriptions of engaging with previously inaccessible sadness and arriving at new understandings. Three participants described gaining new beneficial insights, and five reported perspective shifts. Alterations in sense of self were reported by six participants (three noting narrative self changes, four noting embodied self changes). Somatic effects during high-motion scenes were reported by 36% and described as impactful. Selected brief participant remarks illustrate these themes, e.g. participant P12: "From this place where I got in touch with this emotion [sadness] these other questions also started to unravel...".

Discussion

Aday and colleagues interpret these preliminary findings as indicating that a psychedelic-inspired VR experience, delivered within a brief augmented therapeutic setting, may alleviate mild-to-moderate depressive symptoms in some people. The significant decrease in EST-Q2 scores at 2 weeks, together with a 60% remission rate, led the authors to suggest potential therapeutic utility for VR experiences tailored to mimic psychedelic phenomenology, while emphasising that causal inferences cannot be drawn from this uncontrolled feasibility design. The authors situate their results relative to prior work: effects were similar, though weaker, than those reported in psychedelic-assisted therapy and comparable to at least one earlier VR-based depression study. They highlight that measures of mystical experience, insight and ego-dissolution (MEQ30, PIQ, EDI) did not show statistically reliable group-level increases, but that qualitative interviews revealed instances of insight and self-alteration for some participants. From this pattern the investigators present tentative support for the hypothesis that subjective experience may mediate therapeutic effects, while acknowledging large interindividual variability and limited statistical power. Mechanistic considerations proposed by the authors include: amplification of emotional material by an intense VR experience that allows access to previously avoided feelings; facilitation of "letting go" and relaxation of rigid top-down beliefs (a putative mechanism in psychedelic therapy); and induction of awe or accommodation by unusual, vast, or surreal virtual stimuli which may promote psychological plasticity and new perspectives. The authors also note that purposely induced somatic sensations (e.g., strong visual motion leading to mild cybersickness) may function therapeutically when combined with preparation to surrender and integrate the experience. Limitations acknowledged by the study team are several and substantial. The intervention is an audiovisual approximation and cannot replicate all drug-induced phenomena such as full synesthesia or hyperdimensionality. The open-label, uncontrolled design, small sample size and potential expectancy effects (including the preparatory discussion, guided meditation and the demonstrative VR used as a control) limit attribution of effects to the psychedelic-like content. The authors also discuss measurement challenges: some participants reported unexpectedly high scores on MEQ30 and EDI after the short demo session, raising concerns about the suitability of these questionnaires for non-pharmacological VR contexts and the influence of prior experience and interpretation on responses. Blinding and development of appropriate placebo VR controls are noted as methodological hurdles for future trials. Finally, the investigators outline practical advantages of VR for research and therapy — greater accessibility, controllability, shorter and pausable sessions, and the ability to dissociate and test specific phenomenological components — and suggest future directions including increased interactivity, guided narration, componential experiments, better placebo controls, possible combination with sensory-deprivation or microdosing approaches, and adaptation or development of questionnaires suited to VR-induced altered states.

HARDWARE AND SOFTWARE

The current version of Psyrreal is a stable release of the virtual reality experience which could already be applied in a therapeutic setting. The experience will run on most modern VR headsets, and HTC Vive Pro Eye was used for development and the experiments. Epic Games Unreal Engine (UE) 4.27 was used as the development platform and the experience was written fully in Blueprint visual scripting language. The final software is distributed as open source upon request 1 , with the Creative Commons Attribution-Non-Commercial license. Psyrreal imitates the audiovisual and narrative phenomenology reported during psychedelic experiences(Figure). Certain elements were also included based on descriptions of pharmacologically induced and spontaneously occurring mystical experiences, deep meditative states, and awe-inducing experiencesas in some cases these offered more details about specific phenomena which also occur in psychedelic states. The phenomenological elements and concepts used in the experience (Tableand Supplementary material 7) were selected after careful study of the available literature on psychedelic, meditative, awe-inducing, and mysticalexperiences, written reportsand visual replications) of such experiences. The participants begin the experience in a virtual "real world" which starts to acquire psychedelic phenomenology and continues to progress through a total of 19 distinct visual levels incorporating and combining various psychedelic effects. Screenshots of some of the environments in Psyrreal shown in sequence to exemplify the diversity of visuals presented to the user during the experience. The experience starts in a temple (top left), progresses through different levels of varying abstraction and intensity, and culminates in outer space (bottom right). See also Supplementary material 1 for more illustrations of the environments and Tablefor more detailed descriptions of the implemented concepts. CEV stands for "closed-eye visuals." The visuals for the most part consist of abstract shapes and geometric patterns that would allow participants to project their own meaning to the experience. The duration of levels varies from approximately 30 s to 2 min. A specific soundtrack was composed for Psyrreal implementing narrative (e.g., varying intensity) and perceptual (e.g., temporal alterations) aspects of psychedelic phenomenology matching the visual levels. Psyrreal was validated among participants with extensive psychedelic experiences who evaluated its similarity to psychedelic experiences (see Supplementary material 3 for more details). All participants had prior experiences with lysergic acid diethylamide (LSD) and psilocybin with five (out of seven) participants also having prior experiences with N,N-dimethyltryptamine (DMT) or Ayahuasca. Participants in the validation study were recruited via social media. Five people rated at least one scene from Psyrreal to be visually very similar (4 on a scale from 0 to 5) to psychedelic experiences. Though the experience is purely audiovisual and did not include any physical stimulation, six people also rated the physical sensations induced by Psyrreal to be very similar to those experienced under the effects of psychedelics.

THERAPEUTIC INTERVENTION USING PSYRREAL PARTICIPANTS

The sample consisted of 13 participants (8 women, 5 men) of ages 20-58 (M = 33.8, SD = 10.6; further information on the participants can be found in the data files, linked under Supplementary material). The study was advertised on an Estonian website that promotes discussion about mental health (peaasi.ee) and recruitment was conducted through self-referral from 20th October 2021 until 8th December 2021. The sample size was determined by practical constraints and concurrent COVIDrelated restrictions as well as sample sizes of similar feasibility studies [e.g.,]. Applicability was decided based on their scores on a self-rated depression screening questionnaire (depressive scale cut-off of ≥12, see below) administered during online registration. The scores of the questionnaire were analyzed and updated with a clinical psychologist on the first day of experiments. Additional criteria for exclusion were: hypersensitivity to motion sickness, a diagnosis of psychotic disorders and schizophrenia, a history of epileptic seizures or psychotic episodes, or a family history of schizophrenia. We also excluded people who were currently undergoing treatment for depression (therapy or medication). Most participants had a previous diagnosis of depression (9 out of 13), but participants who were currently receiving treatment were excluded (see also additional analyses Supplementary material 2). All participants had normal or corrected to normal vision. Participants were asked to refrain from consuming alcohol or other substances before the experience to avoid cybersickness and potential confounding. The study was approved by the ethics committee of the University of Tartu and performed in accordance with relevant guidelines and regulations. Participants gave written informed consent prior to participation. All 13 registered people finished the study. One participant (P6) was excluded from the analyses due to receiving antidepressant therapy at the time of the study and another was excluded due to their updated score of depressive symptoms being below the cut-off, thus leaving the final sample at 11 participants. Note that an estimated effect size of 1.11 (based on a relatively similar approach using VR to treat depression) should be detectable with a sample size of 9 [for a statistical power of 0.8, found with G * Power 3.1].

ELEMENTS OF PSYCHEDELIC EXPERIENCES IMPLEMENTATION IN PSYRREAL

Visual acuity and color enhancement. One of the first alterations often noticed in psychedelic experiences is an enhancement of visual acuity where the visual field appears clearer and sharper and objects become more well-defined. This effect is usually accompanied by an intensification and enhanced saturation of colors. The experience starts in a serene, realistic environment overlooking some mountains, with birds singing and calm water flowing around the user (Figure"Main"). After a brief period various open eye visual effects start to appear. Colors become brighter and more saturated; elements of drifting and morphing affect different objects as well as the whole perspective; after-images appear behind falling leaves, and flying butterflies. Certain effects on objects, such as increased contrast, edge aura, texture change and drifting, are gaze-activated (Supplementary Figure). Moving the gaze away from the object decreases the effect strength. As the experience progresses, the affected area can change from object edges to whole objects and to the entire scene (e.g., Figure"Jewel Waterfall"). After-images. Another visual distortion that is often noticed during the early phases of psychedelic experiences is illusory palinopsia, also called after-images, visual tracers, trails or "ghosting" where moving objects leave behind visual trails. Drifting. Objects, parts or the whole visual field often move and distort in many irregular ways, such as drifting, morphing, melting and breathing. These effects can start from a slight oscillation of the outlines of specific objects to seamless drifting of textures and objects changing color or morphing from one to another (153). Closed eye visuals (CEVs). While it is common to experience geometric patterns on real stimuli with eyes open, intricate patterns are also often reported with eyes closed. CEVs usually start out with simple geometric forms like lattices, cobwebs, honeycombs and spirals. Frequently, CEVs include experiences of infinite, kaleidoscopic tunnels formed of geometric patterns and texture repetition. After about 7 min of gradually increasing distortion of the environment, the experience transitions into scenes of CEVs. These start by rather dim 2D patterns which slowly become more vivid and develop into 3D spaces formed of elaborate geometric patterns akin to reports of "DMT hyperspaces" (e.g., Figure"Torus"). Many of these environments also stretch infinitely in all directions (e.g., Figure"Infinity"). The 2D patterns occur recurrently during the rest of the experience, increasing in complexity and acquiring rotating sculptures that generate different mandala-like visuals (Figure"CEV"). One specific example of such patterned scenes are kaleidoscopic rotating tunnels (Figure"Tunnel"), which tend to cause feelings of illusory self-motion and can lead to mild nausea or cyber-sickness (which might, unintuitively, benefit the therapeutic process, see Discussion). DMT hyperspace. A special kind of visionary experience is the so-called "DMT hyperspace" where people are transported into another world. These are often high dimensional spaceswhich contain massive or even infinitely large cathedrals, machines capes or abstract spaces made of geometric patterns (154). The passage into this space, a "DMT breakthrough, " is often accompanied by sensations of overwhelming intensity, fast or accelerating movement along geometric tunnels and an ascending or intensifying sound (74, 92, 154-156). Visions. With higher doses and during more acute phases of psychedelic experiences, CEVs can become increasingly lucid, hyperdimensional with more complex patterns, and acquire profound meaning. Often dreamlikevisions arise which can include whole scenes or landscapes, autobiographical memories or imagined realistic situations, as well as mythical or archetypal imagery. Such visions are sometimes experienced in a synesthetic fashion, i.e., not just seen or imagined visually, but also "felt". While many levels consist of abstract shapes and patterns (e.g., Figure"Organic life"), we also included levels that simulate elements of more coherent visions. "Visions" induce the feeling of being in a completely different environment from the main level. We included views of landscapes and grandiose and vast scenes (e.g., Figure"Ocean"), involving large cathedrals and a mountain ridge with a floating monastery (Figure"Mountains"). We also implemented the "Overview" (157-159) and "Ultraview" effects (160) where, respectively, the subject experiences an overview of the Earth (Figure"Planet") and thereafter the whole Universe. Mystical experiences. Moderate and higher doses of psychedelics often result in participants having mystical experiences. These indescribable and paradoxical experiences are often described to contain a felt union with God, Nature or the Universe, receiving transformative insights and feelings of profound peace and bliss. At the core of mystical experiences is losing a sense of individual self (see also ego-dissolution) and "becoming one" with objects of attention or with "everything". Another common mention is that of a bright white or golden light that could be seen or "felt" in a synesthetic nature. Mystical experiences also often contain alterations and transcendence of time and space, and feelings of vastness, awe and sacredness. The synesthetic and phenomenologically barren nature of mystical experiences creates a significant hurdle in representing them in the audiovisual medium of VR. Nevertheless, we implemented a recurrently appearing level with a bright white light and calm and sacred music (Figure"Mystical Light"). We also included a level with spherical particles that circle around the player, giving the impression that the environment is "alive" and interacting with the player. Psyrreal also has a soundtrack with varying tempo and intensity to induce a sense of temporal alteration (see also "Overview of Psyrreal VR"). Ego-dissolution. Psychedelic experiences also bring about alterations of the sense of self which are often discussed under the term ego-dissolution (or "ego-death"). This is often reported as a dissolution of the embodied self, disintegration of self-related thoughts and felt ownership of thoughts, and/or cessation of implicit subject-object distinction as the subject feels as "one" with their surroundings. To emulate ego-dissolution, we included a virtual body representation of the user in certain levels which consists of a sphere that mimics the environment, thus creating a sense of connectedness to the virtual "world." At the culmination of the experience the particles of the universe converge at the position of the subject to then explode outward and fade, disintegrating the virtual self. remission rate (proportion of participants showing decrease to below 12) based on EST-Q2 scores. The Montgomery-Åsberg Depression Scale (96) (MADRS) was administered by the psychologist before the experiment to validate the depressive symptoms of our sample. One important facet of subjective experiences that could be instrumental for therapeutic benefits is the insight experience. The Psychological Insight Questionnaire (40) (PIQ) was used to capture insights in our sample at the end of the first (control) and second days (Figure; same for the other following questionnaires). Another aspect of subjective experience that has been suggested to underlie the beneficial effects of psychedelic therapy is ego dissolution, measured here by the Ego-Dissolution Inventory (60) (EDI). Mystical experiences have also been proposed as an important mediating factor for the benefits of psychedelic compounds. Here we used The Revised Mystical An illustration of the procedure of the experiment on day 1 and day 2, as well as measurements conducted on the 2 days of experiments and during the follow-up after 2 weeks. The green lines highlight the comparison groups used for the statistical analyses. Experience Questionnaire (29, 62, 63) (MEQ30) to measure the intensity of mystical experience. MEQ30, PIQ, and EDI were administered at the end of the first day and again at the end of the second day. EST-Q2 was administered during registration and 2 weeks after the experiments. More detailed descriptions of the questionnaires can be found in Supplementary material 5. Baseline scores were also reevaluated during the first discussion with the clinical psychologist at the start of the first day. A semi-structured interview about the experience was also conducted by the clinical psychologist at the end of the second day. An additional background and feedback questionnaire was administered at the end of the second day of experiments, and a feedback form was sent to the participants 2 weeks after the experiments. All questionnaires were administered in Estonian.

STUDY PROCEDURE

This open-label feasibility study used a one-group, uncontrolled, longitudinal design to investigate the effects of psychedelic phenomenology in VR. Experiments were conducted on two consecutive days (Figure; see also Supplementary materialfor more details on the experimental setting). The first day included a diagnostic and preparative 30-45 min session with a clinical psychologist, discussing the depressive symptomology of the participant based on their scores on the EST-Q2 Depression scale (filled in during the online registration) and guiding the participants to frame questions and think about their worries. Afterward, the participants were instructed on how to use the VR equipment and partook in a demonstrative 15 min VR experience, which consisted of a 10 min guided meditation (in a cave-like environment, Supplementary Figure; however the participants were instructed to close their eyes for the duration of the meditation) and a further 5 min of being in a non-interactive living-room environment (default Steam VR Home room, Supplementary Figure). Participants were seated comfortably during both VR experiences on day 1 and 2. Then the participants had another shorter (5-10 min) discussion with a clinical psychologist and filled in the rest of the questionnaires (EDI, PIQ, and MEQ30). The demonstrative VR experience on the first day also served as a control condition for comparisons with EDI, PIQ, and MEQ30 measures. Participants were instructed to answer the questionnaires based on the 5 min spent in the living-room VR environment. EST-Q2 was not administered after the control VR as it is not a suitable measure for short term changes in mood. The second day had a similar structure starting with a short discussion with the psychologist to evaluate the effects of the first day and to prepare the participant for the VR experience. During this, the participant was also instructed to look around freely during the experience, sit however they felt comfortable, and not to overly focus on their questions but rather to relax and focus on the experience itself. Then, the participant underwent the same guided meditation in VR as the day before which was directly followed by the 45 min long VR experience. The psychologist was waiting in the next room in case of any psychological emergencies, and a technician was present in the room with the participant to monitor the VR system. After the experience, the participant was allowed to rest for as long as they preferred and then had an integrative session (20-30 min) with the psychologist and answered the questionnaires (EDI, PIQ, and MEQ30). Follow-up EST-Q2 questionnaire was sent to the participants 2 weeks after their participation in the experiment. The experiments were conducted in the virtual reality laboratory at the Institute of Computer Science of the University of Tartu between 29th October 2021 and 11th December 2021. For more additional details on setting and study procedure see also Supplementary material 6.

THERAPEUTIC INTERVENTION

We conducted an open-label feasibility study in adults (n = 11) with mild to moderate depressive symptoms. Note that n = 10 for the EST-Q2 measure, as one participant did not complete the follow up questionnaire. The experiments took place on two consecutive days with Psyrreal being implemented on the second day (see Figure). No adverse effects were reported during the administration of the VR experience, even though the participants were encouraged to express any discomfort. In the interviews afterward, four participants (out of 13) mentioned transient nausea during the VR experience. Baseline EST-Q2 depression subscale results were M = 15.20 (SD = 2.66) and showed good consistency with the MADRS questionnaire results (r = 0.66, p = 0.010). There was a significant decrease in EST-Q2 scores at the 2 week follow-up (M = 11.00, SD = 3.74; paired samples t-test, t (9) = 3.50, p = 0.007, Hedges' g = 1.046; Figure). The response rate of the treatment was 18% and remission rate was 60%. The difference between the response and remission rate is largely due to the mild-to-moderate symptoms reported by the studied population. The anxiety scale results of the EST-Q2 showed a similar pattern, as scores decreased from baseline M = 10. The MEQ30 average score increased from M = 39.58 (SD = 19.57) to 42.73 (σ = 18.43). The change was not statistically significant [t (10) = 0.673, p = 0.520, g = 0.137]. One participant (P3) reported a complete mystical experience (all MEQ30 subscales over 60) on day two. One participant (P7) reported a complete mystical experience on the first day, but not on the second. While the changes of scores on PIQ, MEQ30 and EDI did not reach statistical significance, the results were highly varied. A thematic analysis (99) was conducted based on the transcripts of the integrative semi-structured interview sessions to investigate the effects of the intervention on individual participants. Extracts from the transcripts that were used in the thematic analysis can be found in Supplementary material 4. The analysis revealed certain themes that were often mentioned in the interviews (Table). All participants reported feeling some positive emotions during the experience with 55% of participants reporting calmness or peace and the same amount of people reporting feelings of joy, pleasure, or fun. Seven participants also reported negative emotions (sadness, fear, and anxiety) with four participants mentioning feeling sadness. A total of 45% of participants reported that they had personally relevant thoughts during the experience, for example, one participant mentioned: "From this place where I got in touch with this emotion [sadness] these other questions also started to unravel and I understood many of my [behavioural and cognitive] patterns," (P12). Six participants mentioned that they did not reach any new understandings, while three did arrive at new beneficial understandings: "[.] this novel understanding that I can reprogram myself, that this essence of myself doesn't exist-it's very liberating. It gives me, in some sense, a vitality that I'm looking for, " (P7). Three participants specifically highlighted a physical feeling of insight as illustrated by the following quote from participant seven: "It was a different kind of insight, like a new insight. Like a physical insight, " (P7). Five people reported changes in perspective: "[.] Like a shift in perspective -in the beginning, I was looking more at the details, afterward I was looking at the whole, " (P3). Six participants reported alterations in their sense of self with three reporting alterations in the narrative sense of self and four participants reporting alterations in the embodied sense of self. For example: "Did you experience any change or loss of your self-image or sense of self? Yes, like dissolution, yes. [.] The whole experience was so immersive that you melted into it," (P2). A total of 36% of participants reported somatic effects during the experience: "Specifically the parts with strong motion, these almost physical experiences, those were the most impactful," (P12).

DISCUSSION

We created a novel VR experience based on psychedelic and mystical experiences as well as meditative states and implemented it in a therapeutic intervention for people with mildto-moderate depression. The results of the study suggest that using VR experiences in a therapeutic setting could be beneficial in treating depressive interventions cannot be made. Nevertheless, as 73% of participants showed a decrease in their depressive symptoms 2 weeks after a short 2-day intervention at a 60% remission rate, further research into such methods is warranted. Additionally, a previous study using a VR experience to treat depression also reported a comparable effect (49), offering preliminary tenability for the potential therapeutic benefits of VR experiences. Anxiety scores also decreased significantly at the follow-up. However, the anxiety scores were generally low beforehand with four participants having a score indicative of an anxiety disorder (≥12). That being said, these results suggest using psychedelic-inspired virtual reality for the treatment of anxiety to also be a promising avenue for research. Additionally, results from the thematic analysis suggest that a psychedelic VR experience, when accompanied by a dedicated therapeutic setting, might be able to induce insight and understanding at least for some people. Three participants reported gaining new and beneficial insights related to their problems and two more mentioned gaining new perspectives during the experience. However, across sample the change in insightfulness rating as measured by PIQ did not reach significance, indicating great interindividual variance. Overall, these results add some tentative support to the hypothesis that subjective experiences mediate the benefits of psychedelics. Psyrreal incorporates a wide range of elements common to psychedelic experiences such as specific audiovisual phenomenology (e.g., visual acuity enhancement and CEVs; see Table), different structural elements of these experiences [e.g., overwhelming and oscillating intensity, and progression of the experience (100)], and general experiential themes (e.g., mystical and ego-dissolution experiences; see Table). The effects of our intervention on depressive symptoms were similar (albeit weaker) to those seen in psychedelic-assisted therapy (101). While the questionnaires implemented to evaluate the subjective factors which have been found to mediate the therapeutic benefits of psychedelics did not show statistically significant changes, the results of these questionnaires were highly varied in our small sample and prevent us from making strong conclusions. However, the results of the thematic analysis suggest that implementing surreal awe-inducing environments, and intense and variable experiences in VR could facilitate insights or alterations in sense of self at least for some people. Future studies are required to confirm these speculations and evaluate the mediating factors with a larger sample and a randomized placebo-controlled trial design. Previous similar studies using VR (50, 51) have found slightly higher results on the MEQ30 questionnaire. Specifically, the scores of the Mystical and Positive Mood subscales were higher for Isness-C (for Isness-D only the Positive Mood subscale was significantly higher). However, these studies also implemented a guiding narration by a "trained drama therapist" which emphasized elements of mystical experiencespotentially enhancing the perception of the experience as mystical. While the current version of Psyrreal did not include narration, adding it in the future could further enhance the effect of Psyrreal. The differences on the Positive Mood subscale are likely to be influenced by the symptoms of depression prevalent in our sample and the "amplifying" effect of the experience which allowed some participants to get in touch with their negative emotions.

POSSIBLE MECHANISMS OF PSYCHEDELIC-INSPIRED-VR-AUGMENTED THERAPY

Our augmented therapy intervention combined a therapeutic environment and discussion about one's problems with an engaging VR experience. One potential mechanism how this intervention yields therapeutic benefits could be that the intense and different virtual experience amplifies the therapeutic process and provides an experiential route for the participant to get in touch with their emotions (102-106) as an alternative to cognitive therapies which emphasize the role of explicit verbal discussion and reasoning (107-109). According to current understandings of psychedelic therapy, psychedelic substances in contrast to conventional antidepressants serve to amplify mental content and thus help to address rather than avoid aversive memories and emotions. Some participants mentioned that they were able to access feelings that have otherwise stayed out of reach, for example one participant expressed to the psychologist: "When we met yesterday, [.] I said I could not feel sadness. We could have five more similar sessions and I still wouldn't feel sadness. But thanks to this experience, as short as it was yesterday, suddenly this sadness arose (in me)," (P7). A related possible mechanism is that the intensity of the experience can require relinquishing control which could result in some degree of relaxation of fixed cognitive constraints. The relaxation of top-down beliefs is suggested to be one of the possible mechanisms behind the therapeutic effects of psychedelics, wherein potentially pathological content can be accessed and overwritten (111). Letting go of control and allowing oneself to experience anything that comes up in a psychedelic experience could allow more difficult content to reach consciousness, shorten the challenging episodes and foster integration and healthy interpretation of difficult content. This concept of "letting go" is a central element of psychedelicand other forms of therapy (115, 116), ritual use of psychedelics (117) as well as an important part of meditative practices[see also]. Psyrreal mimics the oscillating and overwhelming intensity of psychedelic experiences. For example, some sections of Psyrreal purposefully depict high-motion visual scenes without actual physical motion that induce quite strong physical sensations and mild symptoms of cybersickness that can be "let go" (e.g., Figure"Tunnel"). Hence, this somatoaudiovisual intensity could also function as something that could be accepted or surrendered to. The beneficial effects of "letting go" were also remarked by some participants, for example: "[.] Then, at one moment, I let go, thinking that it doesn't work like this [focusing on finding answers].Then it actually started to work, yes. [.] I think that the first half of the experience you kind of get into it or start going along with it and then the answers arrive very clearly somehow," (P12). In our study, participants were explicitly instructed to accept and let go of any emotions that might arise during the experience. While Psyrreal does not include any explicitly affective visual stimuli (the music, however, varies in its emotional tone) most participants mentioned experiencing a wide range of emotions with some explicitly reporting "getting in touch" with their emotions (see above). Therefore, we suggest that another potential therapeutic mechanism for this type of therapy could be combining a virtual emotion-eliciting experience with the preparation of "letting go." Somewhat similar ideas have been implemented in VR-augmented exposure therapy where people are exposed to aversive virtual stimuli to facilitate habituation, inhibition or cognitive reappraisal of the psychological reaction (121-123). While the experience of being in virtual reality in itself might facilitate elements that could beneficially augment the therapeutic process, there could also be added value in implementing specific visual content from reports of subjective psychedelic and mystical experiences. Unusual, infinitely vast, and even surreal stimuli common to such experiences might result in emotions of surprise and awe, where the novel stimulus needs to be accommodated into existing cognitive structures. The necessity for accommodating vastly different and novel stimuli would require updating the existing mental frameworkand thereby lead to a state of plasticity or "insightfulness". This could allow the subject to gain different perspectives, revise pathological beliefs, and come to new insights (105, 124, 125). Such effects have also been discussed in contemporary psychedelic science (111). In fact, awe has been suggested to be a central mediator of the beneficial effects of psychedelics (126) and a potential therapeutic asset for different mental health disorders, including depression (127). Psyrreal contains infinite abstract "worlds" as well as vast landscapes and cathedrals which could induce awe. Additionally, virtual environments which break the usual laws of physics might also require accommodation and induce states of relaxed beliefs (105, 128, 129).

LIMITATIONS

Despite our efforts, we are far from claiming that Psyrreal is an exact replication of psychedelic experiences. Psychedelic experiences encompass many aspects of consciousnessthat we tried to replicate within the audiovisually confined medium of virtual reality. Some elements of substance-induced psychedelic experiences are inherently impossible to be implemented in virtual reality (e.g., hyperdimensional spaces, many synesthetic elements). Also, compared to psychedelics, virtual reality has some additional aspects which could contribute to the loss of immersion in the experience. For example, people might lose their immersion due to interactive elements that fail to meet their expectations or due to the graphics not being realistic enough. The open-label design, small sample size and lack of controls in our reported experiment do not allow us to make strong claims about such interventions yet. We were unable to reliably estimate the effect of the control condition on EST-Q2 scores due to the 2-day design, as such short term changes (or lack thereof) would be unlikely to reflect true effects. Hence, the main comparison in depression scores could only be evaluated at least 2 weeks after the intervention. The design was chosen after careful consideration of how to best optimize resources for the purpose of evaluating preliminary results and feasibility for conducting more expensive future studies -which we now hope to conduct. Therefore, it is also possible that an expectancy bias in the participants, initial discussion with the psychologist, guided meditation or even a brief experience of non-psychedelic virtual reality might be responsible for the decrease of depressive symptoms. This is highlighted by a few participants reporting quite high results on the Psychological Insight Questionnaire and Mystical Experience Questionnaire even on the first day. While the psychologist did not apply usual therapeutic techniques and assumed the role of an observer, simply an opportunity to discuss their problems could already have had a beneficial effect. While MEQ30 has been validated for psychedelic compounds and it has seen some use in investigating non-pharmacological methods for inducing mystical experiences [e.g.,)], we are not aware of any studies using non-pharmacological methods that have implemented a control/baseline measurement of MEQ30. Our results suggest some potential difficulties in using the MEQ30 with non-pharmacological methods, as multiple participants had confusing results with one participant reporting a complete mystical experience on day one and a further two participants who only very narrowly missed out on the threshold of a complete mystical experience. While it is not impossible that they actually had a real mystical experience on the first day, it is unlikely and they also did not describe their experience as such during their discussion with the psychologist. We speculate that certain inflated scores could be due to the subjective nature of the questionnaire, and/or difficulties in understanding the questions. As the MEQ30 instructions require people to compare a specific experience (in our case, the VR experience) to other previous experiences in their lives, the results are dependent on the intensity of similar experiences they have had in the past, as well as their previous experience with VR. This also relates to difficulties in understanding the questions: people with varying amounts of mystical experiences can have a very different understanding of the questionnaire items which is further exacerbated by the fact that mystical experiences are ineffable and hard to describe. It is also possible that a VR experience by itself could incline some participants to report high scores on the MEQ30. Finally, it is possible that the participants scored higher due to not wanting to disappoint the experimenters, as the people conducting the experiment were friendly and supportive to create an environment where participants feel safe and comfortable. Though, due to the open-label design, participants were aware that the measurements on the first day served an introductory and demonstrative purpose. The guided meditation and short demonstrative VR (used on the first day) could also be conducive to reporting high scores on the MEQ30, PIQ, and EDI. Additionally, the results of these questionnaires were compared between a 5 min long control VR and 45 min long Psyrreal, which limits the comparability of the conditions. The effects of meditation on inducing altered states of consciousness, insight, self-alterations and mystical experiences are well documented), but even a short experience with VR could have some effect for a couple of reasons. First, for people who have not had much experience with VR, the experience might be something so different that it has a strong effect on them (135). Second, the content of VR might by chance be specifically relevant to the participant, as was the case for one participant (who was excluded from the analysis) who had been pondering whether they should go traveling to the mountains with their ex-spouse. As the demonstrative VR was in a small room with a balcony view onto a mountain range the participant felt it to be very personally meaningful. Third, one of the potential mediators of the beneficial effects of psychedelic experiences as well as a crucial element of mystical experiences-ego-dissolution, might be induced to some degree in any VR experience with an altered image of the body (136, 137). While the EDI did not show a significant change from baseline, half of the participants showed relatively high (a score of over 40) results even after the demo experience on the first day and several participants mentioned alterations in their sense of self during the integrative sessions. Therefore, it can be difficult to disentangle the effects of VR and the specific psychedelic content of our designed experience. Also, blinding procedures for such methods are complicated by a bane common to psychedelic investigation -the active condition is easily distinguishable from the control condition. The issues of blinding and confounding are important to be addressed in future studies.

ADVANTAGES OF VIRTUAL REALITY FOR STUDYING PSYCHEDELIC THERAPY

Although virtual reality is likely a less powerful tool than psychedelic substances[but see], using it to augment therapy could be beneficial for those who suffer from acute side effects of psychedelics or who prefer to avoid consuming these kinds of substances. Virtual reality could also work as a stepping stone before engaging in psychedelic therapy (101) and could be used in countries where psychedelics are not available for medical use. The duration of virtual reality experiences is also less constrained than psychedelic experiences, which (in the case of LSD) can last over 16 h (140). Virtual reality experiences can be stopped at any moment (e.g., in the case of challenging experiences) or paused if the participant would like to immediately discuss something. Virtual reality could also be a powerful tool for investigating the precise therapeutic factors of subjective (e.g., psychedelic) experiences (101) which are often confounded and contain multiple interfering interactions, as it allows to test and separate different elements and concepts that might mediate beneficial effects. In other words, virtual reality allows one to study in a controlled manner which specific subjective experiences (e.g., certain visual experiences, challenging experiences, egodissolution) might be beneficial for therapeutic success. Forms of meditation, audiovisual media, engaging in physical activities (e.g., dancing and hiking) could also be used as therapeutic "amplifiers" (105), but virtual reality offers an especially powerful medium for such a tool. First, it can offer a strong sense of presence and immersion in a specific environment which might be beneficial for the efficacy of such augmentation (101). Second, virtual reality is adaptable and could be tailored to the needs and specific symptomatology of the participant as well as to different disorders (e.g., anxiety and post-traumatic stress disorder). For instance, in Psyrreal it is possible to remove and add specific parts of the experience to customize the virtual reality experience for the specific participant and the circumstances. Third, virtual reality could have some advantages in regard to inducing egodissolutionwhich could be one of the mechanisms behind the therapeutic effects of psychedelics. Fourth, virtual reality assisted therapeutic interventions have high satisfaction rates (143) and are often preferred by patients. This was also echoed by our participants who subjectively evaluated the potential effectiveness of such an intervention with a mean rating of 8.00 out of 10 (n = 12, SD = 2.30).

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