Anorexia nervosa

Anorexia Nervosa (AN) is a severe [1] psychiatric disorder characterized mainly by persistent restriction of food intake, intense fear of weight gain, cognitive rigidity and disturbances in body image [2]. The disorder typically emerges during adolescence or young adulthood with a lifetime prevalence in females up to 4% and in 0.3% in males [3], and is associated with profound psychological suffering, psychiatric and somatic co-morbidity, and the highest mortality rate among psychiatric conditions [4–6]. Despite advances in psychotherapeutic approaches and specialized multidisciplinary care, long-term outcomes remain suboptimal. Approximately one in five individuals with AN develop a severe and enduring course [7], and relapse after remission is common, occurring in roughly 30% within 1–2 years and in 40–50% over even longer follow-up periods [8,9]. Risk of a severe and enduring course in AN is associated with longer duration of untreated illness, persistently low body mass index, psychiatric comorbidity, and cognitive inflexibility, while earlier remission is consistently linked to more favourable long-term outcomes, underscoring the prognostic importance of timely and effective interventions [2,7,8].

Current evidence-based treatments for AN rely primarily on psychological and nutritional interventions, including family-based therapy for adolescents and specialized psychotherapies for adults; however, no pharmacological treatments are approved for core AN psychopathology [10]. These limitations have led to increasing interest in novel interventions targeting transdiagnostic mechanisms implicated in illness persistence, including cognitive inflexibility, maladaptive learning processes related to food and self-image, and emotional avoidance [11].

This need may be particularly salient during adolescence, a developmental period characterized by ongoing cortical maturation and heightened neuroplasticity [12–14]. Neuroimaging studies consistently demonstrate that acute underweight in AN is associated with widespread reductions in cortical thickness and grey matter volume, changes that appear largely related to malnutrition and often show substantial normalization with weight restoration [15]. Importantly, emerging evidence suggests that age and duration of illness influence the extent and trajectory of structural brain recovery, indicating that prolonged underweight during adolescence may intersect with sensitive neurodevelopmental windows [16]. Given that AN most commonly emerges during adolescence and that longer duration of untreated illness is associated with poorer long-term outcomes, early and effective intervention are critical not only for symptomatic recovery but also for preventing the consolidation of maladaptive neural and behavioural patterns. Within this context, careful, staged investigation of innovative interventions for AN in adolescents represents both a clinical and developmental imperative.

Psilocybin

Classic serotonergic psychedelics such as psilocybin act primarily via agonism at the serotonin 5-HT₂A receptor [17] and are known to in medium to high doses induce variations of profound, time-limited alterations in perception, cognition, emotion, and self-experience [18]. Over the past decade, controlled clinical trials have demonstrated that psilocybin interventions may produce rapid and sustained improvements in conditions often characterized by high levels of psychological rigidity and treatment resistance, such as depression [19–22], death related anxiety [23–27], and substance use disorders [28,29]. Psilocybin additionally demonstrates a favourable safety profile with low occurrence of serious adverse events in modern clinical trials [30,31].

Beyond symptom reduction, psilocybin experiences are frequently described by patients as personally meaningful and transformative with sometimes enduring changes in perspective, emotional processing, personality, and self-relation [32–34]. Neuropsychological mechanistic models suggest that increased cognitive and emotional flexibility [35] together with the disruption of maladaptive predictive models [36,37] implicated in psychopathology [38], may enhance learning and behavioural updating during a transient period of heightened plasticity [39–41]. These mechanisms of change can hypothetically benefit the recovery in AN, where rigid cognitive styles, compulsive behavioural patterns, and avoidance are central maintaining factors [42].

Psilocybin and AN

Interest in psychedelic interventions for eating disorders has increased substantially in recent years [23,42–44]. Although the available evidence base remains limited, qualitative and mixed-methods studies (combining self-report measures with in-depth interviews) have reported on therapeutic associations from the naturalistic ceremonial use of ayahuasca, another classical psychedelic, including self-reported reductions in eating-disorder symptomatology associated with increased emotional insight, self-compassion, and enhanced motivation for recovery [45,46]. These preliminary findings align closely with hypothesized mechanisms of change in psychedelic therapy in general, such as increases in cognitive flexibility, enhanced emotional regulation, and mystical experiences with subjective meaning and therapeutic effects. Hypothetically, these self-reported effects might serve as adjunctive or augmentative mechanisms to reduce eating-disorder psychopathology, particularly as adjunctive component with existing biopsychosocial treatment framework [42,47]. Underlying neurobiological mechanisms such as serotonergic modulation [48,49] and plasticity-related signalling pathways, may contribute to both acute and sustained therapeutic effects [50]. Together, the current literature supports the hypothesis that psilocybin therapy may target core mechanisms underlying the persistence of AN rather than merely alleviating secondary symptoms such as comorbid depression or anxiety known to be reduced by psilocybin as well [22,51]. Also, preclinical data lend further support to this rationale. In the activity-based anorexia model, a single dose of psilocybin improved body weight maintenance and enhanced cognitive flexibility in female rats, with effects mediated primarily through 5-HT1A receptor signalling rather than the canonical 5-HT2A pathway alone [52]. These findings suggest that psilocybin may engage disorder-specific mechanisms in AN through multiple serotonergic pathways, and that improvements in flexible behaviour can persist beyond the acute psychedelic experience.

Based on the existing body of evidence, clinical studies have begun to emerge. A phase 1 open-label feasibility study of psilocybin-assisted therapy in adult women with anorexia nervosa found a single 25 mg dose to be safe and well tolerated, with no clinically significant changes in ECG, vital signs, or suicidality, and only transient mild adverse events, including two episodes of asymptomatic low blood glucose [53]. Participants reported subjectively meaningful experiences, and reductions in eating-disorder symptoms were observed at short-term follow-up but not reflected in significant BMI needed for remission. Additionally, most patients wanted a second psilocybin dosing session in the treatment program. Although preliminary, these findings provide early evidence supporting further investigation of psilocybin in this population. A subsequent report from the same trial described the therapeutic emergence of previously dissociated traumatic memories in two of ten participants during psilocybin dosing, both of whom subsequently achieved clinically meaningful improvement in eating disorder symptoms [54]. These observations point to a role for trauma processing in recovery and strengthen the case for trauma-informed preparation and integration support in psilocybin-assisted therapy for AN. Currently, several clinical trials are currently underway exploring the therapeutic potential of psilocybin for patients suffering from AN and other eating disorders (ClinicalTrials.gov Identifier: NCT04052568, NCT06399263, NCT05481736, NCT04505189).

Functional magnetic resonance imaging and AN

Functional magnetic resonance imaging (fMRI) studies demonstrate that patients with active AN have significantly reduced volumes of both grey and white matter, with more pronounced loss observed in adolescents [55]. These reductions appear to reflect the physiological effects of acute starvation rather than enduring structural pathology [15], and they appear to be largely reversible with weight restoration, although the degree of recovery of cortical thickness is negatively correlated with age [16]. Adolescents with restricting-type anorexia nervosa show especially reduced grey matter volumes in the frontal lobes and insula [56].

The brain’s structural white matter connectivity can be examined with diffusion magnetic resonance imaging techniques, such as diffusion tensor imaging [57,58]. Because structural connectivity underpins functional connectivity, which reflects how different brain regions communicate [59], alterations in white matter networks may contribute to the atypical functional brain patterns observed in AN. Although evidence remains limited, one study found that patients with AN showed increased white matter connectivity in frontal tracts and reduced connectivity in subcortical networks compared with healthy controls [60].

These structural observations are consistent with functional neuroimaging findings in individuals with AN, where studies have demonstrated excessive activation in regions of the frontal cortex, implicated in cognitive control. For example, individuals recovered from AN showed altered frontal activation in response to reward-related stimuli compared to healthy controls [61], suggesting that restrictive behaviour may be driven by pronounced top–down regulation of reward cues. In the mentioned study, reward-related activity was induced using a modified version of the Monetary Incentive Delay Task, a commonly used paradigm for examining reward anticipation processing [62]. Similarly, during tasks requiring behavioural response shifting, AN patients displayed impaired cognitive-behavioural flexibility accompanied by predominant prefrontal activation [63]. Together, these findings support the hypothesis that individuals with AN exhibit excessive recruitment of prefrontal networks, which may contribute to cognitive inflexibility and rigid behaviour.

The imbalance between top–down and bottom–up cortical processes is also reflected in the delay discounting task. Underweight AN patients tend to show greater tolerance for delayed rewards [64]. However, this excessive self-control in the context of delayed rewards appears to be associated with altered activity in cingulostriatal circuitry, particularly in the striatum and dorsal anterior cingulate cortex, rather than increased activity in the prefrontal cortex.

Likewise, fMRI paradigms using food-related visual stimuli often show a pattern of hyperactivation in regions involved in cognitive control and, in some cases, emotional processing [65], together with hypoactivation in regions involved in reward-related processing [66].

Complementing task-based paradigms, resting-state fMRI (rs-fMRI) provides additional support for connectivity alterations in AN. A systematic review of resting-state functional magnetic resonance imaging (rs-fMRI) studies in patients with anorexia nervosa (both current and recovered AN) has provided preliminary evidence of altered functional connectivity in networks involved in cognitive control, flexibility and the processing of body signals, such as visual and somatosensory integration [67]. In particular, regions involved in body imaging processing have been associated with decreased functional connectivity [68]. Furthermore, increased activation within fronto-striatal circuits has been linked to the maintenance of restrictive eating behaviours in AN [69].

fMRI and psilocybin

The psychedelic experience and state remain somewhat elusive, reflecting the current state of our understanding of consciousness [70]. Nevertheless, findings indicate that psychedelics and their effect on the serotonin signalling system have been associated with change in standard brain network communication, thus change in functional connectivity [71]. Among other things, these changes are thought to influence how the brain interprets the world and facilitate new learning by attributing greater significance to sensory inputs, thereby enhancing the probability of “belief updating” through reduced prediction error [72–74].

Similarly, psilocybin in the acute state has been shown to reduce brain activity in key brain network regions during resting-state, with the extent of this reduction predicting the intensity of subjective psychedelic effects [75]. The reduced brain activity in default network regions is hypothesised to facilitate a state of cognition free from ordinary bias, patterns and rules.

In patients with major depressive disorder, psilocybin has further been associated with a sustained reduction in brain network modularity three weeks post-treatment, and changes in modularity were associated with improvements in depressive symptoms [76]. Moreover, increased dynamic network flexibility was observed in the executive network (EN) and in regions with high in 5-HT2A-receptor density, that are functionally connected to the EN. Notably, psilocybin disrupts connectivity in the default mode network by causing desynchronization across spatial scales [77].

Beyond functional changes, psilocybin may also affect structural connectivity, as suggested by animal studies and emerging human evidence [78,79]. Also, psilocybin has been shown to affect the fronto-striatal-thalamic circuits reducing top-down regulation and enhancing bottom-up information, an effect attributed to decreased influence of structural conditions, hypothesised to be mediated by serotonin and dopamine signalling [80, preprint].

Overall, emerging evidence highlights how psychedelics may benefit AN patients, such as enhanced serotonin signalling and cognitive flexibility [49]. However, further research is needed to elucidate long-term effects, particularly in clinical context. Functional magnetic resonance imaging (fMRI) has demonstrated utility in detecting neuronal abnormalities in AN. This study’s use of fMRI before and after psilocybin treatment may provide insights into the neurobiological impacts of psilocybin on AN.

Brain-derived neurotrophic factor and AN

Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in synaptic plasticity, neuronal survival, dendritic growth, and activity-dependent learning processes. It is involved in long-term potentiation and experience-dependent neural remodelling, particularly within cortico-limbic and fronto-striatal circuits that support reward learning, emotional regulation, and cognitive flexibility [81,82].

AN can be conceptualized as a disorder characterized by maladaptive learning and habit formation, in which initially goal-directed weight-control behaviours become rigid, compulsive, and resistant to updating despite negative physiological consequences [83,84]. Altered reward processing, impaired fear extinction, and heightened cognitive control are associated with illness persistence.

Peripheral BDNF concentrations have been reported to be reduced in individuals with acute AN, although findings remain heterogeneous across studies and sampling methods. BDNF levels are also associated with nutritional status and illness severity [85,86]. Longitudinal studies suggest partial normalization of BDNF levels with weight restoration. Although the relationship between peripheral BDNF and central nervous system activity is complex and not fully established, these observations are consistent with the hypothesis that prolonged undernutrition may influence neuroplasticity-related signalling pathways relevant for AN recovery. Given that adolescence represents a period of heightened neurodevelopmental plasticity [14,87], alterations in BDNF signalling during this developmental window may influence illness chronicity and recovery trajectories. In the context of eating behaviour, evidence also indicates an anorexigenic role of BDNF/TrkB signalling in hypothalamic circuits, linking BDNF to body weight regulation [85,86].

BDNF and psychedelics

Preclinical and translational research suggests that serotonergic psychedelics, including psilocybin, engage neuroplasticity-related pathways [39,88]. Through agonism at the 5-HT2A receptor, psilocybin has been shown to promote dendritic spine growth, synaptogenesis, and increased expression of plasticity-associated genes, including BDNF [50,89,90]. Although the precise relationship between peripheral BDNF changes and clinical outcomes in humans remains under investigation, converging data support the hypothesis that psilocybin may temporarily enhance neural plasticity, potentially facilitating belief updating, emotional learning, and cognitive flexibility during a transient period of increased plasticity [38].

Given the proposed role of maladaptive learning and rigid habit formation in AN, and the emerging evidence that psilocybin may modulate neuroplasticity-related pathways, longitudinal assessment of peripheral BDNF in psiAN provides an exploratory biomarker of treatment-related plasticity. Measuring BDNF alongside clinical outcomes and psychological process measures may help clarify whether changes in neuroplasticity markers are associated with symptom improvement, relapse trajectories, or subjective psychedelic experiences. While peripheral BDNF cannot be interpreted as a direct measure of central synaptic remodelling, its inclusion may contribute to mechanistic insight.

Adolescents and psychedelic research

AN most commonly emerges during adolescence, with peaks in incidence occurring in mid-to-late teenage years and early adulthood [3]. Early illness trajectories are often marked by rapid consolidation of maladaptive patterns, and longer duration of untreated illness is associated with poorer outcomes [2,7,8]. Despite this, adolescents are frequently excluded from trials of novel psychiatric interventions, including psychedelic research, due to ethical and regulatory concerns. Inclusion of adolescents in clinical research generally requires sufficient evidence of safety and efficacy in the adult population [91–95]. Recent ethical analyses argue that developmental vulnerability alone should not justify categorical exclusion, particularly when existing treatments are insufficient and when safeguards for informed consent, monitoring, and risk minimization are in place. Moreover, exclusion of adolescents from research is not ethically neutral, particularly in disorders such as AN that commonly emerge during adolescence and where delayed access to effective intervention may contribute to chronicity.

While these preclinical findings highlight the importance of developmental caution, observational data in humans indicate that psychedelic use among adolescents and young adults occurs outside clinical settings and when controlling for confounders is not associated with increased rates of psychosis or suicidality at the population level [96,97]. These findings support the importance of generating controlled safety data rather than leaving this population unstudied. Preclinical evidence from a developmental neuroimaging study in mice exposed to psilocybin during adolescence demonstrated persistent changes in brain volume and functional connectivity that extended into adulthood, alongside altered sensory processing, with structural effects more pronounced in males than in females [98]. While cross-species extrapolation requires caution, these findings reinforce the importance of systematic developmental monitoring and support the stepwise safety design adopted in the present protocol.

The present study therefore includes individuals aged 16–35 years with anorexia nervosa who have experienced at least one relapse, a group at high risk for chronic illness with limited treatment options. By adopting a cautious, stepwise design with enhanced monitoring and staged inclusion of minors, this trial aims to address both scientific and ethical imperatives in advancing care for a severely affected population.

Study design

The psiAN study is a phase IIa, open-label, randomized controlled clinical trial evaluating the safety, tolerability, and preliminary therapeutic potential of psilocybin administered with structured and manualised psychological support alongside treatment as usual (TAU) in adolescents and young adults with ongoing AN who have previously achieved at least partial weight restoration (BMI ≥ 17) followed by subsequent weight loss, consistent with relapse. Participants are randomized in a 1:1 ratio to either two 25 mg doses of psilocybin treatment plus TAU, or TAU alone. Where discontinuation of interacting medications is required, a supervised washout period is implemented prior to psilocybin administration, based on the pharmacokinetic properties of the medication, clinical assessment, and patient safety considerations.

At 6-month follow-up, the participants of the control arm are offered psilocybin treatment.

The trial includes repeated assessments from baseline through 12 months of follow-up, enabling evaluation of short-term effects and longer-term relapse-related outcomes. Neurobiological measures, including fMRI and BDNF, are integrated to explore potential mechanisms associated with treatment response.

Study setting

All clinical procedures, including screening, psychological support sessions, and psilocybin administrations, are conducted at the Department of Psychiatry, Lund (Skåne) University Hospital, Lund, Sweden.

Functional magnetic resonance imaging assessments are performed at the National 7T Facility in Lund. The study is conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP), and the EU Clinical Trials Regulation (CTR No. 536/2014), with oversight by relevant national regulatory authorities.

Participants

Eligible participants are adolescents and young adults aged 16–35 years with a DSM-5 diagnosis of AN who have experienced at least one period of partial weight restoration (BMI ≥ 17) followed by subsequent weight loss consistent with relapse. Participants must have a body mass index (BMI) greater than 16.0 at inclusion and be in stable contact with specialized psychiatric care in Region Skåne, Sweden. Key exclusion criteria include current or lifetime psychotic or bipolar disorder, substance use disorder, clinically significant medical or cardiovascular conditions that contraindicate psilocybin administration or MRI procedures, pregnancy or breastfeeding, and ongoing use of medications with known adverse interactions with serotonergic psychedelics that cannot be safely discontinued.

Concomitant medication management is guided by clinical judgment and current evidence. Ongoing treatment with selective serotonin reuptake inhibitors (SSRIs) and serotonin–noradrenaline reuptake inhibitors (SNRIs) may be continued when clinically appropriate and safe, consistent with emerging evidence suggesting that concomitant SSRI use does not invariably preclude therapeutic response to psilocybin [99,100]. Medications with clinically relevant 5-HT2A receptor antagonistic properties, including antipsychotics, are exclusion criteria unless they can be safely discontinued prior to dosing.

A full list of exclusion criteria can be found in the study protocol.

Recruitment and informed consent

Participants are recruited through clinicians within specialized eating disorder services in Region Skåne, Sweden. All potential participants receive comprehensive written and verbal information about the study, including potential risks, benefits, and the voluntary nature of participation. Two weeks are provided for consideration from consent to randomization.

For participants aged 18 years and older, written informed consent is obtained directly. For participants aged 16–17 years, written informed consent is obtained from both the participant and both their legal guardians. Consent procedures for minors emphasize developmentally appropriate communication and assessment of understanding.

Study status

Participant recruitment is ongoing since 2026-03-01. Recruitment is expected to be completed by October 2027. Data collection, including 12-month follow-up assessments for all participants, is anticipated to conclude by October 2028. Results are expected to be available for analysis and dissemination from 2029 onwards.

Patient and public involvement

Prior to protocol finalisation, focus groups were conducted with individuals with lived experience of eating disorders to inform the trial design. Participants highlighted the need for enhanced clarity and adequate advance notice in study procedures, which led to revision of participant and next-of-kin information materials to improve comprehensibility and support informed decision-making. Focus group data will not be published.

Randomization and allocation

Participants are randomized using a computer-generated block randomization sequence in a 1:1 ratio to either psilocybin treatment plus TAU or TAU alone. Randomization is stratified by age group (16–17 years and 18–35 years) to ensure balanced representation. Allocation is conducted by personnel independent of the research team. Due to the nature of the intervention and the pronounced subjective effects of psilocybin, blinding is not employed in this study.

Interventions

General analysis strategy

Study measures

Study measures are selected to comprehensively assess safety, clinical outcomes, psychological processes, subjective experience, and neurobiological correlates of change from baseline, across the acute, post-acute, and long-term follow-up phases of the trial. The timing of all assessments is summarized in the Schedule of Assessments (Fig 1).

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Fig 1. Schedule of assessments.

There is a minimum of 2 weeks from consent to randomization, time from screening to the first psilocybin dose must not exceed 8 weeks, regardless of washout status. Abbreviations: ECG, electrocardiogram; u-hCG, urine human chorionic gonadotropin; u-tox, urine toxicology screening; fMRI, functional magnetic resonance imaging; BDNF, brain-derived neurotrophic factor; BMI, body mass index; AE/SAE, adverse event/serious adverse event; ETS-5, Expectation of Treatment Scale [105]; RMQ, Readiness and Motivation Questionnaire [106]; GCMQ, General Change Mechanisms Questionnaire [107]; PHQ-9, Patient Health Questionnaire-9 [108]; GAD-7, Generalized Anxiety Disorder-7 [109]; EDE-Q, Eating Disorder Examination Questionnaire [110]; C-SSRS, Columbia-Suicide Severity Rating Scale [111]; BPRS + , Brief Psychiatric Rating Scale–Extended [112]; SWLS, Satisfaction with Life Scale [113]; PANAS, Positive and Negative Affect Schedule [114]; HILS, Harmony in Life Scale [115]; TIPI, Ten Item Personality Inventory [116]; HH, Honesty-Humility Scale [117]; 5D-ASC, Altered States of Consciousness Rating Scale [118]; MEQ-4, Mystical Experience Questionnaire [119]; MLE, Meaningful Life Experience Rating [120]; EGON-instrument, clinical assessment tool for evaluating body perception [121].

https://doi.org/10.1371/journal.pone.0352246.g001

Data management

All data are collected by GCP-trained study personnel and entered a secure electronic case report form system (REDCap) compliant with data protection regulations. Data are pseudonymized by a code list with access restricted only to authorized personnel delegated by the principal investigator. All data are stored and processed using secure institutional infrastructure at Lund university, Sweden. Anonymized participant data will be made available upon reasonable written request to the principal investigator, contingent on adherence to a conventional data-sharing agreement and compliance with all applicable ethical and regulatory requirements.

Statistical analysis

Analyses are primarily descriptive and hypothesis-generating, reflecting the pilot nature of the study. Safety outcomes are summarized using frequencies and proportions, with between-group comparisons performed using chi-square or Fisher’s exact tests as appropriate. Longitudinal clinical outcomes are analysed using mixed-effects models to account for repeated measures and individual variability. Time-to-event outcomes, including relapse, are analysed using survival analysis methods.

Neuroimaging analyses focus on within-subject changes from baseline and between-group contrasts at predefined time points. Associations between neuroimaging measures, clinical outcomes, and subjective experience variables are explored using correlational and regression-based approaches. Appropriate correction for multiple comparisons is applied, particularly for neuroimaging analyses. Missing data are handled using maximum likelihood estimation or multiple imputation, depending on the pattern and extent of missingness.

Sample size

No formal power calculation has been performed, as the study is designed as an early-phase trial focused on safety, feasibility, and estimation of effect sizes. The planned sample size of 40 participants is based on feasibility considerations and consistency with prior early-phase psychedelic studies in clinical populations to be able to detect adverse events. The six-month follow-up invites TAU participants for a switch to active treatment protocol, therefore leaving the active treatment arm without control until the 12-month follow-up and end of study.

Participant safety and monitoring

Participant safety is the primary focus of the psiAN trial and is ensured through structured medical and psychiatric screening, continuous monitoring during dosing, repeated short- and long-term follow-up assessments, and independent safety oversight. Attention is given to metabolic stability given the medical vulnerability associated with anorexia nervosa. Nutritional status is assessed at screening and baseline, and participants must meet predefined BMI of 16 and medical stability criteria prior to dosing. Preparation sessions include structured discussion of food intake, hydration, and individualized eating plans for the dosing day to minimize risk of hypoglycaemia. Blood glucose is measured at screening and monitored in accordance with protocol-defined procedures.

This approach is informed by prior psilocybin research in anorexia nervosa, in which an isolated case of transient hypoglycaemia was reported during dosing in a medically stable participant and resolved with oral intake and monitoring [53]. To mitigate similar risks, psiAN incorporates proactive nutritional planning, pre-dose fasting guidance tailored to medical status, real-time clinical monitoring, and availability of oral glucose and medical support during dosing sessions. Adverse events and serious adverse events are recorded continuously from first dosing through the 12-month follow-up and reported in accordance with regulatory requirements. Suicidality is systematically assessed at screening, prior to dosing, during integration, at the primary endpoint, and at all follow-ups. Participants demonstrating medical instability or acute psychiatric risk are withdrawn from dosing and referred for appropriate clinical care.

An independent Safety Review Committee evaluates accumulating safety data at predefined intervals. Recruitment begins with adults (≥18 years), and inclusion of adolescents aged 16–17 years proceeds only after formal safety review and approval, with enhanced monitoring and guardian involvement.

Participants may withdraw at any time, and investigators may discontinue participation if safety concerns arise.

Ethical considerations

This study has received approval from the Swedish Ethical Review Authority (Dnr 2025-05495-01) and the Swedish Medical Products Agency and is conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP), and the EU Clinical Trials Regulation (EU No. 536/2014). Given the vulnerability of the study population and the inclusion of a psychedelic intervention, extensive safeguards are implemented to minimize risk and ensure participant well-being.

In addition to the monitor, a Safety Review Committee is recruited to oversee trial conduct and review all potential serious adverse events, protocol adherence, and emerging safety signals. Interim safety reviews are conducted after predefined numbers of psilocybin administrations. Recruitment initially includes only participants aged 18 years and older. Inclusion of adolescents aged 16–17 years is initiated only after the Safety Review Committee has completed a formal evaluation of safety and tolerability data from the initial adult cohort and has approved progression to the adolescent phase.

Protocol amendments are managed in accordance with EU Clinical Trials Regulation 536/2014. Substantial amendments are submitted to and require approval by the competent authority via CTIS (Clinical Trials Information System) prior to implementation. Non-substantial amendments are documented in a note-to-file and submitted alongside the next substantial amendment or as part of annual reporting, as applicable. All approved amendments are communicated to the trial monitor and the full research team without delay.

The stepwise inclusion of minors reflects a balance between ethical caution and the need to generate clinically relevant evidence. The staged design ensures that exposure of adolescents to psilocybin occurs only after safety has been demonstrated in adults within the same protocol framework. Additional safeguards for minors include guardian involvement in the consent and treatment process and age- appropriate information.

Participants may withdraw from the study at any time without consequences for their standard treatment. Procedures are in place for rapid clinical intervention in the event of medical or sustained psychological deterioration. The ethical design of the psiAN study aims to balance the obligation to protect vulnerable individuals with the responsibility to generate evidence for populations with substantial unmet clinical need.

IMP management

The investigational medicinal product (IMP) is GMP-manufactured psilocybin produced by Filament Health (Vancouver, Canada) and supplied as encapsulated 25 mg oral doses with accompanying batch certification.

EU distribution and release are coordinated by CEFEA in Poland, and importation into Sweden is managed by Oriola in accordance with applicable regulatory requirements. Upon arrival, the IMP is received, stored, and dispensed by the Region Skåne Hospital Pharmacy.

Full traceability is maintained through documented receipt, storage, dispensing, reconciliation, and destruction procedures in accordance with the EU Clinical Trials Regulation and Swedish national regulations.

Dissemination

The findings of the psiAN study will be disseminated through publication in peer-reviewed scientific journals and presentation at national and international conferences in psychiatry, eating disorder research, and psychedelic science. Results will be reported regardless of outcome, in accordance with principles of transparency and responsible research conduct.

In addition to academic dissemination, study findings will be communicated to broader audiences through public lectures, open presentations, and engagement with professional and community organizations. Where appropriate, results may be shared through media channels to promote accurate and responsible public understanding of psychedelic research in eating disorders. Communication will be conducted in a balanced and evidence-based manner, emphasizing both potential benefits and limitations.

Study outcomes will also be shared with participating clinical services and summarized in accessible formats for participants and individuals with lived experience. Trial registration details and key study information will remain publicly available through relevant clinical trial registries in compliance with regulatory requirements (ClinicalTrials.gov Identifier: NCT07169747).

Data reporting will follow established guidelines for clinical trials to promote methodological transparency and facilitate replication. Any secondary analyses will be clearly identified as exploratory.