Psilocybin-Assisted suppoRtive psychoTherapy IN the treatment of prolonged Grief (PARTING) trial: protocol for an open-label pilot trial for cancer-related bereavement

Abstract

Introduction

Prolonged grief disorder (PGD) represents a substantial public health issue, especially in oncology settings where it affects up to 30% of bereaved carers. Current best-practice treatments are lengthy, and up to 50% of participants have persistent PGD. Building on encouraging recent research with psychedelic-assisted therapies, the Psilocybin-Assisted suppoRtive psychoTherapy IN the treatment of prolonged Grief (PARTING) trial is the first study to consider psilocybin-assisted psychotherapy as a potential treatment for prolonged grief.

Methods and analysis

PARTING is an open-label pilot trial of psilocybin-assisted psychotherapy for approximately 15 people with cancer-related PGD. It aims to investigate feasibility, safety, acceptability, participant experience and participant-reported therapeutic effects. Over a 5-week intervention period, participants will undergo three preparation sessions before receiving a psychoactive (25 mg) dose of psilocybin alongside non-directive supportive guidance, followed by four integration sessions. All sessions will be delivered by a psychologist and either a nurse or Indigenous Therapist. An artificial intelligence-assisted tool will be used to create an artwork of participants’ psychedelic experience.

Outcomes will be investigated over a 12-month follow-up period. Feasibility will be assessed through recruitment/retention rates and completion of follow-up assessments. Safety will be evaluated via adverse events over 12 months and the comparison of physiological measures (vital signs, biochemistry, haematology, ECG) recorded during screening and 1 day after the psilocybin dose. Qualitative thematic analysis of semistructured interviews with participants and trial therapists will assess acceptability and the therapeutic potential of the treatment. Diagnostic clinical interviews for PGD and quantitative participant-reported measures of therapeutic effects are also being collected. Participant-reported measures include grief severity, depression, anxiety, grief avoidance, psychological flexibility, connectedness, and quality of life.

Ethics and dissemination

Ethics approval has been obtained from QIMR Berghofer Medical Research Institute Human Research Ethics Committee (P3801). Dissemination of results will occur via conference presentations, peer-reviewed publications and media.

Trial registration number

Australian New Zealand Clinical Trials Registry (ACTRN12623000827639).

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This novel psychedelic-assisted psychotherapy intervention for prolonged grief disorder (PGD) includes three preparation sessions, one psilocybin dosing session and four integration sessions over 5 weeks.

• Participants’ safety and therapeutic outcomes will be followed up for 12 months using mixed methods.

• Qualitative semistructured evaluation interviews will collect rich participant-centred data regarding safety, acceptability and potential of the treatment.

• A validated questionnaire (PG-13-Revised), along with a semistructured clinical interview, will be used to diagnose and track symptoms, in line with the Diagnostic and Statistical Manual of Mental Disorders 5 for PGD.

• A limited sample size and single-arm uncontrolled design preclude statistical investigation of efficacy.

Introduction

Carers of people with chronic diseases such as cancer are vulnerable to a range of physical and psychological harms, especially when experiencing bereavement.^{1 2} While grief is a normal reaction to loss, for some carers their grief develops into a chronic and debilitating reaction termed prolonged grief disorder (PGD). Now an official diagnosis in both the International Classification of Diseases 11th Revision and the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM5-TR),³ PGD is characterised by unrelenting and overwhelming yearning for the deceased person and/or preoccupation with thoughts and memories of the deceased, causing clinically significant impairment in social, occupational or other important areas of functioning. The DSM5-TR diagnostic criteria also require at least three of the following eight symptoms nearly every day: feeling as though a part of oneself has died; a marked sense of disbelief about the death; avoidance of reminders that the person has died; intense emotional pain related to the death; difficulty with reintegration into life; emotional numbness; feeling that life is meaningless as a result of the death and intense loneliness as a result of death.⁴ For a diagnosis, these reactions must exceed cultural and religious norms and be ongoing for at least 12 months.⁴ In the general population, prevalence studies suggest 3–10% of bereaved persons are at risk of developing PGD,^{5 6} but studies with bereaved cancer carers have found rates of up to 30%.^{7 8} PGD is of clinical interest as it is associated with increased risk for a number of negative outcomes, including suicidality, mortality and other negative physical and psychological outcomes.⁹,¹¹ These impairments also represent a significant public health issue, affecting productivity and costs to public health systems.¹²,¹⁴

Presently, the most commonly researched and effective treatments for PGD centre around grief-focused cognitive-behavioural techniques, with several trials demonstrating their efficacy.¹⁵,¹⁹ Such treatments are aligned with the predominant theoretical model of grief, Stroebe and Schut’s dual process model,^{20 21} in that they focus treatment on the two kinds of stressors bereaved individuals are thought to face under the model: loss-oriented stressors (eg, addressing rather than avoiding painful thoughts and emotions relating to the loss), and in the second half of the intervention, restoration-oriented stressors (eg, rebuilding a meaningful life and identity post loss). Grief-focused therapy aims to facilitate processing of the reality of the loss while encouraging a continuing bond with the deceased, integrated within a process of meaning-making and rebuilding of identity post loss^{22 23} that targets specific mechanisms outlined in theoretical models of PGD.^{24 25} However, the need for research into novel approaches is highlighted by meta-analyses^{16 17} identifying that up to 50% of participants continue to experience clinically significant symptoms following treatment across several trials.²⁶,²⁸ Additionally, there are currently no known effective pharmacological approaches to treat PGD. While antidepressants or anxiolytics may treat symptoms of comorbid depression or anxiety, they have limited effectiveness in treating grief-specific symptoms.^{19 29}

Psychedelics have been used for healing and ceremonial practices by Indigenous cultures for millennia.³⁰,³² Recently, a pilot trial demonstrated the potential for the psychedelic ayahuasca, administered in conjunction with restorative retelling techniques, to be an effective treatment for PGD,³³ while another study of almost 9000 ayahuasca drinkers in more than 50 countries identified a ‘new understanding or acceptance of death and dying’ to be one of the most frequently reported personal insights, by 63% of respondents.³⁴ In addition, six landmark double-blinded randomised controlled trials have shown one or two doses of another serotonergic psychedelic, psilocybin, administered alongside supportive psychotherapy, produce profound response and remission rates in people with treatment-resistant depression or clinical anxiety,³⁵,⁴¹ including in those with cancer.⁴²,⁴⁶

With this growing evidence, there is a call for research to examine the potential use of psilocybin and other psychedelic-assisted psychotherapies in treating PGD.^{47 48} Psilocybin activates the serotonin 2a receptors, and in psychoactive doses causes a range of somatic, perceptual and cognitive effects⁴⁹ and can elicit profound altered states of consciousness, including highly salient spiritual or ‘mystical’ experiences.^{50 51} Such experiences are characterised by reports of a sense of unity, awe, positive mood, as well as ineffability, transcendence of time and space, and a noetic quality (sense of encountering ultimate reality).^{52 53} In the cancer setting, mystical psychedelic experiences have been linked to cognitive and emotional reframing of cancer, dying and death; enhanced appreciation of life; viewing death as a transition rather than an end; a deeper sense of meaning and purpose; and greater acceptance and peace with death.^{4446 54},⁵⁶ These experiences and insights, interpreted and consolidated through post-dosing integration, may be one mechanism that underlies the purported therapeutic effects of psilocybin-assisted psychotherapy by providing a unique perspective on life, eliciting a reframing of maladaptive schemas.^{40 57 58}

Other potential mechanisms of psilocybin for PGD include its capacity to facilitate perceived new interactions with the deceased person, often experienced as vivid visualisations that are emotionally meaningful and may symbolise reconciliation, closure or a sense of continued connection. Research has demonstrated that exposure components of grief-focused cognitive behavioural therapies are specifically associated with improved PGD symptoms through promotion of loss-oriented coping.^{2547 59},⁶² Thus, psilocybin may inhibit grief avoidance or other psychological defence mechanisms through exposure experiences.

Psilocybin also reduces activity in the brain’s default mode network.⁶³ This is where we construct our sense of self. Through the process of integration that follows psilocybin dosing, it may be possible to reframe personal narratives and rebuild patient’s identity about oneself in relation to others and the world, which goes beyond being dominated by the deceased. This may allow for the adaptive shift to restoration-oriented coping.

Psilocybin may also increase psychological⁶⁴,⁶⁷ and cognitive⁶⁸ flexibility, which may assist individuals in finding new ways to live with their loss, while deficits in psychological flexibility may impair an individual’s ability to oscillate between loss-oriented and restoration-oriented stressors implicated in the dual process model.²⁴⁶⁹,⁷⁵

Psychological flexibility is proposed to overlap with Watts et al’s⁷⁶ conceptualisation of connectedness to the self, others^{65 77} and the natural world.^{78 79} Connectedness across these inter-related domains is positively associated with serotonergic psychedelic use⁷⁶⁸⁰,⁸⁸ and a broad range of mental and physical well-being measures.⁸⁹,⁹⁴ Ehrenkranz et al⁴⁸ suggest enhanced connectedness may be a mediator through which psychedelics address feelings of yearning, a key symptom of PGD.

PGD is distinct from other disorders in which psilocybin-assisted psychotherapy has been studied.⁹⁵,⁹⁷ In Australia, the Therapeutic Goods Administration rescheduled psilocybin in 2023 to allow use for treatment-resistant depression by licensed prescribers; however, it remains a prohibited substance for all other indications unless used in a clinical trial. Psilocybin-Assisted suppoRtive psychoTherapy IN the treatment of prolonged Grief (PARTING) is a world-first pilot trial being conducted in Australia to examine psilocybin-assisted psychotherapy as a potential treatment of PGD for people experiencing cancer-related bereavement. It aims to determine if psilocybin-assisted psychotherapy is feasible, acceptable and safe in this population. This clinical trial will also establish an initial impression of its therapeutic potential.

Methods and analysis

Overview of the PARTING trial design

The PARTING trial is a single-arm (open-label) feasibility trial of a psilocybin-assisted psychotherapy being conducted at the QIMR Berghofer Medical Research Institute in Brisbane, Australia. It began recruitment on 2 May 2024, with a target of approximately 15 participants. Recruitment will conclude once this target is reached. Bereaved people who lost someone to cancer who meet the DSM5-TR criteria for PGD will be invited to take part in the trial after undergoing screening against the general medical and psychiatric eligibility criteria (see figure 1). The intervention will include three psychotherapy sessions in preparation for one psilocybin dosing session and then four post-experience psychotherapy integration sessions (see figure 2). An Australian Health Practitioner Regulation Agency Registered Psychologist with the Psychology Board and a co-therapist (Nurse or Indigenous Therapist) will be present at all sessions. Validated questionnaires and a semistructured diagnostic clinical interview based on this measure administered at baseline and follow-ups (6 weeks, 6 months and 12 months) post baseline will measure prolonged grief symptoms; that is, the proposed outcome for the future full-scale trial. 1 week after the participants’ final intervention session and at the 6- and 12-month follow-ups, we will conduct semistructured evaluation interviews to (1) gain insight into their expectations, observations and thoughts on the therapists and therapy content and structure, including aspects that were most helpful or that could be changed; and (2) understand their psychedelic experience, adverse events, additional treatments used and potential therapeutic effects. We postulate that the treatment will be well-tolerated and accepted, and that grief symptoms will be substantially reduced. The findings of this pilot study are expected to support the adaptation of minor changes to the intervention, sequencing/dosing schedule, delivery and/or duration to enhance the feasibility of future clinical trials.

Figure 1. Key inclusion and exclusion criteria for participation in the PARTING trial.

Figure 2. Psilocybin-Assisted supportive psychoTherapy IN the treatment of prolonged Grief trial schedule of activities. PGD, prolonged grief disorder.

Sample size

While there is no set sample size for feasibility studies,^{98 99} some authors have suggested approximately 12 participants may be appropriate.¹⁰⁰ Based on this and recent experience of our team,¹⁰¹ we plan to enrol approximately 15 participants in the PARTING trial. This sample is sufficient to demonstrate safety, feasibility and acceptability and provide an initial impression of the therapeutic potential of the intervention.

Recruitment

Recruitment will be promoted through a national media campaign, including television, radio and newspaper releases, conducted by the QIMR Berghofer Medical Research Institute. Additionally, the trial team, their affiliate institutes and collaborators, including Compassionate Friends, one of the largest mutual support self-help bereavement organisations in the world, will promote the study through their networks, including social media and e-newsletters. All promotion directs people to the PARTING trial website where they can register their contact details for a trial staff member to contact them if they are interested in further information.

Participant eligibility, screening and consent

Participants will be screened according to the inclusion and exclusion criteria outlined in figure 1. This will involve the following steps.

Prescreening

Potential participants will complete initial online screening questions that assess basic eligibility; ≥18 years old, relative or friend of a person who had cancer and died more than 12 months ago, experiencing intense overwhelming grief, not pregnant, able to complete eight therapy sessions over 5 weeks, able to travel to Brisbane, Australia, at their own expense for screening and week 1 of the intervention. People meeting these basic eligibility criteria will then be sent the Participant Information and Consent Form (PICF) for screening and baseline assessment (see online supplemental material).

Checkpoint 1

Trial staff will contact potential participants by telephone to explain the study in detail, answer any questions and ask medical history prescreening questions about cardiovascular conditions, current medications and personal and family history of psychiatric conditions. If they have a good command of the English language, are still interested in participating and not deemed ineligible at this first checkpoint, informed consent for screening and baseline assessment will be obtained via signing a PICF before participants commence formal screening. The participant will receive a copy of the signed and dated PICF and a copy of any amendments to the written information.

Screening

Checkpoint 2

Participants will complete electronic screening questionnaires about their demographic characteristics, prolonged grief symptoms, prior treatments, psychedelic use, adverse events, traumatic events, drug and alcohol use, concurrent medications, therapy and support. Questionnaires are expected to take about 20 min to complete. They have predetermined thresholds to meet eligibility criteria at Checkpoint 2. If they are ineligible and score 30 or over on the PG-13-R, indicating grief symptoms suggestive of requiring clinical care, they will receive a call from our trial staff and be referred to a psychologist or psychiatrist as appropriate.

Checkpoint 3

If participants passed the previous checkpoint, they will complete ‘In-person screening session 1’. This session will take about 60 min. The trial nurse will measure their height, weight, heart rate and blood pressure, perform an ECG and collect a blood sample to assess renal, hepatic and thyroid function, as well as the full blood count. A trial psychologist will conduct a clinical interview to understand and assess recency of trauma history for safe exposure to psilocybin and the psychological eligibility criteria. At Checkpoint 3, the Trial Psychiatrist will discuss results in case review meetings with the Nurse, Psychologist and Coordinating Principal Investigator, and then decide regarding eligibility to progress.

Checkpoint 4

If participants passed the previous checkpoint, they will complete ‘In-person screening session 2’. This session will take about 60 min. A Trial Psychologist will conduct a diagnostic clinical interview for PGD. At Checkpoint 4, during a case review meeting with the Nurse, Psychologist and Coordinating Principal Investigator, the Trial Psychiatrist will decide if participants are excluded or eligible to progress.

If participants are still deemed eligible, the trial staff will contact the participant’s designated support person to ensure they are aware and supportive of the participant taking part in the trial and that they could be available on suggested dates to collect the participant after the dosing session and stay with them overnight. They will be informed about how to best support the participant after the dosing session, should they be enrolled in the trial.

Participants who do not complete all screening activities or who are deemed ineligible from the in-person screening will not be enrolled and a full explanation will be provided to these interested participants. Additionally, if they have a medically actionable finding their general practitioner will be contacted with results attached and if they scored in the clinical ranges for any mental health disorders, they will receive a call from our trial psychologist to assess current care and coordinate referral to a psychologist or psychiatrist via their general practitioner if required.

Checkpoint 5

Finally, the Trial Psychiatrist will contact the participant’s general practitioner (and other health professionals if necessary) and verify the participant’s medical history and current medications. If the participant is currently taking antidepressant medication and indicates in the consent form that they are willing to stop this to enable them to take part in the trial, their prescribing doctor will be contacted by the Trial Psychiatrist to discuss this possibility. If they approve, the Trial Psychiatrist and prescribing doctor will agree on a schedule for stopping their antidepressant medication and a shared duty of care for titrating off the medication will be provided. At Checkpoint 5, when the participant’s support person is confirmed and medical eligibility is verified by the Trial Psychiatrist, the Trial Psychiatrist will sign off on the participant being enrolled into the trial. The participant will be sent a subsequent PICF with the full trial details to read.

The participant’s baseline (enrolment) questionnaire will be sent 1 week before their psilocybin-assisted psychotherapy programme is scheduled to start and must be completed before the therapy commences.

Immediately before the enrolled participant’s first intervention session commences, the participant will meet the Trial Psychiatrist, who will again explain the therapy and assessments, answer any questions and discuss if there have been any changes to the participants’ medical history since screening. If the participant is still eligible and agrees to proceed, both the participant and Trial Psychiatrist will be required to sign the subsequent consent form for enrolment into the trial.

Psilocybin-assisted psychotherapy programme

Our manualised psilocybin-assisted psychotherapy programme consists of three phases delivered over eight sessions across a 5-week period: (A) preparation (sessions 1–3); (B) psilocybin dosing (session 4) and (C) integration (sessions 5–8).

During the dosing session, participants will receive a 25 mg dose of psilocybin. This dose was identified in prior studies as providing therapeutic effects with limited and manageable undesirable side effects.⁵⁶¹⁰²,¹⁰⁴

Participants will see the same trial therapist dyad throughout the intervention. The dyad will include a Registered Psychologist and either a Registered Nurse with training in bereavement counselling or a community-endorsed Indigenous Therapist with training in culturally informed trauma integration healing.¹⁰⁵ All therapists will receive additional specific training in psychedelic-assisted therapy, diagnosis of prolonged grief and grief-focused cognitive behavioural therapy, delivered by the trial’s chief investigators who are experienced practitioners in these fields. The Indigenous Therapist will facilitate cultural safety of the trial procedures and cultural responsiveness to the participant experience.¹⁰⁶ Irrespective of cultural heritage, participants will be asked if they prefer a Registered Nurse or Indigenous Therapist as their co-therapist and given the option if schedulable. As per current standard practice which aims to provide a sense of safety, therapist pairing will be with one male and one female therapist or two females.

The Trial Psychiatrist will oversee baseline medical assessments on dose day (outlined below). They will also be present on-site during the duration of the psilocybin dosing session to support the management of adverse events if required.

The overall intervention is modelled after psychedelic ‘peak’ therapy^{50 107} and other recent protocols.⁶⁵¹⁰⁸,¹¹¹ Session checklists will be used to promote adherence to the protocol, and intervention sessions will be video recorded to assess treatment fidelity.

Set and setting

Psychological (‘set’) and environmental factors (‘setting’) fundamentally influence the quality and nature of psychedelic experiences.¹¹²,¹¹⁴ Therapeutic alliance is a vital component of any psychotherapeutic process¹¹⁵; in psychedelic-assisted psychotherapy, this is even more important due to participants’ unique vulnerability and suggestibility under the influence of psychedelics.^{116 117} We include three preparatory sessions designed to enhance ‘set’ by building rapport and trust between participants and therapists^{108 109} and promoting feelings of safety and preparedness.^{116 118} The ‘setting’ of the dosing sessions is a comfortable, private, living room-like clinic room with a comfortable bed. All in-person screening and preparatory sessions will occur in the clinic room to promote familiarity.¹¹⁸

Preparation

The three psychotherapy sessions in preparation for dose day will be 60–120 min duration, in-person and provided three-to-six working days before psilocybin dosing. During these sessions, the therapist dyad will build therapeutic alliance with participants and prepare participants for the dosing session and the broader programme of psychotherapy.

In the first session, therapists will summarise the grief story as captured in screening to ensure understanding and determine if anything new has surfaced. The session will also cover expectations for and likely experiences during the dosing session, and the participant will be asked about preferred type of music and discuss options that are available for the dosing session (from carefully curated preselected playlists). They will be oriented to the headphones, eyeshades and bed within the clinic room. Participants will be provided with the option to work with clay during the discussion to help calm and ground participants in the present moment and enable access to and expression of emotions and experiences that can be difficult to articulate verbally.^{119 120} This moulded clay will be kept on hand for future sessions.

The second session will focus on setting intentions and managing expectations for the dosing session and introduce relaxation and meditation exercises that may assist in dealing with any challenging experiences during the dosing session.¹¹⁸ Participants will be oriented to the optional use of therapeutic touch during the dosing session, for which written consent is required. Therapeutic touch consists of a gentle and reassuring touch through holding the participant’s hand, placing one’s hand on the participant’s shoulder or placing both hands on the participant’s feet in an act of grounding.¹¹⁸ Therapists will allow the participant to make an informed decision whether they consent to touch during the psilocybin session or not, and can rescind consent at any time. Noting the uniquely vulnerable and highly suggestive state of participants during psilocybin sessions, consent can only be given before dosing.^{121 122} Participants must agree that during the dosing session they will remain in the clinic room, refrain from using a phone and commit to not harming themselves or staff.

The final preparatory session will revise the main points from the prior sessions, including intentions, expectations and procedures for dose day. Participants will also complete an assessment of all concurrent medications/therapy, COVID screening questions and the Mind(SET) Questionnaire which assesses readiness to undergo a psychedelic experience.¹¹⁴

Dose day

On dose day, participants will arrive approximately 1 hour before the dosing session, having eaten a light breakfast. They will undergo baseline assessments, including COVID test, blood pressure and heart rate assessment, urine drug screen, alcohol breath test and, for people of childbearing potential, urine pregnancy test. The Trial Psychiatrist will review and confirm post-screening adverse events (if any), bloodwork, concurrent medications/therapy, Mind(SET) and other eligibility criteria. Procedures, intentions and expectations for the psilocybin experience will be briefly discussed, and participants may choose to have their clay mould in view during the session. The Trial Psychiatrist will then dispense a 25 mg dose of psilocybin at approximately 09:00 that will be immediately administered by the Trial Nurse. Participants will be encouraged to lie on the bed wearing eye shades and to ‘trust, let go and be open’.¹⁰⁷ A preselected music playlist, designed to mirror the temporal-intensity sequence of the psilocybin experience and provide emotional support and guidance, will be played simultaneously through headphones and speakers, with options for the patients to skip tracks or stop the music.¹²³,¹²⁵

Therapists will take a non-interventional approach providing mindful, non-directive guidance and support as required, including attending to food, water and bathroom needs. If the participant has not spoken by 1 hour after administration, the therapists will verbally check-in.

Where appropriate, and with prior informed consent, therapeutic touch may be used to assist participants with challenging experiences that may arise. In case of severe anxiety or agitation not adequately resolved through supportive care and/or relaxation or meditation exercises taught during preparation, a ‘rescue’ medication (benzodiazepine) may be administered by the Trial Psychiatrist.

Heart rate and blood pressure will be assessed at approximately half-hourly intervals in the first two hours of the dosing session and every hour thereafter. If established thresholds (≥160 systolic blood pressure, ≥110 diastolic blood pressure, ≥110 pulse rate) are exceeded, measurements will be taken every 5 min until the values stabilise below threshold levels or until they have been decreasing for 15 min. Trial therapists will monitor participants’ psychiatric state throughout the dosing session with periodic gentle check-ins to gauge how the participant is feeling without interrupting the flow of their experience. They will also record observations about participants’ body language, facial expressions, vocalisations, signs of distress, discomfort or agitation, as well as positive engagement, relaxation, or moments of insight.

The dosing session (including predosing discussion) is expected to take approximately 8 hours, with psilocybin effects peaking in intensity after 1–2 hours and lasting approximately 5–6 hours.¹²⁶ Following the session, a designated ‘support person’ of the participant’s choosing will meet them and escort them home.

Integration

Four 60–90 min integration sessions will occur, beginning the day after dose day and subsequently at 1, 2 and 4 weeks after dose day. These psychotherapy sessions are designed to help participants make sense of their psilocybin experience, including any memories of their grief or loss, and help integrate these experiences into their lives (eg, by reframing maladaptive grief-related appraisals or taking steps towards lasting adaptive behaviour change).

The first session will be held in-person and focus on discussing the participant’s psilocybin experience, thoughts and feelings arising from it, and perceived psychological and emotional effects and insights. The therapist dyad will help participants process any residual psychological distress they may be experiencing and record any adverse events. The therapist dyad will be supportive, validate the participant’s experience, facilitate emotional processing, allow exploration of content and consolidate any therapeutic insights gained. Following the session’s conclusion, participants will complete several online questionnaires assessing grief and other outcomes and aspects of their experience (figure 3).

Figure 3. PARTING trial outcome measures, data collection tools and assessment timing.

Psychedelic sessions often represent a significant emotional journey. Artwork may offer a unique way to capture and explore the therapeutic experience, allowing the participant to reflect on their growth and journey over time.¹²⁷ During the first integration session, participants will be asked if they would like to have an artwork generated for them via Midjourney (an artificial assistant-assisted image generation tool). If they consent to this, a selection of images will be derived using salient words describing their feelings, thoughts and experiences in the dosing session and presented to them at their next session. They will have the opportunity to discuss if and how any of these artworks feel aligned with or representative of their experience of dose day. Through an iterative process over the integration sessions, they will be able to make suggestions for changes to the artwork (if required) and then be provided with the final work to keep.

Integration sessions 2–4 will be held via videoconferencing or in-person. During these psychotherapy sessions, participants will be invited to continue to discuss their psilocybin experience, and trial therapists will use clinical interview techniques to determine whether there is still unresolved grief. If there are unresolved grief issues, trial therapists will provide psychoeducation about specific cognitive restructuring strategies to reframe common maladaptive grief-related appraisals (eg, hopelessness and guilt). If grief issues are resolved, trial therapists and participants will plan integration activities (eg, changes participants may make to their lives following the experience).

In the final session, trial therapists will devise and communicate appropriate referral pathways for post-study care.

Outcomes

A mixed-methods approach is being employed to investigate the potential of this psilocybin-assisted psychotherapy intervention as a treatment for PGD in people with cancer-related loss. Figure 3 summarises outcome measures and when they are assessed during the trial.

Specific endpoints

Measures of feasibility

Feasibility will be assessed with reference to (1) recruitment percentage, (2) retention to intervention percentage and (3) attrition percentage to follow-up assessments (surveys and clinical interviews).

Intervention acceptability and experience

Participant semistructured interviews will be conducted at 5 weeks post-dose day, and trial therapists will complete an evaluation interview at the study completion. Participants will also complete questionnaires about the intensity of their acute psilocybin experience (Mystical Experiences Questionnaire, Revised (MEQ-30)^{51 128}; Psilocybin Experience Questions (PEQ))⁵¹ 1 day after their dosing session.

Measures of psilocybin safety

Safety will be assessed via adverse event reporting and a pre-post psilocybin comparison of vital signs, biochemistry and haematology profile, and ECG findings measured 1 day after psilocybin dosing, compared with baseline measures. Adverse events are assessed through spontaneous self-report (participants are provided a ‘memory aid’ card to educate them about adverse events and how to report them) and observation by the trial staff during screening, intervention sessions and in interviews at 5, 6 and 12 weeks, and 6 and 12 months post-dose day.

Therapeutic potential

Semistructured evaluation interviews with participants at 5 weeks and 6 and 12 months post-dose day will provide a qualitative initial impression of therapeutic potential. As a secondary analysis of the potential for therapeutic benefit, we will also explore changes in pre-post quantitative measures of grief (Prolonged Grief Disorder Scale, Revised³ and diagnostic semistructured clinical interview for PGD), depression and anxiety symptoms (Depression, Anxiety and Stress Scale (DASS-21)),¹²⁹ well-being (Assessment of Quality of Life Scale, 6-Dimensions (AQoL-6D)),¹³⁰ connectedness (Watts’ Connectedness Scale (WCS)⁷⁶ and Nature Relatedness Scale, Short Form Version (NR-6)),⁷⁸ psychological flexibility (Comprehensive assessment of Acceptance and Commitment Therapy processes (CompACT))¹³¹ and grief-related avoidance (the avoidance subscale of the Impact of Event Scale—Revised (IES-R)).^{132 133}

Analysis

Quantitative analysis of feasibility

Descriptive statistics assessing feasibility will include (1) recruitment per cent among those who registered interest (enrolled/registered and prescreened) and the recruitment per cent among those who signed the screening PICF (enrolled/determined ineligible during screening+eligible); (2) intervention retention per cent (percentage of people who proceeded to dosing and of those who were dosed the number of post-dosing sessions completed) and (3) attrition per cent to five follow-up questionnaires at 1 day and 6 and 12 weeks and 6 and 12 months post-dose day (questionnaires not completed/active participants).

Qualitative analyses of acceptability and therapeutic potential

Transcripts of the semistructured evaluation interviews will be coded and analysed using the inductive, comparative and cyclic thematic analysis procedure^{134 135} to understand participants’ and trial therapists’ experiences of the acceptability and therapeutic potential of the treatment. The qualitative research approach and reporting will be guided by the Consolidated criteria for Reporting Qualitative research,¹³⁶ while an inter-rater reliability procedure¹³⁷ will proceed, with trial investigators reading the data set and its analysis and discussing the findings with the research team to promote reliability and rigour in the analysis.

Quantitative analyses of participants’ experience and therapeutic potential

Descriptive statistics (n,%; median, range) will be used to summarise questionnaire item results about participant expectations (Mind(SET)) and mystical experience, meaning and challenge experienced in relation to taking psilocybin (MEQ-30; PEQ).

Summary statistics derived from raw scores will be used to summarise quantitative measures of therapeutic potential (PG-13-R, DASS-21, AQoL-6D, WCS, NR-6, CompACT, IES-R) over time. These will be presented numerically and graphically. Given the lack of statistical power in our sample (n≈15), we will not use tests of statistical significance. A priori minimal important differences of 0.5 SD will be considered clinically meaningful changes between baseline and follow-up timepoints.^{138 139} The number of participants who have a clinical diagnosis of PGD based on the clinical interview will also be reported at each timepoint.

Significance

PGD is a substantial public health issue in the oncology setting, and current treatments have limited effectiveness and adherence.^{16 17} There is a pressing need to evaluate new strategies to alleviate the psychological suffering of bereavement, to place the cycle of life in a context that makes sense. It is time to take psychedelic treatments in psychiatry and oncology seriously.¹⁴⁰ The PARTING trial is required to assess feasibility, tolerability and initial impression of therapeutic effect in the setting of this distinct disorder. This world’s first trial adds a promising new modality to address the therapeutic nihilism and sense that nothing can be done to help.

Ethics and dissemination

Ethics approval was granted by the QIMR Berghofer Medical Research Institute Human Research Ethics Committee (P3801). The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12623000827639) and notified to the Therapeutic Goods Administration of Australia. Study outcomes will be disseminated via conference presentations, peer-reviewed journal articles and relevant media networks.

Data availability statement

No data are available.