The CAnadian Network for Psychedelic-Assisted Cancer Therapy (CAN-PACT): A Multi-Phase Program Overview

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This protocol outlines an ambitious and timely initiative to integrate Psychedelic-Assisted Therapy (PAT) into Canadian oncology care, addressing the severe, often refractory, demoralization experienced by patients with advanced cancer. The network approach (CAN-PACT) is commendable, correctly identifying the systemic challenges of lack of infrastructure, training, and evidence outside of specific academic centers. However, for a document presented as a foundational research protocol, the central objectives, particularly the planned multi-site Randomized Controlled Trial (RCT), are described with some insufficient methodological detail. The level of dependency on future steps (Objectives 2 and 4) makes the definitive efficacy trial (Objective 5) an ill-defined concept within this current manuscript.

The manuscript correctly highlights that previous trials suffer from small, homogeneous samples and lack of generalizability to real-world palliative populations. The solution proposed is a multi-site RCT nested within the Canadian Cancer Trials Group (CCTG) network, using publicly funded clinicians as therapists. This is a critical pragmatic element, yet the core design remains undefined, stating key parameters are "subject to modification" based on the feasibility pilot (Objective 4) and the priority setting process (Objective 2). Presenting a multi-site Phase III equivalent trial as a core objective without defining its primary endpoint, blinding procedures, or definitive sample size based on an assumed effect size renders this section largely programmatic rather than scientific. Question: What is the minimum effect size (e.g., on the Demoralization Scale) that the authors will deem clinically meaningful and use to power the eventual RCT? Given the unmistakable psychoactive effects of psilocybin, what specific, detailed procedures will be implemented to address the significant challenge of maintaining masking and mitigating expectancy/placebo effects, which is a known confounding factor in PAT trials? Will this involve a truly active comparator or simply a low-dose, potentially sub-perceptual, psilocybin control?

PAT requires a defined psychotherapeutic model (preparation, dosing, integration) to isolate the drug-specific efficacy. The manuscript is vague on the therapy component. While it mentions the pilot test (Objective 4) will involve a 25mg psilocybin session in conjunction with Mindfulness-Based Cancer Recovery (MBCR), it is unclear if this specific combination (psilocybin + MBCR) is the definitive intervention for the subsequent multisite RCT. The lack of a standardized, replicable manual for the psychotherapy is a major threat to the internal validity of the definitive trial. The description of training for clinicians as "hands-on PAT delivery training through videos, observation and personal experience" is an insufficient standard for a rigorous, high-impact RCT and raises concerns about fidelity. If MBCR is the chosen therapeutic adjunct, please provide a justification beyond "shared mechanisms of action". How will the authors ensure that the effects observed are due to the PAT (drug plus therapy) and not solely to the established efficacy of MBCR as a standalone intervention for cancer distress?   The protocol mentions extensive exploratory analyses, including inflammatory and gut microbiome biomarkers, alongside wearable device data, to elucidate mechanisms of action. While translational science is valuable, the inclusion of "biomarker collection" and "wearable device data" appears to add substantial complexity, cost, and patient burden to a trial whose primary goal is to assess a psychological intervention (PAT for Demoralization Syndrome) in a vulnerable, real-world palliative care setting. This risks mission creep. Please justify the integration of gut microbiome and inflammatory marker collection specifically within the pragmatic trial setting. Will the funding and logistical capacity be clearly ring-fenced to prevent these complex, exploratory analyses from delaying or compromising the successful execution of the primary, psychosocial endpoint data collection across the CCTG network?

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript reads less like a research protocol and more like a hybrid between a grant application, a policy white paper, and an advocacy document. In fact, while a protocol article should describe the rationale and methods for a planned study, this manuscript expands far beyond that purpose.

Below are some pints that need to be considered by the authors before the paper is ready to be published:

1. The Introduction is disproportionately long and unfocused. I suggest to substantially shorten and refocus the Introduction, if the authors aimed at presenting a protocol rather than narrative review or administration project.

2. If this should be considered as a protocol, the manuscript should face the requirements of so. Therefore, although results are not expected in a protocol, the manuscript still lacks the core methodological elements that normally replace results: clearly defined primary and secondary outcomes, finalized inclusion/exclusion criteria, etc. Instead, many sections presented in the methodology are relevant for project administration but not for a protocol intended for scientific readership.

3. The Conclusions are written in a way that implies outcomes or impact that have not yet been studied.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors' considerations have been reviewed. I recommend the publication of the article.

Reviewer 2 Report

Comments and Suggestions for Authors

the Authors have now improved the paper by providing significant changes that make the paper more easy to read and understand