Development of an Australian Clinical Practice Guideline on methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy for Post-traumatic Stress Disorder

Development of an Australian Clinical Practice Guideline on methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy for Post-traumatic Stress Disorder | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Development of an Australian Clinical Practice Guideline on methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy for Post-traumatic Stress Disorder Alene Sze Jing Yong , Sue E Brennan , Suzie Bratuskins , Aimée Freeburn , Gillinder Bedi , Rimona Burke , Terry Haines , Mary Hollick , Kimberley Ann Jones , Andrew J Lawrence , Yong Yi Lee , Alexander C McFarlane , Stephen Parker , Nicholas Procter , Liam Spicer , Andrew A. Somogyi , Simon Stafrace , Stacey Watts , Clare Walton , Kay Wilson , J Simon Bell doi: https://doi.org/10.1101/2025.02.18.25322184 Alene Sze Jing Yong 1 Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University , Parkville, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sue E Brennan 2 School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University , Melbourne, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Suzie Bratuskins 3 Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Aimée Freeburn 3 Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gillinder Bedi 4 Centre for Youth Mental Health, The University of Melbourne, and Orygen , Melbourne, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rimona Burke 5 Paddington Family Practice , Paddington, NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Terry Haines 6 School of Primary and Allied Health Care, Monash University , Melbourne, Victoria, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mary Hollick 7 Grampians Interim Regional Body, Mental Health and Wellbeing Division Department , VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kimberley Ann Jones 8 Indigenous Health Equity Unit, Onemda, Melbourne School of Population and Global Health, The University of Melbourne , Melbourne, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew J Lawrence 9 The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yong Yi Lee 10 Health Economics Group, School of Public Health and Preventive Medicine, Monash University , Melbourne, Australia 11 School of Public Health, The University of Queensland , Herston, QLD, Australia 12 Queensland Centre for Mental Health Research , Brisbane, QLD, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alexander C McFarlane 13 The University of Adelaide , Adelaide, SA, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stephen Parker 14 Faculty of Medicine, The University of Queensland , Brisbane, QLD, Australia 15 Metro North Mental Health, Royal Brisbane and Women’s Hospital , Herston, QLD, Australia 16 Faculty of Medicine, Griffith University , Brisbane, QLD, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nicholas Procter 17 Clinical and Health Sciences, The University of South Australia , Adelaide, South Australia , Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Liam Spicer 18 The Cairnmillar Institute , Melbourne, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew A. Somogyi 19 Faculty of Health and Medical Sciences, The University of Adelaide , Adelaide, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Simon Stafrace 20 Alfred Mental and Addiction Health, Alfred Health , Melbourne, Victoria, Australia 21 Faculty of Medicine, Nursing and Health Sciences, Monash University , Melbourne, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stacey Watts 22 Faculty of Education, Monash University , Melbourne, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Clare Walton 23 The University of Melbourne , Melbourne, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kay Wilson 24 Melbourne Law School, The University of Melbourne , Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site J Simon Bell 1 Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University , Parkville, VIC, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: simon.bell2{at}monash.edu Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Introduction Despite recent clinical and research interest, medical use of psychedelics has not been legalised in most jurisdictions. The Australian Therapeutic Goods Administration rescheduled methylenedioxymethamphetamine (MDMA) in July 2023 to permit authorised prescribing of MDMA for Post-traumatic Stress Disorder (PTSD) outside of the clinical trial setting. Objective This manuscript describes the development of the Australian Clinical Practice Guideline on MDMA-assisted psychotherapy (MDMA-AP) for PTSD. Methods The Guideline will be developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) process. The Guideline will consider the benefits and harms of MDMA-AP compared to other treatments in people with PTSD. High quality systematic reviews identified via an overview of systematic reviews will be used as index and supplementary reviews. Using the GRADE Evidence-to-Decision framework, the multidisciplinary Guideline Development Group (GDG) will consider treatment benefits and harms, certainty of evidence, patient preferences and values, resources, equity, acceptability and feasibility. The GDG will be supported by a Stakeholder Group, Expert Group, Conflict of Interest Oversight Committee, and Evidence Review Team. The Guideline will be developed using an integrated knowledge translation approach, emphasising the co-production of knowledge through active participation and shared decision-making with end-users. Conclusion The Guideline will be published on the digital platform MAGICapp and disseminated in peer-reviewed publications, professional conferences and via specific stakeholder groups. A Companion Guide will be developed for people living with PTSD and their carers, family members, and supports. 1. Introduction Medical use of psychedelics has not been legalised in most countries. Canada, Israel and Switzerland restrict access to supervised use of psychedelics for compassionate reasons ( Mocanu et al., 2022 ; Oehen & Gasser, 2022 ). In the US, the therapeutic use of psychedelics is legalised in some states, such as Oregon and Colorado (Psychedelic Alpha; Siegel et al., 2023 ). However, there is no approved psychedelic-containing product because the new drug application for methylenedioxymethamphetamine (MDMA)-assisted psychotherapy (MDMA-AP) was rejected by the US Food and Drug Administration (FDA) in August 2024, with the FDA citing the need for more research prior to approval (Lykos Therapeutics, 2024b ). In July 2023, the Australian Therapeutic Goods Administration rescheduled MDMA and psilocybin from being prohibited drugs (Schedule 9) to being controlled drugs (Schedule 8) ( Therapeutic Goods Administration, 2023 ). This rescheduling permitted authorised psychiatrists to prescribe MDMA and psilocybin for post-traumatic stress disorder (PTSD) and treatment-resistant depression respectively, outside of the clinical trial setting. To be an authorised prescriber, a psychiatrist is required to follow a clinical treatment protocol and obtain approval from a human research ethics committee ( Therapeutic Goods Administration, 2024 ). Following the rescheduling, the Royal Australian and New Zealand College of Psychiatrists (RANZCP) published a clinical memorandum for psychiatrists about the therapeutic use of MDMA and psilocybin ( Royal Australian and New Zealand College of Psychiatrists, 2023 ). The memorandum recommended that MDMA and psilocybin in conjunction with psychotherapy should be reserved for those who have tried all other established evidence-based treatments without lasting success. Both international and local stakeholders reported mixed perspectives toward psychedelic use for mental health conditions (Barnett et al., 2022; Barnett et al., 2018 ; Kucsera et al., 2023 ; Kunstler et al., 2023 ; Page et al., 2021 ). In the US, healthcare professionals, including psychiatrists, psychologists, therapists, and social workers, reported being unprepared to discuss with patients the medical use of psychedelics due to concerns about the lack of trained providers, logistical challenges, safety issues, potential psychiatric risks, and managing patients with contraindications (Barnett et al., 2022; Kucsera et al., 2023 ). Australian community surveys have shown indecision or indifference towards the use and approval of psychedelics for treating mental health conditions ( Kunstler et al., 2022 ; Nadeem et al., 2024 ). However, those people with mental illness may have more positive attitudes ( Nadeem et al., 2024 ). Half of the Australian psychiatrists surveyed did not consider themselves knowledgeable about psychedelic therapies and many were concerned about safety, access, and regulation ( Berger & Fitzgerald, 2023 ). Similarly, a more recent survey of general practitioners, psychiatrists, and psychologists indicated positive attitudes towards psychedelic-assisted psychotherapy’s potential to improve outcomes, but highlighted ongoing concerns about safety, efficacy, and the scientific rigor of current research (Nadeem et al., nd). In a context where patients have access to psychedelic-assisted treatment but no approved products available, development of guidelines can support clinicians to deliver appropriate care and patients to make informed decisions. This manuscript describes the development of an Australian clinical practice guideline for the use of MDMA-AP in PTSD (herein referred to as the Guideline). This protocol details in advance the methods that will be used in the development of the guideline, with the aim of ensuring a transparent process and minimising the risk of bias ( Ford et al., 2022 ). To our knowledge, this will the first clinical practice guideline related to the use of MDMA-AP for PTSD. 2. Methods 2.1 Governance Structure The Guideline will be developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) process (The GRADE Working Group, 2024) in accordance with National Health and Medical Research Council (NHMRC) Guidelines for Guidelines and 2016 Standards for Guidelines ( National Health and Medical Research Council, 2016 ). The intent to develop the Guideline was registered by NHMRC on 7 February 2024 and NHMRC appointed a Guideline liaison person. The Guideline will be developed by the Guideline Development Group (GDG) supported by a Stakeholder Group, Expert Group, Conflict of Interest (COI) Oversight Committee, and Evidence Review Team (ERT) ( Figure 1 ). Download figure Open in new tab Figure 1. Guideline governance structure. 2.1.1 Guideline Development Group The GDG comprises members with clinical (e.g., general practice, nursing, pharmacy, psychiatry, psychology, psychotherapy), health economics, knowledge translation, mental health policy, methodological, neuroscience, pharmacology, and legal expertise, and lived experience. GDG members will be offered training in Aboriginal and Torres Strait Islander cultural awareness provided by the Australian Indigenous Doctors’ Association (Australian Indigenous Doctors’ Association) or Royal Australian College of General Practitioners (Royal Australian College of General Practitioners). GDG members will also be offered the opportunity to undertake We Al-li Trauma-informed Aboriginal and Torres Strait Islander Cultural Capability training (We Al-li). The GDG will formulate recommendations and good practice statements using the GRADE Evidence-to-Decision framework (refer to Methodology for Developing Recommendations section for details). Each GDG member will complete a declaration of interests form, which will be assessed by the COI Oversight Committee to ensure that members are not conflicted or that conflicts are managed according to a management plan in compliance with NHMRC requirements. The GDG is co-chaired by a pharmacist and guideline methodologist with no direct or indirect financial interactions with any companies (or their foundation) involved in the development, production, or delivery of MDMA, another psychedelic, psychedelic-like drug, or related services. In line with NHMRC requirements, the co-chairs were appointed based on their independence and expertise in chairing and facilitating guideline meetings using GRADE methodology ( National Health and Medical Research Council, 2018 ). Having two co-chairs will help maintain balance and independence. Both co-chairs have experience in leading or guiding the development of NHMRC-approved guidelines. The co-chairs will lead GDG and Stakeholder Group meetings, promote balanced participation of group members, and facilitate best practice application of the GRADE process. The guideline methodologist has a non-voting role, and no direct or indirect financial or non-financial interests, so will take primary responsibility for ensuring compliance with the conflict of interest policy. 2.1.2 Stakeholder Group The Stakeholder Group will comprise government agencies (e.g., Department of Veterans’ Affairs), professional organisations (e.g., Australian Psychological Society, Pharmaceutical Society of Australia, Royal Australian College of General Practitioners, Australian Indigenous Psychologists Association, Psychotherapy and Counselling Federation of Australia), peak bodies or research organisations (e.g., Australians for Mental Health Limited, Phoenix Australia, Black Dog Institute), and consumer representatives (e.g., Fearless, Arafmi, Tandem Carers, LGBTIQ+ Health Australia, Victorian Aboriginal Community Controlled Health Organisation, Heroic Hearts Project Australia, Indigenous Psychedelic-Assisted Therapies). The Stakeholder Group will provide strategic advice on the project, advise on barriers and risks, be invited to provide feedback during the public consultation process, and assist in disseminating the Guideline. Organisations represented on the Stakeholder Group may be invited to endorse the Guideline. 2.1.3 Expert Group The Expert Group will comprise authorised prescribers, consumers and carers, general practitioners, psychiatrists, psychologists, social workers, researchers, and others with relevant expertise. This includes but is not limited to, clinicians and consumers with direct experience providing and receiving MDMA-AP but who could not be part of the GDG due to involvement in industry-sponsored psychedelic clinical trials, private clinics, or other COIs. The Expert Group will not be a decision-making body but exists to provide input without compromising the actual or perceived integrity of the recommendation process. The Expert Group will not meet and discuss together as a group. The perspectives from the Expert Group will be solicited via one-on-one interviews (or, in the case of consumers, one-on-two interviews) facilitated by the Project Manager. The interviews will be audiotaped, transcribed verbatim and thematically analysed following the process outlined by Braun and Clarke (2021) . Ethics approval has been obtained from the Monash University Human Research Ethics Committee for the in-depth interviews (Project ID: 44868). The interview findings will be presented to the GDG by a member of the ERT. A member of the COI Oversight Committee will review the material to be presented in advance of the meeting to ensure that the GDG is made aware of the COIs of the Expert Group. With the exception of the co-chairs and ERT, the GDG will not have direct contact in relation to the Guideline with the Expert Group members. Communication between the GDG and Expert Group relevant to the guidelines will be via the Project Manager. 2.1.4 Conflict of Interest Oversight Committee The COI Oversight Committee includes two guideline methodologists with no direct or indirect interests relevant to the Guideline topic. The COI Oversight Committee will advise on the COI policy and process, review the declarations of prospective GDG candidates, evaluate the interests of each GDG member, assess whether an interest reflects a conflict, and devise appropriate conflict management plans. A COI will be defined in accordance with the Australian Code for the Responsible Conduct of Research as a ‘situation where an independent observer might reasonably conclude that the professional actions of a person are or may be unduly influenced by other interests’ ( Australia Universities, 2018 ). Potential COIs will include financial, organisational, or intellectual interests (refer to Supplementary material 1 for the COI Policy). All potential GDG members were asked to complete a Declaration of Interests Form prior to appointment. Disclosed interests will be updated and reviewed by the COI Oversight Committee prior to the start of each GDG meeting. Each disclosed interest will be individually assessed for its level of conflict risk based on the COI matrix adapted from the Clinical Guidelines Committee of the American College of Physicians ( Qaseem et al., 2019 ) (Supplementary material 1). The COI Oversight Committee will notify the members of their management plans before the start of each meeting. Individuals with interests assessed as serious COIs will not be appointed to the GDG but may be invited to join the Expert Group. Members with moderate-risk COIs may contribute to discussions and be permitted to vote independently ahead of meetings. This vote will only be used to elicit the perspectives of members of the GDG and facilitate discussion. Members with a moderate-risk will not be permitted to vote in the meeting on either the judgements required in the GRADE Evidence-to-Decision framework or the recommendations. Members with low-risk COIs will be permitted to contribute to discussion and voting without restriction. 2.1.5 Evidence Review Team The ERT comprises the Project Manager and researchers with experience in evidence synthesis. The ERT will collate evidence on benefits and harms that the GDG will use to formulate recommendations and good practice statements. The ERT will provide evidence to support the GDG’s decision-making and may provide clarifying information during the GDG meetings, but will not contribute to the decision-making process itself. The ERT will conduct literature searches, formulate an overview of systematic reviews, and extract relevant data. 2.1.6 Funder The Guideline is funded by a philanthropic donation to the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University. Funding was also received from Monash University, University of Melbourne, and The Florey Institute of Neuroscience and Mental Health. The philanthropic donor had no role in the design, data collection and analysis, decision to publish, or preparation of the Guideline, and they will not benefit materially from the outcomes of their funding. The philanthropic donor will be requested to sign a declaration stating that they have no potential COIs including financial, organisational, or intellectual interests, and that they will not have influence over the Guideline’s processes and outputs. 2.2 Methodology for Evidence Synthesis The GRADE Evidence-to-Decision framework will be used by the GDG to make recommendations from the evidence and other information ( Alonso-Coello et al., 2017 ; Alonso-Coello et al., 2016 ). The criteria considered in the GRADE Evidence-to-Decision framework are (1) benefits and harms, (2) certainty of the evidence, (3) values and preferences, (4) resources, (5) equity, (6) acceptability, and (7) feasibility ( Alonso-Coello et al., 2017 ; Alonso-Coello et al., 2016 ). 2.2.1 Question to be Addressed in the Guideline The Guideline will address a single clinical question “In people living with PTSD, what are the benefits and harms of MDMA-AP compared to other or no treatment?” This Guideline will focus on MDMA because MDMA is at a more advanced stage of clinical development than psilocybin. MDMA has been the subject of two Phase 3 clinical trials ( Mitchell et al., 2021 ; Mitchell et al., 2023 ). 2.2.2 Criteria for Considering Studies for the Evidence Review A hierarchical and staged approach will be used to identify and synthesise evidence about the effects of MDMA-AP on prioritised outcomes (benefits and harms) ( Figure 2 ). The Participants, Interventions, Comparators, and Outcomes (PICO) eligible for inclusion in the evidence review are as follows. Population: people living with PTSD. Specific populations with possible different treatment needs and outcomes will be considered while making recommendations, such as Aboriginal and Torres Strait Islander peoples, military and ex-military personnel, emergency services personnel, adolescents, older people, culturally and linguistically diverse peoples, neurodivergent individuals such as people with Autism Spectrum Disorder (ASD) or Attention Deficit Hyperactivity Disorder (ADHD), people with mental health co-morbidities, and people with different trauma types. Intervention: MDMA-AP. The intervention was defined as MDMA-AP because the TGA approval does not include the use of MDMA as a standalone therapy and MDMA is typically combined with psychotherapy components. MDMA-AP reported in Phase 3 clinical trials has comprised three sessions of preparation, three sessions of experimental or dosing, and three sessions of integration following each experimental session. The psychotherapy component in the clinical trials – the “inner-directed” method has been described as a “non-directive approach that pertains to inviting inquiry and providing suggestion rather than directing the participant in the therapeutic approach”. The psychotherapy component itself is not a treatment option recommended in current PTSD treatment guidelines, such as the Australian Guidelines for the Treatment of Acute Stress Disorder, Posttraumatic Stress Disorder, and Complex PTSD ( Phoenix Australia, 2020 ) and Effective Treatments for PTSD: Practice Guidelines from the International Society for Traumatic Stress Studies ( Bisson et al., 2019 ; International Society for Traumatic Stress Studies, 2018). Comparators: Other or no treatment. For the purpose of the evidence review, the comparator was deliberately defined broadly to include inactive comparators (e.g. placebo) and all types of treatment, such as psychological interventions, pharmacological interventions, watchful waiting, or no treatment. This broad definition was deemed necessary due to several challenges: the lack of evidence and treatment protocol for emerging treatments, inconsistent adoption of current guidelines by practitioners, limited accessibility of recommended treatments for certain populations (e.g., those in regional or remote areas), and issues of non-tolerance to exposure-based treatments. The broad definition of comparator accounted for clinical trials that have used active or inactive placebos together with psychotherapy. Active placebos have included low-dose MDMA in Phase 2 MDMA trials to mimic some of the physiological or psychological effects of MDMA without providing its full therapeutic benefits. Evidence from trials using an active placebo will be considered because active placebos may improve blinding and inclusion of these trials will maximise data availability. For safety outcomes, data from comparisons with an inactive placebo will be prioritised to avoid underestimation of potential MDMA-related adverse events. Outcomes: Outcomes were determined through an outcome prioritisation process involving the GDG (see next) and included PTSD symptoms/diagnosis (e.g., symptom severity, remission, loss of diagnosis), co-occurring mental health symptoms, other patient-reported outcome measures (e.g., daily functioning, health-related quality of life), and adverse events (e.g., adverse drug events, suicide risk, MDMA diversion or misuse, treatment related discontinuity/ withdrawal, treatment burden). Types of studies: systematic reviews of randomised trials (for effectiveness outcomes) and non-randomised studies (for safety outcomes only). Supplemental primary studies will be considered if meta-analyses for prioritised outcomes require updating (i.e. to include new or missing studies). Download figure Open in new tab Figure 2. The process of synthesising evidence for benefits and harms. SR, systematic review 1 Manuscipt has been published in a peer-reviewed journal ( Yong et al., 2025 ). 2 This was planned but the step was not needed because high-quality systematic reviews that met the PICO criteria were identified. 2.2.3 Overview of Systematic Reviews An overview of systematic reviews or meta-analyses was conducted to critically evaluate published and unpublished systematic reviews and meta-analyses relevant to the clinical question ( Yong et al., 2025 ) ( Figure 2 , Step 1). The overview included a systematic search for reviews using keywords and Medical Subject Headings related to “MDMA”, “PTSD”, and “systematic review or meta-analysis” without any date or language restrictions. A grey literature search was conducted using the exact keywords to identify government reports, conference proceedings, or unpublished reports. The literature search and abstract screening were conducted independently by two reviewers. Any disagreements were resolved by discussion or involvement of a third reviewer when necessary. The lists of primary studies included in each review were compared and the degree of overlap was estimated using the corrected covered area (CCA) method proposed by Pieper et al. (2014) . The methodological quality of the included reviews was assessed independently by two reviewers using the A MeaSurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) tool ( Shea et al., 2017 ). 2.2.4 Rating Outcome Importance GDG members rated the importance of specific outcomes for decision-making ( Figure 2 , Step 2). Potentially relevant outcomes were identified from the outcomes prioritised in existing PTSD guidelines ( Bisson et al., 2019 ; International Society for Traumatic Stress Studies, 2018; Phoenix Australia, 2020 ), outcomes measured in systematic reviews or meta-analyses of psychological and pharmacological interventions for PTSD ( Coventry et al., 2020 ; Karatzias et al., 2019 ; Mavranezouli et al., 2020 ), and safety outcomes raised in the US FDA’s Psychopharmacologic Drugs Advisory Committee Meeting with Lykos Therapeutics (Food and Drug Administration, 2024). Of the 13 prioritised outcomes, eight were rated as “critical” (mean score of 7 to 9), including suicide risk, change in PTSD symptoms, daily functioning, health-related quality of life, change in self-organisation/emotional regulation, change in depressive symptoms, cardiac-related adverse events, impact on productivity, and change in anxiety symptoms (Supplementary material 2). Five outcomes were rated as “important” (mean score of 4 to 6), including change in anxiety symptoms, treatment discontinuation/withdrawal, adverse events, sleep quality, and diversion or misuse of MDMA. It was noted that GDG members showed diverse opinions regarding the importance of the proposed outcomes. Of the 13 outcomes presented, 11 were selected by at least one GDG member as being among the top three most important outcomes for the Guideline, except change in anxiety symptoms and treatment discontinuation. Since all 13 proposed outcomes were rated as either critical or important for decision-making, they will all be included in the Summary of Findings. GDG members also identified several critical outcomes not covered in the list (Supplementary material 2). These outcomes will be considered in the Evidence-to-Decision framework. For each prioritised outcome, the GDG discussed the minimal important difference for each outcome ( Guyatt et al., 2011 ; Neumann et al., 2022 ; Zeng et al., 2021 ). 2.2.5 Selection of Systematic Reviews and Additional Studies for Informing the Guideline High-quality (AMSTAR-2 overall rating as high) systematic reviews identified in the overview of systematic reviews may be used as index systematic reviews (for data extraction into the evidence profile) or as supplementary reviews (for additional data needed to address missing studies or apply the GRADE Evidence-to-Decision framework) ( Figure 2 , Step 3). Four systematic reviews were identified in the overview of systematic reviews: Colcott et al. (2024) ; Heath et al. (2022) ; Kisely et al. (2023) ; Mustafa et al. (2024) . If the literature search in an index systematic review used to generate the evidence profile is more than 12 months old when the draft Guideline is released for public consultation, the literature search will be updated to identify any new studies ( Figure 2 , Step 4). It was not deemed necessary to conduct a new systematic review because high quality systematic reviews meeting the PICO criteria were identified. 2.2.6 Data Extraction For each prioritised outcome, data will be extracted for each primary study from the index systematic review, supplementary systematic reviews and primary studies (if needed) by one reviewer and checked by another ( Figure 2 , Step 5). From the index systematic reviews, the following information will be extracted: characteristics of each trial (trial PICO, participant characteristics, risk of bias, number of participants randomised), outcomes measured, measurement methods, measurement timepoints, results data (meta-analytic effect estimates for each prioritised outcome, number of studies and participants contributing to each analysis, outcome measures in mean difference, and details required for interpretation), and other data needed to assess certainty of evidence (such as assessment of bias due to missing results from the synthesis, sensitivity analyses, subgroup analyses, and data needed to assess inconsistency such as forest plots). If comparison across systematic reviews indicates that a study is missing from the meta-analyses in the index systematic review, primary study data will be extracted from a supplementary systematic review and the meta-analyses will be updated. If a prioritised outcome is not addressed in any of the systematic reviews, the data will be extracted from relevant primary studies and relevant trial registries and reports will be checked to identify if the outcome has been measured or reported. Primary studies will also be used to extract other missing information or where there are unexplained discrepancies between systematic reviews. The quality of additional primary studies identified from an updated search will be assessed using the Cochrane risk-of-bias tool for randomised trials (RoB 2) ( Higgins et al., 2019 ). 2.2.7 Data Synthesis Meta-analyses identified from existing reviews will be updated if needed, such as to add or remove studies or change the grouping within the analyses ( Figure 2 , Step 6). When an update is needed, the summary statistics of each study will be extracted from the forest plots or tables of the index systematic review to be pooled with that from additional primary studies. New meta-analyses will be conducted if none have been identified. Mean differences will be calculated if all included studies use the same scale, whereas standardised mean differences will be used for studies with different scales. Binary outcomes will be estimated using relative risks or hazard ratios. Meta-analyses of the subgroups will be conducted if there is sufficient homogenous population. The subgroups will be prioritised by the GDG ahead of synthesis. If necessary, sensitivity analyses will be undertaken to assess the impact of low-quality or withdrawn trials on the overall findings. If a meta-analysis is not possible, the results will be presented narratively. 2.2.8 GRADE Assessment of the Certainty of Evidence The certainty of evidence for all critical and important outcomes will be assessed using the GRADE approach based on five GRADE domains: risk of bias, imprecision, inconsistency, indirectness, and publication bias ( Figure 2 , Step 7) ( Balshem et al., 2011 ). 2.2.9 GRADE Evidence Profile Evidence for benefits and harms will be presented in a GRADE Evidence Profile. This profile will include all outcomes considered to be critical and important for making a recommendation, results for each outcome (reported as the absolute and relative magnitude of effect), number of participants and studies, overall certainty of evidence for each outcome, and a plain language summary to convey the evidence findings based on GRADE informative statements ( Figure 2 , Step 8) ( Santesso et al., 2020 ). 2.2.10 Evidence-to-Decision Framework Evidence for domains 1 and 2 (benefits and harms, certainty of the evidence) will be derived from the GRADE Evidence Profile. Narrative literature reviews will be conducted to identify evidence for domains 3 to 7 (values and preferences, resources, equity, acceptability, and feasibility). Summary of findings from the semi-structured interviews with each member of the Expert Group that are relevant to the framework will be presented to the GDG. Input derived from the discussions among the GDG members will also be captured. 2.3 Development of Recommendations The Evidence Profile and findings from the narrative review and in-depth interviews will be presented to the GDG at a series of GDG meetings. Prior to group discussion, each GDG member will independently judge whether the evidence and other information for each domain in the Evidence-to-Decision framework support a recommendation for the intervention (MDMA-AP) or the alternative option. The summary judgements for each domain are shown in Table 1 . Anonymous voting will be conducted using electronic polls. This will ensure that the views and perspectives of each member are captured without the influence of other members. The Methodology Chair will then facilitate a group discussion about each domain to explore possible differences in voting. The voting process will be repeated after the group discussion. View this table: View inline View popup Table 1. Phrasing implemented in MAGICapp to express the GDG judgement of whether the evidence and other information for each Evidence-to-Decision (EtD) factor supports a recommendation for the intervention or the alternative option. After voting on each domain within the Evidence-to-Decision framework has been completed, the GDG will vote on the direction (for or against MDMA-AP) and strength (strong or conditional) of the overall recommendation ( Table 2 ) ( Andrews et al., 2013 ). Where possible, voting on the overall recommendation will be by unanimous agreement or consent by all members. If unanimity cannot be achieved, the group will discuss the concerns and reservations, which may lead to modification or rewording of the recommendation. If unanimity is still not reached after discussion, a majority vote will be sought. The reasons for disagreement or objection of members will be documented in the Technical Report. View this table: View inline View popup Table 2. Types of possible recommendations and their definitions based on GRADE Handbook. 2.4 Development of Good Practice Statements A series of Good Practice Statements related to principles important to follow prior to, during, and after the initiation of MDMA-AP for PTSD will be formulated if there is clear indirect evidence that their implementation will provide unequivocal benefits. Good Practice Statements are actionable statements grounded in either: (1) ethical principles or human rights (e.g., the right to health and to make decisions about treatment with informed consent), (2) essential principles, practices, and protocols (e.g., to guide standards for infection control), or (3) established scientific evidence. The Evidence-to-Decision criteria will be considered for each Good Practice Statement to decide if there is high certainty that the desirable effects outweigh undesirable effects or that the opposite course of action would be clearly inappropriate ( Dewidar et al., 2023 ). All recommendations and Good Practice Statements will be discussed, drafted, and approved by the GDG. These recommendations and Good Practice Statements will not require endorsement by Monash University, the funders, or any of the other GDG members organisations in order to be published. 2.5 Dissemination and Implementation The Guideline will be published on the digital platform MAGICapp and in peer-reviewed publications. The findings will be disseminated to medical and allied health professionals via digital dissemination, professional networks, conferences, and member organisations of the Stakeholder Group. A Consumer Companion Guide will be developed and disseminated to people living with PTSD and their carers, family members, and other supports. 3. Discussion This protocol outlines a governance structure designed to uphold transparency, independence, and objectivity in accordance with NHMRC standards. The recommendations in the Guideline will be formulated based on a systematic process that considers evidence on benefits and harms in the context of the local health system and clinical practice. The Guideline will be developed by utilising an integrated knowledge translation approach, emphasising the co-production of knowledge through active participation and shared decision-making between researchers and end-users ( Gagliardi et al., 2017 ; Graham & Tetroe, 2009 ; Jull et al., 2017 ). Early engagement and sustained collaboration have been shown to enhance the uptake and implementation of research recommendations significantly ( Gagliardi et al., 2016 ; Kothari & Wathen, 2013 ). For the context of this Guideline, the integrated knowledge translation approach enables the researchers and guideline developers to better understand the practice environment, interpret results within their contextual framework, and enhance the real-world applicability of the Guideline. At the same time, end-users gain a clearer understanding and awareness of the research process and are given opportunities to highlight their clinical needs. The in-depth interviews with the Expert Group will be conducted as part of the integrated knowledge translation process to ensure that the perspectives of end-users are incorporated throughout the guideline development. The Stakeholder Group, comprising key government agencies, non-government organisations, and professional organisations, will be convened throughout the Guideline development to advise implementation barriers and sensitivities and identify implementation strategies. Perspectives of different populations will be considered, such as those in non-metropolitan settings (rural and remote), Aboriginal and Torres Strait Islander peoples, culturally and linguistically diverse peoples, neurodivergent individuals, and LGBTQIA+ communities. Given the nascent stage of psychedelic research, it is anticipated that the GDG and Expert Group will include some members with financial, organisational or intellectual COIs. Therefore, measures have been taken to ensure decisions are independent and objective. These measures include (1) ensuring diversity of perspectives and interests among members, (2) requiring GDG and Expert Group members to declare relevant interests, (3) allowing GDG members to vote on the Evidence-to-Decision framework independently before group discussion, and (4) forming an Expert Group to provide input while remaining independent from the GDG. These measures ensure perceived COIs are identified and managed, thereby reducing potential concerns about objectivity and increasing public trust ( National Health and Medical Research Council, 2019 ; Schünemann et al., 2015 ). In conclusion, the development of an Australian clinical practice guideline for MDMA-AP in PTSD will provide clinicians with evidence-based recommendations to advance the field of psychedelic-assisted therapy. The Guideline will involve input from a broad clinical experts, researchers, and consumers to help ensure appropriate use of MDMA-AP. Data Availability Details of the current protocol are included within the manuscript and supplementary material. Footnotes Declaration of interests: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NP currently receives funding from SA Health, Victorian Foundation for Survivors of Torture Inc., Sonder, Mates in Construction, and Overseas Services to Survivors of Torture and Trauma. All funds are paid to the employing institution. JSB has received grant funding or consulting funds from the National Health and Medical Research Council, Victorian Government Department of Health and Human Services, Dementia Australia Research Foundation, Yulgilbar Foundation, Aged Care Quality and Safety Commission, Dementia Centre for Research Collaboration, Pharmaceutical Society of Australia, Society of Hospital Pharmacists of Australia, GlaxoSmithKline Supported Studies Programme, Amgen, and several aged care provider organisations unrelated to this work. All grants and consulting funds were paid to the employing institution. GB has received grant funding from the US National Institute of Drug Abuse, the Medical Research Future Fund, Victorian Government Department of Health and Human Services, the National Centre for Clinical Research on Emerging Drugs, the Youth Support and Advocacy Service, and several philanthropic organisations unrelated to this work. All the other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding sources: This work was supported by philanthropic funding to the Neuromedicines Discovery Centre, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University. Funding was also received from Monash University, The University of Melbourne, and The Florey Institute of Neuroscience and Mental Health. The philanthropic donor had no role in the design, data collection and analysis, decision to publish, or preparation of the Guideline. References ↵ Alonso-Coello , P. , Oxman , A. D. , Moberg , J. , Brignardello-Petersen , R. , Akl , E. A. , Davoli , M. , Treweek , S. , Mustafa , R. A. , Vandvik , P. O. , & Meerpohl , J . ( 2017 ). GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices . 2: Clinical practice guidelines. Gaceta sanitaria , 32 ( 2 ), 167. e161 – 167 . e110. OpenUrl ↵ Alonso-Coello , P. , Schünemann , H. J. , Moberg , J. , Brignardello-Petersen , R. , Akl , E. A. , Davoli , M. , Treweek , S. , Mustafa , R. A. , Rada , G. , Rosenbaum , S. , Morelli , A. , Guyatt , G. H. , & Oxman , A. D . ( 2016 ). GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices . 1: Introduction. BMJ , 353 , i2016 . doi: 10.1136/bmj.i2016 OpenUrl FREE Full Text ↵ Andrews , J. , Guyatt , G. , Oxman , A. D. , Alderson , P. , Dahm , P. , Falck-Ytter , Y. , Nasser , M. , Meerpohl , J. , Post , P. N. , Kunz , R. , Brozek , J. , Vist , G. , Rind , D. , Akl , E. A. , & Schünemann , H. J . ( 2013 ). GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations . J Clin Epidemiol , 66 ( 7 ), 719 – 725 . doi: 10.1016/j.jclinepi.2012.03.013 OpenUrl CrossRef PubMed ↵ Australia Universities . ( 2018 ). Australian code for the responsible conduct of research . National Health and Medical Research Council . Australian Indigenous Doctors’ Association . Cultural Awareness – Online Training . Retrieved 29 January 2025 from https://aida.org.au/cultural-safety-program/cultural-awareness-foundations-of-cultural-safety/ ↵ Balshem , H. , Helfand , M. , Schünemann , H. J. , Oxman , A. D. , Kunz , R. , Brozek , J. , Vist , G. E. , Falck-Ytter , Y. , Meerpohl , J. , & Norris , S . ( 2011 ). GRADE guidelines: 3. Rating the quality of evidence . Journal of clinical epidemiology , 64 ( 4 ), 401 – 406 . OpenUrl CrossRef PubMed Web of Science Barnett , B. S. , Beaussant , Y. , King, F. t., & Doblin, R. ( 2022 ). Psychedelic Knowledge and Opinions in Psychiatrists at Two Professional Conferences: An Exploratory Survey . J Psychoactive Drugs , 54 ( 3 ), 269 – 277 . doi: 10.1080/02791072.2021.1957183 OpenUrl CrossRef PubMed ↵ Barnett , B. S. , Siu , W. O. , & Pope , H. G. , Jr . . ( 2018 ). A Survey of American Psychiatrists’ Attitudes Toward Classic Hallucinogens . J Nerv Ment Dis , 206 ( 6 ), 476 – 480 . doi: 10.1097/NMD.0000000000000828 OpenUrl CrossRef PubMed ↵ Berger , J. J. , & Fitzgerald , P. B . ( 2023 ). The prescription of psychedelic therapies in Australia and New Zealand: A brief survey of psychiatrists . Australas Psychiatry , 31 ( 2 ), 190 – 194 . doi: 10.1177/10398562231156684 OpenUrl CrossRef PubMed ↵ Bisson , J. I. , Berliner , L. , Cloitre , M. , Forbes , D. , Jensen , T. K. , Lewis , C. , Monson , C. M. , Olff , M. , Pilling , S. , & Riggs , D. S . ( 2019 ). The international society for traumatic stress studies new guidelines for the prevention and treatment of posttraumatic stress disorder: Methodology and development process . Journal of traumatic stress , 32 ( 4 ), 475 – 483 . OpenUrl CrossRef PubMed ↵ Braun , V. , & Clarke , V . ( 2021 ). Thematic analysis: a practical guide. SAGE Publications . ↵ Colcott , J. , Guerin , A. A. , Carter , O. , Meikle , S. , & Bedi , G. ( 2024 ). Side-effects of mdma-assisted psychotherapy: a systematic review and meta-analysis . Neuropsychopharmacology . doi: 10.1038/s41386-024-01865-8 OpenUrl CrossRef ↵ Coventry , P. A. , Meader , N. , Melton , H. , Temple , M. , Dale , H. , Wright , K. , Cloitre , M. , Karatzias , T. , Bisson , J. , Roberts , N. P. , Brown , J. V. E. , Barbui , C. , Churchill , R. , Lovell , K. , McMillan , D. , & Gilbody , S . ( 2020 ). Psychological and pharmacological interventions for posttraumatic stress disorder and comorbid mental health problems following complex traumatic events: Systematic review and component network meta-analysis . PLoS Med , 17 ( 8 ), e1003262 . doi: 10.1371/journal.pmed.1003262 OpenUrl CrossRef PubMed ↵ Dewidar , O. , Lotfi , T. , Langendam , M. W. , Parmelli , E. , Saz Parkinson , Z. , Solo , K. , Chu , D. K. , Mathew , J. L. , Akl , E. A. , Brignardello-Petersen , R. , Mustafa , R. A. , Moja , L. , Iorio , A. , Chi , Y. , Canelo-Aybar , C. , Kredo , T. , Karpusheff , J. , Turgeon , A. F. , Alonso-Coello , P. , … Schünemann , H. J. ( 2023 ). Good or best practice statements: proposal for the operationalisation and implementation of GRADE guidance . BMJ Evidence-Based Medicine , 28 ( 3 ), 189 – 196 . doi: 10.1136/bmjebm-2022-111962 OpenUrl Abstract / FREE Full Text Food and Drug Administration. ( 2024 ). FDA Briefing Document: Psychopharmacologic Drugs Advisory Committee Meeting . https://www.fda.gov/media/178984/download ↵ Ford , N. , Thomas , R. , & Grove , J . ( 2022 ). Transparency: A central principle underpinning trustworthy guidelines . J Clin Epidemiol , 142 , 246 – 248 . doi: 10.1016/j.jclinepi.2021.11.025 OpenUrl CrossRef PubMed ↵ Gagliardi , A. R. , Berta , W. , Kothari , A. , Boyko , J. , & Urquhart , R . ( 2016 ). Integrated knowledge translation (IKT) in health care: a scoping review . Implementation Science , 11 ( 1 ), 38 . doi: 10.1186/s13012-016-0399-1 OpenUrl CrossRef ↵ Gagliardi , A. R. , Kothari , A. , & Graham , I. D . ( 2017 ). Research agenda for integrated knowledge translation (IKT) in healthcare: what we know and do not yet know . Journal of Epidemiology and Community Health , 71 ( 2 ), 105 – 106 . doi: 10.1136/jech-2016-207743 OpenUrl FREE Full Text ↵ Graham , I. D. , & Tetroe , J. M . ( 2009 ). Getting evidence into policy and practice: perspective of a health research funder . J Can Acad Child Adolesc Psychiatry , 18 ( 1 ), 46 – 50 . OpenUrl PubMed ↵ Guyatt , G. H. , Oxman , A. D. , Kunz , R. , Atkins , D. , Brozek , J. , Vist , G. , Alderson , P. , Glasziou , P. , Falck-Ytter , Y. , & Schünemann , H. J . ( 2011 ). GRADE guidelines: 2. Framing the question and deciding on important outcomes . Journal of clinical epidemiology , 64 ( 4 ), 395 – 400 . OpenUrl CrossRef PubMed ↵ Heath , L. , Gonzales , V. , Luloh , M. , Marble , Q. , Henkels , R. , Knippenberg , K. , & LaFleur , J. ( 2022 ). MDMA-assisted therapy for post-traumatic stress disorder: Phase 2 evidence synthesis-A report to the UTAH Psychotherapy Drug Task Force . https://www.utah.gov/pmn/files/903931.pdf ↵ Higgins , J. P. , Savović , J. , Page , M. J. , Elbers , R. G. , & Sterne , J. A. ( 2019 ). Assessing risk of bias in a randomized trial. In Cochrane Handbook for Systematic Reviews of Interventions (pp. 205-228) . doi: 10.1002/9781119536604.ch8 OpenUrl CrossRef International Society for Traumatic Stress Studies. ( 2018 ). ISTSS Prevention and Treatment Guidelines . https://istss.org/treating-trauma/new-istss-prevention-and-treatment-guidelines.aspx ↵ Jull , J. , Giles , A. , & Graham , I. D. ( 2017 ). Community-based participatory research and integrated knowledge translation: advancing the co-creation of knowledge . Implementation Science , 12 ( 1 ), 150 . doi: 10.1186/s13012-017-0696-3 OpenUrl CrossRef PubMed ↵ Karatzias , T. , Murphy , P. , Cloitre , M. , Bisson , J. , Roberts , N. , Shevlin , M. , Hyland , P. , Maercker , A. , Ben-Ezra , M. , Coventry , P. , Mason-Roberts , S. , Bradley , A. , & Hutton , P. ( 2019 ). Psychological interventions for ICD-11 complex PTSD symptoms: systematic review and meta-analysis . Psychol Med , 49 ( 11 ), 1761 – 1775 . doi: 10.1017/s0033291719000436 OpenUrl CrossRef PubMed ↵ Kisely , S. , Connor , M. , Somogyi , A. A. , & Siskind , D . ( 2023 ). A systematic literature review and meta-analysis of the effect of psilocybin and methylenedioxymethamphetamine on mental, behavioural or developmental disorders . Australian & New Zealand Journal of Psychiatry , 57 ( 3 ), 362 – 378 . doi: 10.1177/00048674221083868 OpenUrl CrossRef PubMed ↵ Kothari , A. , & Wathen , C. N . ( 2013 ). A critical second look at integrated knowledge translation . Health Policy , 109 ( 2 ), 187 – 191 . doi: 10.1016/j.healthpol.2012.11.004 OpenUrl CrossRef PubMed ↵ Kucsera , A. , Suppes , T. , & Haug , N. A . ( 2023 ). Psychologists’ and psychotherapists’ knowledge, attitudes, and clinical practices regarding the therapeutic use of psychedelics . Clin Psychol Psychother , 30 ( 6 ), 1369 – 1379 . doi: 10.1002/cpp.2880 OpenUrl CrossRef PubMed ↵ Kunstler , B. , Hatty , M. , Genat , A. , Smith , L. , Goodwin , D. , & Langmead , C . ( 2022 ). Attitudes and beliefs about the medically supervised use of psychedelic medications for the treatment of mental health conditions . ↵ Kunstler , B. , Smith , L. , Langmead , C. , Goodwin , D. , Wright , B. , & Hatty , M . ( 2023 ). “We don’t want to run before we walk”: the attitudes of Australian stakeholders towards using psychedelics for mental health conditions . Public Health Research & Practice , 33 ( 3 ). doi: 10.17061/phrp3332321 OpenUrl CrossRef ↵ Lykos Therapeutics . ( 2024b , 9 August 2024). Lykos Therapeutics Announces Complete Response Letter for Midomafetamine Capsules for PTSD https://news.lykospbc.com/2024-08-09-Lykos-Therapeutics-Announces-Complete-Response-Letter-for-Midomafetamine-Capsules-for-PTSD ↵ Mavranezouli , I. , Megnin-Viggars , O. , Daly , C. , Dias , S. , Welton , N. J. , Stockton , S. , Bhutani , G. , Grey , N. , Leach , J. , Greenberg , N. , Katona , C. , El-Leithy , S. , & Pilling , S . ( 2020 ). Psychological treatments for post-traumatic stress disorder in adults: a network meta-analysis . Psychol Med , 50 ( 4 ), 542 – 555 . doi: 10.1017/s0033291720000070 OpenUrl CrossRef PubMed ↵ Mitchell , J. M. , Bogenschutz , M. , Lilienstein , A. , Harrison , C. , Kleiman , S. , Parker-Guilbert , K. , Ot’alora , G. M. , Garas , W. , Paleos , C. , Gorman , I. , Nicholas , C. , Mithoefer , M. , Carlin , S. , Poulter , B. , Mithoefer , A. , Quevedo , S. , Wells , G. , Klaire , S. S. , van der Kolk , B. , … Doblin , R. ( 2021 ). MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study . Nat Med , 27 ( 6 ), 1025 – 1033 . doi: 10.1038/s41591-021-01336-3 OpenUrl CrossRef PubMed ↵ Mitchell , J. M. , Ot’alora , G. M. , van der Kolk , B. , Shannon , S. , Bogenschutz , M. , Gelfand , Y. , Paleos , C. , Nicholas , C. R. , Quevedo , S. , Balliett , B. , Hamilton , S. , Mithoefer , M. , Kleiman , S. , Parker-Guilbert , K. , Tzarfaty , K. , Harrison , C. , de Boer , A. , Doblin , R. , Yazar-Klosinski , B. , & Group , M. S. C. ( 2023 ). MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial . Nat Med , 29 ( 10 ), 2473 – 2480 . doi: 10.1038/s41591-023-02565-4 OpenUrl CrossRef PubMed ↵ Mocanu , V. , Mackay , L. , Christie , D. , & Argento , E . ( 2022 ). Safety considerations in the evolving legal landscape of psychedelic-assisted psychotherapy . Subst Abuse Treat Prev Policy , 17 ( 1 ), 37 . doi: 10.1186/s13011-022-00468-0 OpenUrl CrossRef PubMed ↵ Mustafa , R. , McQueen , B. , Nikitin , D. , Nhan , E. , Zemplenyi , A. , DiStefano , M. , Kayali , Y. , Richardson , M. , & Rind , D. ( 2024 ). MDMA-Assisted Psychotherapy for Post-Traumatic Stress Disorder: Effectiveness and Value (Evidence Report., Issue. https://icer.org/assessment/ptsd-2024/#overview ↵ Nadeem , Z. , Parker , S. , McGovern , H. , & Oestreich , L. K . ( 2024 ). Attitudes toward psychedelics and psychedelic-assisted therapy among potential mental health service users and the general population in Australia . Australian & New Zealand Journal of Psychiatry , 58 ( 10 ), 904 – 913 . doi: 10.1177/00048674241261779 OpenUrl CrossRef PubMed Nadeem , Z. , Parker , S. , McGovern , H. , Sebben , B. , & Oestreich , L. (nd). Attitudes toward psychedelics and psychedelic-assisted therapy among potential mental healthcare providers. Unpublished manuscript, The University of Queensland . National Health and Medical Research Council . Guidelines for Guidelines Handbook. Retrieved 16 September 2024 from https://www.nhmrc.gov.au/guidelinesforguidelines ↵ National Health and Medical Research Council . ( 2016 ). 2016 NHMRC Standards for Guidelines . Retrieved 16 September 2024 from https://www.nhmrc.gov.au/guidelinesforguidelines/standards ↵ National Health and Medical Research Council . ( 2018 , 22/11/2018). Guidelines for Guidelines: Identifying and managing conflicts of interest . https://www.nhmrc.gov.au/guidelinesforguidelines/plan/identifying-and-managing-conflicts-interest . ↵ National Health and Medical Research Council . ( 2019 ). Disclosure of interests and management of conflicts of interest: A guide supporting the Australian Code for the Responsible Conduct of Research . ↵ Neumann , I. , Quiñelen , E. , Nahuelhual , P. , Burdiles , P. , Celedón , N. , Cerda , K. , Herrera-Omegna , P. , Kraemer , P. , Cancino , K. D. , Valenzuela , J. P. , Sepúlveda , D. , Morgano , G. P. , Akl , E. A. , & Schünemann , H. J . ( 2022 ). Using Explicit Thresholds were valuable for judging Benefits and Harms in partially contextualized GRADE Guidelines . J Clin Epidemiol , 147 , 69 – 75 . doi: 10.1016/j.jclinepi.2022.03.017 OpenUrl CrossRef PubMed ↵ Oehen , P. , & Gasser , P . ( 2022 ). Using a MDMA- and LSD-Group Therapy Model in Clinical Practice in Switzerland and Highlighting the Treatment of Trauma-Related Disorders . Front Psychiatry , 13 , 863552 . doi: 10.3389/fpsyt.2022.863552 OpenUrl CrossRef PubMed ↵ Page , L. A. , Rehman , A. , Syed , H. , Forcer , K. , & Campbell , G . ( 2021 ). The Readiness of Psychiatrists to Implement Psychedelic-Assisted Psychotherapy . Front Psychiatry , 12 , 743599 . doi: 10.3389/fpsyt.2021.743599 OpenUrl CrossRef PubMed ↵ Phoenix Australia . ( 2020 ). Australian Guidelines for the Treatment of Acute Stress Disorder, Posttraumatic Stress Disorder, and Complex PTSD In . ↵ Pieper , D. , Antoine , S. L. , Mathes , T. , Neugebauer , E. A. , & Eikermann , M . ( 2014 ). Systematic review finds overlapping reviews were not mentioned in every other overview . J Clin Epidemiol , 67 ( 4 ), 368 – 375 . doi: 10.1016/j.jclinepi.2013.11.007 OpenUrl CrossRef PubMed Psychedelic Alpha . Psychedelic Legalization & Decriminalization Tracker . Retrieved 29 January 2025 from https://psychedelicalpha.com/data/psychedelic-laws ↵ Qaseem , A. , Wilt , T. J. , Forciea , M. A. , Kansagara , D. , Crandall , C. J. , Fitterman , N. , Hicks , L. A. , Horwitch , C. A. , Lin , J. S. , Maroto , M. , McLean , R. M. , Mustafa , R. A. , Roa , J. , Tufte , J. , & Vijan , S . ( 2019 ). Disclosure of Interests and Management of Conflicts of Interest in Clinical Guidelines and Guidance Statements: Methods From the Clinical Guidelines Committee of the American College of Physicians . Ann Intern Med , 171 ( 5 ), 354 – 361 . doi: 10.7326/m18-3279 OpenUrl CrossRef PubMed ↵ Royal Australian and New Zealand College of Psychiatrists . ( 2023 ). Clinical Memorandum: Therapeutic use of MDMA for PTSD and psilocybin for treatment resistant depression . https://www.ranzcp.org/clinical-guidelines-publications/clinical-guidelines-publications-library/therapeutic-use-of-mdma-for-ptsd-and-psilocybin-for-treatment-resistant-depression Royal Australian College of General Practitioners . Cultural awareness and cultural safety training . Retrieved 29 January 2025 from https://www.racgp.org.au/the-racgp/faculties/aboriginal-and-torres-strait-islander-health/education-and-training/cpd-activities-for-gps-and-health-professionals/cultural-awareness-and-cultural-safety-training ↵ Santesso , N. , Glenton , C. , Dahm , P. , Garner , P. , Akl , E. A. , Alper , B. , Brignardello-Petersen , R. , Carrasco-Labra , A. , De Beer , H. , Hultcrantz , M. , Kuijpers , T. , Meerpohl , J. , Morgan , R. , Mustafa , R. , Skoetz , N. , Sultan , S. , Wiysonge , C. , Guyatt , G. , Schunemann , H. J. , & Group , G. W. ( 2020 ). GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions . J Clin Epidemiol , 119 , 126 – 135 . doi: 10.1016/j.jclinepi.2019.10.014 OpenUrl CrossRef PubMed ↵ Schünemann , H. J. , Al-Ansary , L. A. , Forland , F. , Kersten , S. , Komulainen , J. , Kopp , I. B. , Macbeth , F. , Phillips , S. M. , Robbins , C. , & van der Wees , P. ( 2015 ). Guidelines International Network: principles for disclosure of interests and management of conflicts in guidelines . Annals of Internal Medicine , 163 ( 7 ), 548 – 553 . OpenUrl CrossRef PubMed ↵ Shea , B. J. , Reeves , B. C. , Wells , G. , Thuku , M. , Hamel , C. , Moran , J. , Moher , D. , Tugwell , P. , Welch , V. , Kristjansson , E. , & Henry , D. A . ( 2017 ). AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both . BMJ , 358 , j4008 . doi: 10.1136/bmj.j4008 OpenUrl FREE Full Text ↵ Siegel , J. S. , Daily , J. E. , Perry , D. A. , & Nicol , G. E . ( 2023 ). Psychedelic Drug Legislative Reform and Legalization in the US . JAMA Psychiatry , 80 ( 1 ), 77 – 83 . doi: 10.1001/jamapsychiatry.2022.4101 OpenUrl CrossRef PubMed The GRADE Working Group. ( 2024 ). The GRADE Book (I. Neumann & H. Schünemann, Eds. 1 ed.) . https://book.gradepro.org ↵ Therapeutic Goods Administration . ( 2023 , 3 July 2023). Update on MDMA and psilocybin access and safeguards from 1 July 2023 https://www.tga.gov.au/news/news/update-mdma-and-psilocybin-access-and-safeguards-1-july-2023 ↵ Therapeutic Goods Administration . ( 2024 ). Authorised Prescriber Scheme: Guidance for medical practitioners, Human Research Ethics Committees, specialist colleges and sponsors Retrieved from https://www.tga.gov.au/sites/default/files/2024-03/authorised-prescriber-scheme-guidance.pdf We Al-li . Culturally Informed Trauma Integrated Healing Approach . Retrieved 29 January 2025 from https://www.wealli.com.au/ ↵ Yong , A. S. J. , Bratuskins , S. , Sultani , M. S. , Blakeley , B. , Davey , C. G. , & Bell , J. S . ( 2025 ). Safety and efficacy of methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in post-traumatic stress disorder: An overview of systematic reviews and meta-analyses . Australian & New Zealand Journal of Psychiatry (accepted for publication ). ↵ Zeng , L. , Brignardello-Petersen , R. , Hultcrantz , M. , Siemieniuk , R. A. C. , Santesso , N. , Traversy , G. , Izcovich , A. , Sadeghirad , B. , Alexander , P. E. , Devji , T. , Rochwerg , B. , Murad , M. H. , Morgan , R. , Christensen , R. , Schünemann , H. J. , & Guyatt , G. H . ( 2021 ). GRADE guidelines 32: GRADE offers guidance on choosing targets of GRADE certainty of evidence ratings . J Clin Epidemiol , 137 , 163 – 175 . doi: 10.1016/j.jclinepi.2021.03.026 OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted February 21, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Development of an Australian Clinical Practice Guideline on methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy for Post-traumatic Stress Disorder Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Development of an Australian Clinical Practice Guideline on methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy for Post-traumatic Stress Disorder Alene Sze Jing Yong , Sue E Brennan , Suzie Bratuskins , Aimée Freeburn , Gillinder Bedi , Rimona Burke , Terry Haines , Mary Hollick , Kimberley Ann Jones , Andrew J Lawrence , Yong Yi Lee , Alexander C McFarlane , Stephen Parker , Nicholas Procter , Liam Spicer , Andrew A. Somogyi , Simon Stafrace , Stacey Watts , Clare Walton , Kay Wilson , J Simon Bell medRxiv 2025.02.18.25322184; doi: https://doi.org/10.1101/2025.02.18.25322184 Share This Article: Copy Citation Tools Development of an Australian Clinical Practice Guideline on methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy for Post-traumatic Stress Disorder Alene Sze Jing Yong , Sue E Brennan , Suzie Bratuskins , Aimée Freeburn , Gillinder Bedi , Rimona Burke , Terry Haines , Mary Hollick , Kimberley Ann Jones , Andrew J Lawrence , Yong Yi Lee , Alexander C McFarlane , Stephen Parker , Nicholas Procter , Liam Spicer , Andrew A. Somogyi , Simon Stafrace , Stacey Watts , Clare Walton , Kay Wilson , J Simon Bell medRxiv 2025.02.18.25322184; doi: https://doi.org/10.1101/2025.02.18.25322184 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Psychiatry and Clinical Psychology Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (298) Cardiovascular Medicine (4421) Dentistry and Oral Medicine (443) Dermatology (382) Emergency Medicine (607) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1507) Epidemiology (15215) Forensic Medicine (30) Gastroenterology (1122) Genetic and Genomic Medicine (6582) Geriatric Medicine (667) Health Economics (996) Health Informatics (4522) Health Policy (1366) Health Systems and Quality Improvement (1611) Hematology (540) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15907) Intensive Care and Critical Care Medicine (1103) Medical Education (621) Medical Ethics (144) Nephrology (667) Neurology (6580) Nursing (345) Nutrition (998) Obstetrics and Gynecology (1143) Occupational and Environmental Health (956) Oncology (3328) Ophthalmology (970) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (663) Pediatrics (1690) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5436) Public and Global Health (9215) Radiology and Imaging (2193) Rehabilitation Medicine and Physical Therapy (1368) Respiratory Medicine (1194) Rheumatology (593) Sexual and Reproductive Health (709) Sports Medicine (529) Surgery (709) Toxicology (99) Transplantation (288) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9ff704beba8ee2c5',t:'MTc3OTQwMjU1Mg=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();