Australia's first clinical practice guideline on the appropriate use of methylenedioxymethamphetamine-assisted psychotherapy (MDMA-AP) to treat post-traumatic stress disorder (PTSD) is a step closer following the publication of a new Monash-led study.
The study - published in the Australian & New Zealand Journal of Psychiatry (ANZJP) - assessed the current evidence regarding the safety and efficacy of MDMA-AP compared to psychotherapy alone among adults with PTSD.
The researchers will use findings from the study, combined with the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) process, to develop the Australian Clinical Practice Guideline on MDMA-AP for PTSD.
In 2023, Australia became the first country to reschedule MDMA and psilocybin from Prohibited Substances (Schedule 9) to Controlled Substances (Schedule 8). This has allowed authorised prescribers to administer MDMA and psilocybin for the treatment of PTSD and treatment-resistant depression outside of clinical trials, respectively.
The ANZJP study found that despite improvement in PTSD outcomes following MDMA-AP, the evidence is of low to very-low certainty.
The researchers analysed 14 systematic reviews, of which four were considered high-quality. All 14 reviews included studies of one-to-three sessions of 50-125mg MDMA-AP (some with supplemental dosage) compared to either 25-40mg of MDMA or inactive placebo with psychotherapy.
The study's lead author and Research Fellow at Monash's Centre for Medicine Use and Safety (CMUS) within the Monash Institute of Pharmaceutical Sciences, Dr Alene Sze Jing Yong, said while the reviews showed a substantial overall improvement in PTSD symptoms, based on the four high-quality reviews the evidence presented was insufficient or low-certainty due to several factors.
"Overall, meta-analysis from the reviews reported benefits of MDMA-AP in improving PTSD symptoms, response rate and remission rate compared to psychotherapy alone after one-to-three sessions of MDMA-AP," Dr Yong said.
"However, for reviews that assessed the certainty of evidence pertaining to MDMA-AP efficacy, evidence that 80-125mg of MDMA-AP results in a reduction in PTSD scores when compared to psychotherapy with active or inactive placebo was rated as low to very-low certainty.
"This can be attributed to a number of factors including small sample sizes in clinical trials, results only being able to be applied to a very narrow population and concerns of 'unblinding', whereby participants believe they know whether or not they have been administered MDMA.
"Furthermore, most systematic reviews did not critically evaluate the effect of psychotherapy session, supplemental dosage, and intervention duration on the reported outcomes."
In terms of safety, one high-quality systematic review comprehensively compared the risk of various adverse events between the intervention and control groups. However, this review concluded that the evidence about adverse events was limited by weaknesses in adverse event assessment and reporting, and the relatively short follow-up periods.
Director of CMUS and a Senior Author on the study, Professor Simon Bell, said the outcomes from the ANZJP study, combined with a range of other factors, need to be considered to inform comprehensive recommendations on the use of MDMA-AP in clinical practice in Australia.
"As far as next steps go, the high-quality systematic reviews identified in this overview can be used to assist in generating evidence profiles to be considered when making recommendations," Professor Bell said.
"With Australia's rescheduling of MDMA from Schedule 9 to 8, a clinical practice guideline to support MDMA-AP in the clinic needs to include evidence of benefits and harms, certainty of the evidence, patient values and preferences, resources, equity, acceptability, and feasibility.
"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."
Promising results in Phase 2 and 3 clinical trials has led MDMA to being proposed as a potential pharmacological adjunct to psychotherapy on the premise that MDMA increases serotonin levels, which may reduce feelings of anxiety and depression and therefore potentially help some people with PTSD to revisit traumatic memories with more ease.
PTSD is a debilitating mental health condition and major public health concern due its impact on daily functioning, association with suicidal ideation, chronic disease and premature death.
It's experienced by an estimated 11 per cent of Australians in their lifetime. Women are at almost twice the risk of men (14 per cent and 8 per cent respectively, ABS 2022), while specific groups such as people who experience homelessness, refugees, people experiencing domestic violence, LGBTQIA+ people, First Nations people and certain occupation groups (emergency services, armed forces and veterans) are all at higher risk of experiencing PTSD in their lifetime.
Cognitive processing therapy or trauma-focused cognitive behavioural therapy are generally the first line management of PTSD, however it is estimated nearly half of patients with PTSD do not achieve clinically significant improvement with this approach, highlighting the need for new and innovative therapeutic interventions.
In addition to CMUS, the study, titled Safety and efficacy of methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in post-traumatic stress disorder: An overview of systematic reviews and meta-analyses was conducted by researchers from the Neuromedicines Discovery Centre within the Monash Institute of Pharmaceutical Sciences, University of Nottingham in the United Kingdom and the Department of Psychiatry at The University of Melbourne.
Subsequently, CMUS has led the publication of the protocol for developing the guideline, titled Development of an Australian Clinical Practice Guideline on methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy for Post-traumatic Stress Disorder. The preprint (not peer reviewed) can be read here.
