Psychedelics in psychiatry – a world first in Australia

On July 1, 2023, the Therapeutic Goods Administration (TGA) in Australia rescheduled 3,4-methylenedioxy-methamphetamine (MDMA) and psilocybin as Schedule 8 (Controlled Drugs) medicines for treatment-resistant depression and post-traumatic stress disorder (PTSD), respectively¹

Prescribing is restricted to authorised psychiatrists and must be provided in conjunction with psychotherapy¹. For all other medical uses, psilocybin and MDMA remain in Schedule 9 (Prohibited Substances)¹. The rescheduling reflects the lack of effective treatments for people with specific treatment-resistant mental illnesses^2,3:

• Approximately one third of people with depression have treatment resistant depression, defined as those who do not respond to available pharmacologic interventions
• Prevalence rates of PTSD continue to rise; while there are available treatments, only 31% of people’s symptoms recover or improve
• Even for people whose symptoms improve, PTSD scores often remain above diagnostic thresholds

Psychedelic substances have been used for spiritual or healing purposes for thousands of years in indigenous communities worldwide⁴. Medical research on psychedelics has recommenced in Western medicine following easing of legal restrictions imposed since the 1970s⁵.

Imaging studies with psychedelics show they modulate connectivity in a neural network associated with ‘ego dissolution’ and increase global network integration, theorised to facilitate a psychological ‘reset’^6,7. While MDMA is not considered a classical psychedelic, it has similar subjective and potential therapeutic effects, allowing people to experience insight into their psychology⁵.

MDMA and psilocybin phase 2 and 3 trial data

As of September 2023, there are 49 clinical trials investigating psilocybin for depression and 36 investigating MDMA for PTSD

A randomised, double-blind, placebo-controlled trial phase 3 trial of MDMA for PTSD observed people treated with MDMA-assisted therapy (n=46) had a significant reduction in PTSD symptoms (p<0.0001) compared to placebo (n=44)⁸. In people treated with MDMA-assisted therapy, 67% no longer qualified for PTSD diagnosis compared to 32% placebo with therapy⁸. In addition, 33% in the MDMA group met remission criteria compared to 5% in the placebo group⁸. There were no serious safety or tolerability issues⁸. A phase 3 open-label extension study of this (MAPPUSX) and a long-term safety and effectiveness study (MPLONG) are underway^9,10.

Phase 2b trial results of psilocybin for treatment-resistant depression observed significant (p<0.001) reductions in depression scores at Week 3 from baseline in a single 25 mg dose group (n=79) compared to 1 mg (n=79)¹¹. Adverse events (AEs) including headache, nausea and dizziness occurred in 77% of all participants on Day 1, with no serious AEs (SAEs)¹¹. Suicidal ideation (n=2) and self-injury (n=2) were reported in the 25 mg group as SAEs from Day 2 to Week 3¹¹.

A phase 2 trial of single 25 mg dose of psilocybin in people taking a concomitant serotonin reuptake inhibitor saw a clinically meaningful reduction in depression scores at Week 3, with no serious treatment-emergent AEs observed¹².

A phase 3 trial of a single dose of psilocybin with psychological support for treatment-resistant depression is due to be complete in October 2024¹³.

Concerns about psychedelic-assisted therapy

Susan Rossell, a psychiatrist at Swinburne University of Technology and the lead on Australia’s largest trial for psilocybin-assisted therapy for treatment-resistant depression, states that the unpublished research suggests that 10–20% of people have a ‘really terrible time’¹⁴. However, research is ongoing to predict responders and the optimal routes of administration to minimise harm and maximise benefits^15-17. The optimal context and setting for psychedelic-assisted therapy, such as music choice, is under investigation^16,18,19.

Professor Steve Kisely, a psychiatrist at the University of Queensland, said “As this is essentially a nationwide experiment, I’d say they should wait and learn from the experience of the early enthusiasts who take up this option”, when asked what advice he would give psychiatrists who may be considering psilocybin- or MDMA-assisted therapy.

Kisley also expressed concerns over the speed of the rescheduling, suggesting available scientific evidence is lacking²⁰. Long-term data are yet to be published, and there are challenges in conducting randomised controlled trials in this area, including effectively blinding participants and researchers²⁰.

What’s next in Australia for psychedelic-assisted therapy?

In Australia, roll out of psychedelic-assisted therapy in psychiatry could be slow as best-practice protocols have not been stipulated by the Australian government¹⁴. However, the Royal Australian and New Zealand College of Psychiatrists (RANZCP) have produced protocols for MDMA and psilocybin therapy, and psychedelic clinics are being prepared¹⁴. Richard Harvey, a psychiatrist and chair of RANZCP’s Psychedelic-Assisted Therapy Steering Group has confidence in the protocols¹⁴.

Mind Medicine Australia, a charity that supports the rescheduling, is now offering training for psychedelic-assisted therapy for clinicians in Australia, New Zealand and Asia Pacific, of which some will be involved in clinical trials in Australia²¹.

While we await upcoming clinical trial data to be published, Australia will lead the world in providing real-world evidence on MDMA and psilocybin as potential therapies

References

1. Australian Government. Therapetic Goods Administration (TGA). Change to classification of psilocybin and MDMA to enable presribing by authorised psychiatrists. https://www.tga.gov.au/news/media-releases/change-classification-psilocybin-and-mdma-enable-prescribing-authorised-psychiatrists. Accessed 14 August.
2. Halaris A, Sohl E, Whitham EA. Treatment-resistant depression revisited: A glimmer of hope. J Pers Med. 2021;11(2).
3. Wallace D. Post-traumatic stress disorder in Australia: 2020. Australas Psychiatry. 2020;28(3):251–252.
4. Rucker JJH, Iliff J, Nutt DJ. Psychiatry & the psychedelic drugs. Past, present & future. Neuropharmacol. 2018;142:200–218.
5. Nutt D. Psychedelic drugs—a new era in psychiatry? Dialogues Clin Neurosci. 2019;21(2):139–147.
6. Daws RE, Timmermann C, Giribaldi B, Sexton JD, Wall MB, Erritzoe D, et al. Increased global integration in the brain after psilocybin therapy for depression. Nat Med. 2022;28(4):844–851.
7. Gattuso JJ, Perkins D, Ruffell S, Lawrence AJ, Hoyer D, Jacobson LH, et al. Default mode network modulation by psychedelics: A systematic review. Int J Neuropsychopharmacol. 2023;26(3):155–188.
8. Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, Parker-Guilbert K, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025–1033.
9. ClinicalTrials.gov. A multi-site open-label extension study of MDMA-assisted psychotherapy for PTSD (MAPPUSX). https://classic.clinicaltrials.gov/ct2/show/NCT04714359. Accessed 23 August.
10. ClinicalTrials.gov. Long-term safety and effectiveness of MDMA-assisted therapy for PTSD (MPLONG). https://classic.clinicaltrials.gov/ct2/show/NCT05066282. Accessed 23 August.
11. Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637–1648.
12. Goodwin GM, Croal M, Feifel D, Kelly JR, Marwood L, Mistry S, et al. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacol. 2023;48(10):1492–1499.
13. ClinicalTrials.gov. Efficacy, safety, and tolerability of a single administration of COMP360 in participants with TRD. https://classic.clinicaltrials.gov/ct2/show/NCT05624268 Accessed 14 August.
14. Haridy R. Australia to prescribe MDMA and psilocybin for PTSD and depression in world first. Nature. 2023;619(7969):227–228.
15. Romeo B, Hermand M, Pétillion A, Karila L, Benyamina A. Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: A systematic review. J Psychiatr Res. 2021;137:273–282.
16. Carhart-Harris RL, Roseman L, Haijen E, Erritzoe D, Watts R, Branchi I, Kaelen M. Psychedelics and the essential importance of context. J Psychopharmacol. 2018;32(7):725–731.
17. Haijen ECHM, Kaelen M, Roseman L, Timmermann C, Kettner H, Russ S, et al. Predicting responses to psychedelics: A prospective study. Front Pharmacol. 2018;9.
18. Modlin NL, Miller TM, Rucker JJ, Kirlic N, Lennard-Jones M, Schlosser D, Aaronson ST. Optimizing outcomes in psilocybin therapy: Considerations in participant evaluation and preparation. J Affect Disord. 2023;326:18–25.
19. Kaelen M, Giribaldi B, Raine J, Evans L, Timmerman C, Rodriguez N, et al. The hidden therapist: evidence for a central role of music in psychedelic therapy. Psychopharmacol (Berl). 2018;235(2):505–519.
20. Kisely S. The down-scheduling of MDMA and psilocybin(e): Too fast and too soon. Aust N Z J Psychiatry. 2023;57(7):933–934.
21. Mind Medicine Australia. Certificate in Psychedelic-Assisted Therapies (CPAT). https://mindmedicineaustralia.org.au/certificate-in-psychedelic-assisted-therapies-cpat/. Accessed 4 September.