998785ANP ANZJP PerspectivesPerkins et al. Viewpoint Australian & New Zealand Journal of Psychiatry 1 –7 Medicinal psychedelics for mental https://doi.org/10.1177/0004867421998785DOI: 10.1177/0004867421998785 © The Royal Australian and health and addiction: Advancing New Zealand College of Psychiatrists 2021 Article reuse guidelines: research of an emerging paradigm sagepub.com/journals-permissions journals.sagepub.com/home/anp Daniel Perkins1 , Jerome Sarris2,3 , Susan Rossell4,5 , Yvonne Bonomo6,7, David Forbes8, Christopher Davey8, Daniel Hoyer9,10, Colleen Loo11,12 , Greg Murray4, Sean Hood13 , Violeta Schubert1, Nicole Leite Galvão-Coelho14, Meaghen O’Donnell8, Olivia Carter15, Paul Liknaitzky16,17 , Martin Williams18, Dan Siskind19,20 , David Penington21, Michael Berk8,22,23,24 and David Castle25 Abstract The medical use of psychedelic substances (e.g. psilocybin, ayahuasca, lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine) is attracting renewed interest, driven by a pressing need for research and development of novel therapies for psychiatric disorders, as well as promising results of contemporary studies. In this Viewpoint, we reflect upon the ‘Clinical Memorandum on Psychedelics’ recently released by the Royal Australian and New Zealand College of Psychiatrists and note subsequent developments including the application for down- scheduling of psilocybin and 3,4-methylenedioxymethamphetamine presently being considered by the Therapeutic Goods Administration and approvals for access via the Special Access Scheme. We suggest that this field is worthy of rigorous research to assess potential benefits, address safety parameters and clarify therapeutic mechanisms. To this end, we outline recent research findings, provide an overview of current knowledge relating to mechanisms of 1School of Social and Political Science, The University of Melbourne, Parkville, VIC, Australia 2NICM Health Research Institute, Western Sydney University, Westmead, NSW, Australia 3Professorial Unit, The Melbourne Clinic, Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia 4Centre for Mental Health, Swinburne University, Hawthorn, VIC, Australia 5Department of Psychiatry, St Vincent’s Hospital, Fitzroy, VIC, Australia 6Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia 7Department of Addiction, St Vincent’s Hospital, Melbourne, VIC, Australia 8Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia 9Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC, Australia 10Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA 11School of Psychiatry, University of New South Wales, Sydney, NSW, Australia 12Black Dog Institute, Sydney, NSW, Australia 13Division of Psychiatry, UWA Medical School, Faculty of Health & Medical Sciences, The University of Western Australia, Perth, WA, Australia 14Department of Physiology and Behavior, Federal University of Rio Grande do Norte, Natal, Brazil 15Melbourne School of Psychological Science, The University of Melbourne, Melbourne, VIC, Australia 16Turner Institute, School of Psychological Sciences, Monash University, Clayton, VIC, Australia 17Dept of Psychiatry, School of Clinical Sciences, Monash University, Clayton, VIC, Australia 18Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia 19Mobile Intensive Rehabilitation Team, Metro South Addiction and Mental Health Service, Brisbane, QLD, Australia 20School of Clinical Medicine, University of Queensland, Brisbane, QLD, Australia 21Vice-Chancellor’s Office, The University of Melbourne, Melbourne, VIC, Australia 22School of Medicine, IMPACT Research Institute, Deakin University, Geelong, VIC, Australia 23Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia 24Orygen The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia 25Scientific Director, Centre for Complex Interventions, Centre for Addictions and Mental Health; and Professor, Department of Psychiatry, University of Toronto, Toronto, Canada Corresponding author: Daniel Perkins, School of Social and Political Science, The University of Melbourne, John Medley Building, Parkville, VIC 3052, Australia. Email: [email protected] Australian & New Zealand Journal of Psychiatry, 00(0) 2 ANZJP Perspectives action and discuss salient aspects of the psychedelic-assisted psychotherapy treatment model. The sum of this research points towards medicinal psychedelics as a potential new class of psychiatric treatments when used within a medically supervised framework with integrated psychotherapeutic support. However, before widespread translation into clinical use can occur, appropriately designed and sufficiently powered trials are required to detect both potential positive and negative outcomes. Unique safety and regulatory challenges also need to be addressed. As for any new medical therapy, psychedelic research needs to be conducted in a rigorous manner, through the dispassionate lens of scientific enquiry. Carte blanche availability to practitioners, without specific protocols and appropriate training, would be potentially harmful to individuals and detrimental to the field. Keywords Psychedelic-assisted psychotherapy, psilocybin, ayahuasca, LSD, MDMA, psychiatry, mental disorders, neuroscience, post- traumatic stress disorder, depression Introduction illnesses, with further research involving psychedelic compounds for required to assess efficacy, effective- psychiatric disorders. These report Following an initial phase of research ness and safety. Psychological support evidence of short- and long-term ben- and subsequent decline between the delivered by researchers with appro- efits relating to mood, depression, 1950s and 1970s, the medical use of priate training is also stated to be an anxiety, PTSD and substance use, as psychedelic substances is seeing essential component of these treat- well as a satisfactory safety profile; renewed academic and media atten- ments. The memorandum further however, small sample sizes and other tion in Australia. This has been driven, notes that these drugs are currently methodological limitations are also inter alia, by changing attitudes fol- ‘illicit substances’ that cannot be pre- noted (see Table 1). lowing the legalisation of medicinal scribed or administered outside Psilocybin is the most researched of cannabis; an increasing number of approved research trials (although all of the classic psychedelics, with evi- international research studies report- potential access via the Special Access dence for reduction of both depres- ing promising results; and the continu- Scheme [SAS] is acknowledged). ing unmet medical need relating to sion and anxiety symptoms in patients In this Viewpoint, we reflect upon (Nutt et al., 2020). A recent meta- various psychiatric conditions includ- the RANZCP memorandum by provid- ing major depressive disorder (MDD), analysis of three placebo-controlled ing an overview of three substances, studies (n = 117) of psilocybin for generalized anxiety disorder (GAD), namely psilocybin, ayahuasca and alcohol and drug use disorders, and depression calculated large and statis- MDMA, framing this discussion within tically significant effects sizes (Gs = post-traumatic stress disorder (PTSD) the context of a psychedelic-assisted (Nutt et al., 2020; Reiff et al., 2020). 0.82–0.83) (Goldberg et al., 2020). On psychotherapy model. We consider the basis of such evidence, psilocybin There are around 100 clinical trials current evidence pertinent to potential using psychedelics currently being has been granted Breakthrough Therapy clinical use, as well as unique regulatory status by the US Food and Drug conducted globally, focused primarily challenges. These include access via the on the ‘classic’ psychedelics, namely Administration (FDA) for further Therapeutic Goods Administration’s investigation in treatment-resistant psilocybin, ayahuasca and lysergic acid (TGA) SAS and the current application diethylamide (LSD), as well as the depression and MDD. Other recent under consideration for down-schedul- studies using psilocybin have reported entactogen 3,4-methylenedioxymeth- ing of MDMA and psilocybin. We also substantial abstinence rates when amphetamine (MDMA). Initial results make several recommendations to used for tobacco and alcohol addic- from these studies indicate that reduce risks associated with possible tion treatment (Aday et al., 2020). psychedelics may provide a new class access via the SAS pathway. Microdosing Recent systematic reviews of aya- of treatments for mood, anxiety and of classical psychedelics such as psilocy- huasca (a traditional Amazonian decoc- substance use disorders (Luoma et al., bin is beyond the scope of this paper, as tion containing N,N-dimethyltryptamine 2020). is the use of ketamine for depression. In this context, the Royal Australian [DMT] and harmala alkaloids) reported and New Zealand College of Psychiatrists consistent evidence of anxiolytic, antide- (RANZCP) published a ‘Clinical pressant and anti-addictive effects in Memorandum on Psychedelics’ in May Current evidence human and animal studies, including 2020. The memorandum notes lim- There have been numerous system- open-label and randomised controlled ited but emerging evidence of thera- atic reviews and meta-analyses sum- trials for treatment-resistant depression peutic benefit for a