998785ANP ANZJP PerspectivesPerkins et al.

Viewpoint

Australian & New Zealand Journal of Psychiatry 7–­1 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 range of mental marising outcomes from clinical trials (Dos Santos and Hallak, 2019). Insights

Australian & New Zealand Journal of Psychiatry, 00(0) Perkins et al. 3 AEs Nil serious Nil serious AEs; anxiety, nausea, headaches noted Nil serious Nil serious; transient anxiety, dysphoria, psychotic-like features noted Nil serious; transient anxiety, headaches, nausea noted Low potential for abuse, although may be higher for MDMA Some acute difficult experiences days): 0.84** months (−1.07***) Result and effect size and effect Result Acute and enduring reductions in negative mood and depressive symptoms with moderate-large effects sizes: Acute (3 hours–1 day): 0.50**; Long-term (16–60 Rapid decrease in depressive symptoms from day 1 (−1.4**) to 6 Support for efficacy in four conditions investigated (1.21*** at study primary endpoint) Low-moderate/high evidence of anxiolytic, antidepressive and anti-addictive effects Evidence of enduring positive change in personality/attitudes, depression, affect/mood, anxiety, substance use Initial evidence of efficacy for MDMA/psilocybin. Preliminary but promising research for ayahuasca/LSD Subjects report clinically and personally meaningful outcomes beyond symptom reduction. Decreases in craving and withdrawal symptoms in SUD studies Psychedelic Psilocybin, ayahuasca, LSD Psilocybin, ayahuasca, LSD Psilocybin, ayahuasca, LSD, MDMA Psilocybin, ayahuasca, LSD, DMT Psilocybin, ayahuasca, LSD Psilocybin, ayahuasca, LSD Psilocybin, LSD, ibogaine, ayahuasca, ketamine, MDMA Outcome Positive and negative mood and depressive symptoms Depressive symptoms PTSD, anxiety, depression, social anxiety Efficacy, tolerability and safety for mood, anxiety and substance use Long-term effects Efficacy for the treatment of psychiatric conditions Thematic analysis of patient experiences in the treatment of psychiatric disorders Studies 12 8 9 10 34 14 15 Type SR and MA MA MA SR of SR/MAs SR ER SR < 0.01. Recent meta-analyses and systematic reviews of psychedelic substances. of psychedelic meta-analysesreviews and systematic Recent < 0.001; ** p Authors Galvão et al. (2021) Romeo et al. (2020) Luoma et al. (2020) Dos Santos et al. (2018) Aday et al. (2020) Reiff et al. (2020) Breeksema et al. (2020) Table 1. Table MA: meta-analysis; SR: systematic review; ER: evidence LSD: lysergic acid diethylamide; AEs: adverse events; PTSD: post-traumatic stress disorder; MDMA: 3,4-methylenedioxymethamphetamine; DMT: N,N -dimethyltryptamine; SUD: substance use disorder. *** p

Australian & New Zealand Journal of Psychiatry, 00(0) 4 ANZJP Perspectives into long-term effects are enabled by virtually unknown with psilocybin and and lack of controls, while in those analysis of studies of the use of aya- ayahuasca (Aday et al., 2020). that are controlled, adequate blinding huasca by various syncretic religious Current evidence indicates that is difficult to achieve due to the obvi- groups, which show no evidence of classic psychedelics are not associated ous subjective and objective effects of adverse neuropsychological impacts; with physical dependence, abuse or the drug, further complicated by high apparent positive effects on mood and withdrawal (confirmed in animal stud- expectation of benefit (introducing well-being; and reductions in problem- ies) and have a low level of toxicity expectancy bias). Some studies have atic use of other substances of abuse (Reiff et al., 2020). However, as noted attempted to address this through the (Dos Santos and Hallak, 2019). in the RANZCP memorandum, use of active controls such as antihista- MDMA-assisted psychotherapy for potential psychiatric risks for people mines, amphetamines or high-dose nia- PTSD was granted Breakthrough with premorbid schizoid and paranoid cin. Statistical power is a problem for Therapy status by the FDA in 2017, traits, or a family history of schizo- adverse events, because psychotropic with Phase 3 trials slated for comple- phrenia, have been identified (Dos changes will be seen in the majority of tion in 2022. Interim analysis of Phase Santos and Hallak, 2019; Reiff et al., users but adverse events only in a small 3 data conducted by an independent 2020). While absence of evidence minority. data monitoring committee suggests a does not extrapolate to evidence of greater than 90% probability of a sta- absence, population studies have Mechanisms of action tistically significant result. If con- established no links between lifetime firmed, FDA approval of MDMA as a classic psychedelic use and mental ill- Understanding biological pathways of prescription drug may occur as early ness, psychological distress or suici- action for these substances is impor- as 2023. On the strength of these dality (Aday et al., 2020). MDMA, by tant in elucidating the potential mech- results, the FDA recently approved contrast, has been found to have anisms that underlie their beneficial early access for 50 patients outside some potential for abuse, although effects, as well as for predicting clinical trials via an Expanded Access lower than amphetamine and meth- potential adverse events and drug Program. A recent systematic review amphetamine. However, addiction is interactions. of the efficacy of MDMA-assisted psy- rare and long-term follow-up in stud- Classical psychedelics are known chotherapy for the treatment of ies to date have identified no patients to induce alterations in mood and PTSD rated the evidence as ‘moder- subsequently obtaining and self- perception via a modulation of the ate’ and concluded that further administering illicit ecstasy (Reiff serotonergic, dopaminergic and gluta- research is warranted (Varker et al., et al., 2020; Sessa et al., 2019). matergic systems (Dos Santos et al.,

2020). The Australian Drug Harms 2018). Effects on 5-HT2A receptors In the context of careful screening, Ranking Study provides a useful expressed in frontal and paralimbic preparation, monitoring and follow- assessment of relative risk, based on a brain structures (involved in emo- up, the studies discussed above have comparison of 22 drugs. Alcohol was tional processing and regulation, reported no serious adverse events ranked as the most harmful, with a introspection and interoception) over (typically) long follow-up peri- score of 77, fentanyl scored 51, pre- appear to be central to these effects. ods. However, trials conducted to scription opioids 30 and cannabis 17, It is noteworthy that the 5-HT2A date were not powered for adverse while ecstasy and LSD/mushrooms receptor plays a particular role in psy- event detection, given that serious were in the lowest five ranked drugs, chosis, which may explain identified adverse events such as psychosis scoring 7 and 5 respectively, with very risks for individuals with, or predis- remain relatively uncommon. It is similar results obtained by an equiva- posed to, psychotic disorders (Dos acknowledged that transient adverse lent UK study (Bonomo et al., 2019; Santos et al., 2018; Reiff et al., 2020). reactions including nausea, anxiety, Reiff et al., 2020). Risks may be fur- For note pimavanserin, a known novel panic and disorientation are not ther reduced by use within a psyche- antipsychotic with evidence of efficacy uncommon with classic psychedelics delic treatment framework involving in psychosis associated with (Aday et al., 2020; Reiff et al., 2020). only one to three administrations Parkinson’s disease, has the opposite Reviews of the clinical use of MDMA under strict medical supervision, with effect, being an inverse agonist of this report predominantly positive acute psychotherapeutic support and exclu- receptor. subjective drug effects and no evi- sion of high-risk individuals. Serotonin receptor agonism has dence of neurotoxicity (Sessa et al., Despite these overall promising also been shown to lead to a synthesis 2019). Hallucinogen-persisting per- results, we are in agreement with the of brain-derived neurotrophic factor ception disorder (HPPD), which has RANZCP memorandum that there are (BDNF), as well as reduced amygdala occasionally been associated with LSD several reasons to remain cautious. and default mode network (DMN) use (estimated to occur in a chronic/ Many studies remain limited by highly activity (Ly et al., 2018; Romeo et al., invasive form in 1/50,000 users), is selected cohorts, small sample sizes 2020). Such effects are proposed to

Australian & New Zealand Journal of Psychiatry, 00(0) Perkins et al. 5 alleviate the dysfunctional brain net- addiction behaviours as well as being addition to ‘mystical’ aspects of healing work connectivity that is evident in involved in depression, anxiety and fear (Breeksema et al., 2020). Neurologically, many psychiatric and substance use extinction (Rodrigues et al., 2019). such effects are hypothesised to reflect disorders (Zhang and Volkow, 2019). There is also interest in potential thera- a revival of emotional responsiveness Changes in resting-state functional peutic effects of ayahuasca’s harmala with medicinal psychedelics, paralleled connectivity (RSFC) in the DMN have alkaloids, with preclinical studies of by functional magnetic resonance imag- been found in patients with depres- harmine, for example, demonstrating ing (fMRI) scans showing increased sion taking part in psilocybin trials, antidepressant-like effects (equivalent in amygdala responsiveness to emotional and these changes have been shown one pilot study to fluoxetine), which are stimuli, compared with a moderation or to be predictive of treatment posited to come about via astrocyte- blunting of emotional responsiveness, to response, with a suggestion that this mediated restoration of BDNF protein both negative stimuli and more broadly, is reflective of a therapeutic ‘reset’ levels and hippocampal neurogenesis, as with selective serotonin reuptake inhibi- mechanism (Aday et al., 2020; Nutt well as anti-addictive effects, possibly via tors (SSRIs) (Roseman et al., 2018). et al., 2020). Such effects are also the glutamate transporter subtype 1 potentially relevant for substance (GLT-1) (Brierley and Davidson, 2012). Psychedelic treatment dependence, where abnormal pat- In contrast to the serotonergic terns of RSFC in the DMN have been psychedelics, the primary mechanism model reported across various classes of of action of MDMA is as an indirect Although still evolving, evidence to illicit drugs and are associated with serotonergic agonist, increasing sero- date indicates that the optimal treat- craving and relapse via impaired self- tonin release. In addition, agonism at ment model for the safe and effective awareness, negative emotions and the 5-HT1A and 5-HT1B receptors is therapeutic use of medicinal psyche- rumination. DMN interactions with theorised to mediate anxiolytic effects, delics involves several unique features. the salience and executive control reduced amygdala fear responses, as In addition to obvious differences in networks have also been shown to be well as increased self-confidence, com- dosing (usually given only once or disrupted in drug-dependent individu- passion and empathy. Elevated levels of twice) and approach (to achieve pro- als (Zhang and Volkow, 2019). oxytocin attenuate stress response found altered states of conscious- Other recent research has con- and support prosocial feelings, and it ness), this also includes an expanded firmed that serotonergic psychedelics appears likely from animal models that and somewhat unfamiliar collection of can promote both structural and increased BDNF in the amygdala may extra-pharmacological parameters functional plasticity in the prefrontal facilitate the safe recall of usually that impact clinical outcomes. These cortex, robustly increasing neuri- avoided traumatic memories (Sessa include the patient’s mental state and togenesis and spinogenesis, and lead- et al., 2019). Consistent with this psychological preparation prior to ing to increased synapse numbers and mechanism is the rationale for the use administration; the experience and function. These effects, reported to of MDMA in alcohol dependence, context of consumption during the come about via TrkB, mTOR and based not on anti-addictive pharmaco- acute (dosing) phase; and quality of

5-HT2A signalling pathways, are again logical effects but on facilitating psy- psychological support and integration highly relevant for the treatment of chotherapeutic processes to treat post consumption (see Figure 1). depression and addiction, as these underlying psychological trauma (Sessa Subjective mystical experiences conditions have been associated with et al., 2019). have been demonstrated across mul- prefrontal cortex dysfunction or neu- tiple studies to be predictive of clinical ronal atrophy (Ly et al., 2018). Finally, Psychotherapeutic response to classic psychedelics, with agonism at 5-HT receptors appears 2C mechanisms one psilocybin study, for instance to be relevant for both the non-addic- finding this to be predictive of thera- tive nature of classic psychedelics A range of potential psychotherapeutic peutic effect on depressive symptoms themselves (vide lorcaserin) and their mechanisms have also been proposed (Aday et al., 2020; Romeo et al., ability to counteract several core for psychedelic treatments, and a recent 2020). Russ et al. (2019) reported addiction-related behaviours (Higgins systematic review of qualitative data that a mental state of lower preoccu- and Fletcher, 2015). identified a range of common mecha- pation (being occupied with daily con- Several additional mechanisms of nisms across substances (classic psych- cerns) and an increased sense of action have been identified for aya- edelics and MDMA) and various ‘surrendering’ (wilful release of goals, huasca, positioning it as a potential psychiatric disorders. These included preferences) at the time of ingestion ‘multi-target’ drug. These include the gaining insights (into self, their disorder/s of psilocybin were predictive of a ben- activation (by DMT) of both sigma-1 and its origin), altered self-perception, eficial response. Moreover, in a chal- and trace amine-associated receptors increased feelings of connectedness and lenge to some psychotherapeutic (TAAR), suggested to play a key role in an expanded emotional spectrum, in support models, it was found that

Australian & New Zealand Journal of Psychiatry, 00(0) 6 ANZJP Perspectives

Figure 1. Factors affecting clinical outcomes for psychiatric conditions.

exposure to words or conversation for use in Australia via the TGA’s according to a manualised treatment during the acute dosing session was a Australian Register of Therapeutic approach used within clinical trials (e.g. negative predictor of mystical experi- Goods (ARTG). Indeed, psilocybin, the MAPS Manual for MDMA-Assisted ence, supporting the current focus on DMT and MDMA are listed as con- Psychotherapy for PTSD, or the Yale the use of music and controlled audi- trolled substances in Schedule 9 (S.9) Manual for psilocybin-assisted therapy of tory stimuli during dosing sessions of the Australian Poisons Standard. As depression); and (3) patients with a his- (Russ et al., 2019). noted in the RANZCP memorandum, tory or risk of psychosis are excluded. Other research has suggested neg- it may still be possible to prescribe and Previous supervised practice in psyche- ative effects associated with extremely administer these substances outside delic-assisted psychotherapy model challenging acute experiences, as well clinical trials via the TGA’s SAS would also be prudent, as would active as the constructs of ‘emotional break- Category B (SAS-B), and we under- ongoing surveillance of outcomes and through’ (facing and resolving/releas- stand that a number of such approvals caution when using these substances in ing difficult feelings or memories) and have recently been granted. However, patients with a prior addictive disorder peak experiences, which are reported additional authorisation is also required (although they may sometimes be the to be positively associated with thera- from the relevant state or territory target group). peutic outcomes (Roseman et al., health department, and some jurisdic- The current application for down- 2019). Some differences in MDMA tions cannot approve S.9 substances scheduling of psilocybin and MDMA compared with classic psychedelics for use outside of research contexts. from Schedule 9 to Schedule 8 (declined protocols include therapists tending The SAS is intended to make treat- in an interim decision) would position to have greater engagement with the ments available on a case-by-case basis these substances alongside tetrahydro- patient during the acute phase to facil- (following a medical review) where cannabinol (THC) containing medicines. itate the therapeutic process, and that ARTG- listed medicines have not been As non-ARTG registered products, an the subjective experience appears to successful, and evidence can be pro- SAS-B approval would still be required; be less relevant (Sessa et al., 2019). vided that expected clinical benefits however, state approvals for SAS-B There remains much to be outweigh potential risks. SAS-B can be would be easier or not necessary, explored, but existing evidence sup- used for medicines that may or may depending on the jurisdiction. To note, ports the utilisation of appropriate not be registered overseas. down-scheduling these substances treatment models involving suitably While an access pathway such as would also facilitate research by reduc- trained clinicians, pre-dosing prepara- SAS-B may be appropriate in judicious ing approvals and security required for tion, acute session support and post- cases for use of medicinal psychedelics, clinical research in several states. session therapy, to optimise clinical we believe that any such approvals benefit and reduce risks of harm. should include the following additional Future directions conditions: (1) that the administering Regulation clinician is a psychiatrist or addiction In sum, we concur with the RANZCP medicine specialist who has undertaken memorandum that evidence of benefit At present, there are no psychedelic specific training in psychedelic-assisted for psychedelic-assisted psychotherapy medicines that have been registered therapy; (2) that the drug is administered is emerging, but that further research

Australian & New Zealand Journal of Psychiatry, 00(0) Perkins et al. 7 is required. Acknowledging methodo- Fellowship (GNT1154651). C.L. has received Dos Santos RG, Bouso JC, Alcazar-Corcoles MA, logical limitations of extant studies, NHMRC funding for a clinical trial of keta- et al. (2018) Efficacy, tolerability, and safety of serotonergic psychedelics for the management including small sample sizes, expec- mine in depression (1105089). C.D. is sup- ported by an NHMRC Career Development of mood, anxiety, and substance-use disorders: A tancy bias and difficulties with blinding, systematic review of systematic reviews. Expert Fellowship (1141738) and has received the promising results being obtained, Review of Clinical Pharmacology 11: 889–902. NHMRC funding for a clinical trial of keta- with large effects sizes for benefit and a Galvão-Coelho NL, Marx W, Gonzalez M, et al. mine in depression (1138736). M.W. is very low signal for adverse outcomes, (2021) Classic serotonergic psychedelics for Executive Director of DGR-1 Health mood and depressive symptoms: a meta-anal- make a strong case for further high- Promotion charity, Psychedelic Research in ysis of mood disorder patients and healthy quality controlled studies. Science & Medicine Ltd. P.L. is a member of participants. Psychopharmacology (Berl) 238: However, numerous challenges the Medical Advisory Board of Incannex 341–354. exist with governments proving reluc- Healthcare Limited. Goldberg SB, Pace BT, Nicholas CR, et al. (2020) The experimental effects of psilocybin on tant to fund research, and the psyche- symptoms of anxiety and depression: A meta- delic treatment model based on Funding analysis. Psychiatry Research 284: 112749. long-term remission of symptoms The author(s) received no financial sup- Higgins GA and Fletcher PJ (2015) Therapeutic potential of 5-HT2C receptor agonists for after one or two administrations, port for the research, authorship and/or using existing compounds, being unat- addictive disorders. ACS Chemical Neuroscience publication of this article. 6: 1071–1088. tractive to big pharma. Venture capital Luoma JB, Chwyl C, Bathje GJ, et al. (2020) A may offer an alternative, but high lev- ORCID iDs meta-analysis of placebo-controlled trials els of speculation and hype, as has Daniel Perkins https://orcid.org/0000- of psychedelic-assisted therapy. Journal of Psychoactive Drugs 52: 289–299. been seen with medicinal cannabis, 0002-2055-1649 Ly C, Greb AC, Cameron LP, et al. (2018) present other risks. In this context Jerome Sarris https://orcid.org/0000- Psychedelics promote structural and functional and with the growing interest in com- 0001-9287-8854 neural plasticity. Cell Reports 23: 3170–3182. passionate access pathways, establish- Susan Rossell https://orcid.org/0000- Nutt D, Erritzoe D and Carhart-Harris R (2020) ing registry type data collection 0002-7415-8252 Psychedelic psychiatry’s brave new world. Cell Colleen Loo https://orcid.org/0000- 181: 24–28. systems to advance knowledge relat- Reiff CM, Richman EE, Nemeroff CB, et al. (2020) ing to effectiveness and safety would 0003-3267-0554 Sean Hood https://orcid.org/0000- Psychedelics and psychedelic-assisted psycho- be of particular benefit. therapy. American Journal of Psychiatry 177: 0003-2852-7923 391–410. 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