Clinical Memorandum

Therapeutic use of psychedelic substances

June 2023

Authorising Committee/Department: Committee for Evidence-Based Practice and Committee for Research
Responsible Committee/Department: Practice, Policy and Partnerships Committee
Document Code: CM: Therapeutic use of psychedelic substances

Purpose
The Royal Australian and New Zealand College of Psychiatrists (RANZCP) has developed this
memorandum to provide information for psychiatrists about the potential utility of psychedelic
substances to assist in treating mental illness.

In Australia, the use of MDMA and psilocybin to treat any conditions other than post-traumatic
stress disorder (PTSD) and treatment resistant depression (TRD),1 respectively, remain restricted
under the existing Schedule 9 classification. Please refer to the Clinical Memorandum: Therapeutic
use of MDMA for PTSD and psilocybin for treatment resistant depression for more information. All
other psychedelic drugs remain in Schedule 9. This memorandum also excludes ketamine as the
RANZCP has developed a separate Clinical Memorandum: Use of ketamine in psychiatric practice.

Key messages
• Further research is required to assess the efficacy and safety of psychedelic therapies to
inform future potential use in psychiatric practice.
• There is limited but emerging evidence that psychedelic therapies may have therapeutic
benefits in the treatment of a range of mental illnesses.
• Additional and larger randomised-control trials (RCTs) are needed to confirm initial
promising results for all psychedelic therapies.
• Current evidence is drawn from research trials that feature psychotherapy as a core
component of the treatment model. This requires trials to be carefully designed and led by
researchers with appropriate training, experience, and supervision.

Definitions and scope

Psychedelic substances: A class of drug, also called hallucinogens, that can induce states of
altered perception and thoughts2. Methylenedioxymethamphetamine (MDMA) is classified as an
empathogen or entactogen but for simplicity it will be referred to as a psychedelic throughout this
memorandum.3
Psychedelic therapy: refers to therapeutic practices involving psychedelic substances.
This statement is a general statement to inform psychiatrists about the potential utility of
psychedelic substances in the treatment of mental illness, and considerations to inform their use.
This statement does not cover the recreational use of psychedelic substances.

1
This memorandum uses the term treatment resistant depression in line with regulatory frameworks but acknowledges
that difficult-to-treat depression or other terms many be preferred.
2
Source Encyclopaedia Britannica: https://www.britannica.com/science/psychedelic-drug
3 Alcohol and Drug Foundation: https://adf.org.au/drug-facts/mdma/

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Background
There has been a recent resurgence in research trials into the potential utility of psychedelic
therapies in the treatment of mental illness in adults. Used most notably as aids to psychotherapy
for the treatment of mood disorders and alcohol dependence, a large amount of research into
psychedelic therapies in the treatment of mental illness was undertaken in the 1950s and 1960s.
Psychedelics were declared as prohibited substances in the mid-1960s which effectively ended all
major psychedelic research programs. [1, 2] Renewed interest in the utility of psychedelic
therapies is relatively recent, increasingly steadily since the 1990s. [3]
There is emerging but limited evidence that psychedelic therapies may have therapeutic benefits in
the treatment of a range of mental illnesses. Further research is needed to confirm initially
promising results.

Psychedelic assisted psychotherapy

Unlike conventional psychotropic pharmacotherapy, psychedelic therapy includes intense
psychotherapy sessions, in highly supportive and structure environments. This is known as
‘psychedelic assisted psychotherapy’. This includes psychological preparation prior to
administration and understanding of the subjective experience during treatment, as well as
psychological support with assimilation and integration afterwards.[4]
The mechanism of how the therapy works is still developing. [5]. Both the classical psychedelics
and MDMA appear to increase the affective bond between patient and therapist thereby enhancing
the therapeutic alliance through increasing a sense of closeness, openness and trust. [4, 6]

Research findings indicate that the presence of psychological support is a core component of the
psychedelic treatment model. [2,5]. It is unclear how much of the therapeutic effect comes from the
psychedelic therapy and how much is derived from the psychological support surrounding the
treatment. It appears that the interaction between the pharmacological action of both agents and
concurrent psychotherapy is important for success.[4, 6] A major unknown is the degree to which
the psychedelic/psychotherapy interaction is dependent on the specific type of psychotherapy
administered. [5] This needs to be better defined and tested. [5]

Evidence and current research

• Recent research has been undertaken, and is ongoing, with results published to demonstrate
potential utility and minimal side effects for a range of disorders when taken in controlled
research environments, at therapeutic doses over short timeframes (1-2 sessions), when
accompanied by psychotherapy.

• Worldwide, more than 100 psychedelic trials are currently active for the treatment of
depression and anxiety in the terminally ill, alcohol and drug use disorders, dementia, anorexia
and chronic pain. The UK, Canada, the United States and Israel are active research hubs and
research is informed by international collaboration. Trials for the use of psychedelic therapy in
Australia and New Zealand are now also underway with many in Australia funded under the
2021 Innovative Therapies for Mental Illness grants offered as part of the Medical Research
Future Fund (MRFF) Clinical Trials Activity Initiative.

• Information about the use of MDMA for PTSD and psilocybin for TRD, respectively, is available
in Clinical Memorandum: Therapeutic use of MDMA for PTSD and psilocybin for treatment
resistant depression.

• Evidence relating to the use of MDMA and psilocybin is outlined in recent systematic literature
reviews and meta-analyses on the effect of psilocybin and MDMA on mental, behavioural or
developmental disorders. [5, 7]

• MDMA has shown statistically significant improvements for treatment of social anxiety in adults
with autism although participant numbers were low [8]. Future clinical research examining the

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 effectiveness of MDMA is necessary to test the hypothesised effectiveness of MDMA for social
anxiety disorder. [9]

• Psychedelic therapy is being researched for use in anxiety or depression in end-of-life terminal
illness and may show promise as potential therapeutic options in end-of-life treatment. [10]
Statistically significant differences in two studies investigating psilocybin in the treatment of
anxiety or depression due to end of life illness have been identified, but with limitations. [5] A
systematic review found that recent (controlled) trials with LSD, psilocybin, and MDMA of
higher methodological quality indicate positive effects on existential and spiritual well-being,
quality of life, acceptance, and reduction of anxiety and depression in patients with terminal
illness with few adverse and no serious adverse effects. [11] To draw final conclusions on
effectiveness and safety, larger high-quality studies are needed. [11]

• Psychedelic therapy has not shown any significantly statistic effect for treatment of obsessive-
compulsive disorder (OCD). [5, 6]

• A systematic review investigating treatment using psilocybin, ibogaine, and ayahuasca, alone
or adjunct with psychotherapy for the treatment of substance use disorder or substance misuse
found no sufficient research evidence to suggest effectiveness of any of the psychedelics on
any specific substance use disorder or substance misuse. [12] A further systematic review on
psilocybin with some form of psychotherapy identified four studies showing a beneficial effect
of psilocybin-assisted therapy in patients with alcohol and tobacco use disorder, but the risk of
bias ranged from some concerns to critical. [13] Both reviews conclude that further research
(double-blinded, placebo-controlled RCTs) using rigorous effectiveness evaluation methods
with larger sample sizes and longer-term follow-up is required. [12, 13]

• Research into the use of ibogaine in substance use disorders (particularly opioid dependence)
is in its infancy and there are safety concerns. [14] A range of observational and retrospective
trials suggest there may be potential for Phase 2 trials for further determining efficacy with a
particular focus on managing cardiac safety. [3] Treatment outcomes in New Zealand, where
ibogaine can be prescribed as a non-approved medicine, confirm the need for more research.
[15]

• Potential use of LSD as a treatment is largely based on historical research. Risks associated
with the use of LSD require further investigation. [3, 13, 16, 17]

• Trials into the use of ayahuasca, particularly for the treatment of depression and addiction, are
also of research interest. [17-19]

• A systematic review evaluating evidence related to the therapeutic potential of psychedelics in

individuals diagnosed with eating disorders and body dysmorphic disorder highlight that more
research is needed to determine the safety and efficacy. [20]

• Research is being conducted into ‘microdosing’ psilocybin or LSD, which involves low-dose
regular consumption of psychedelic substances, without concurrent psychotherapy, to
determine impact on mental health. Recent studies suggest the perceived benefits associated
with microdosing may outweigh the challenges and may have utility for a variety of uses while
having minimal side effects. [21] However, evidence for this is currently limited. [22-25].
Double-blind, placebo-controlled experiments are required to substantiate these reports. [21]
Constraints on study design that prohibit outpatient use of psychedelics may explain failure of
several microdosing studies to reproduce grey literature reported benefits (from recreational
and self-medicating users) and limit translatability of any findings. [26]

Risks and side effects

• To date in controlled trials, with psychedelic substances given at therapeutic doses,
psychedelic therapies demonstrate an initial high safety ratio and low risk profile with limited
physiological concerns.[2, 3]

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• Practical steps (e.g. patient screening, concomitant medication management, and psychiatrist
support) have been taken to minimise risks in psychedelic trials. [2, 26, 27] As well as positive
effects there is potential for psychedelic substances to elicit acute sensitivity to context and
psychologically toxic reactions or ‘bad trips’ (e.g. fear, panic and re-traumatisation). [28] Proper
preparation and support of the person undergoing psychedelic therapy, as well as an
appropriate setting led by researchers with appropriate psychiatric and psychotherapy training,
including specific training in psychedelic psychotherapy, is crucially important to help mitigate
risk.

• Current trials suggest there is minimal risk of prolonged psychotic disorders in patients using
psychedelic therapy. [2] However, people with a personal or family history of psychosis (those
with a first or second-degree relative with these disorders) are generally excluded from such
trials because they have a higher risk of developing a psychotic disorder. [27] Giving
psychedelic substances to these populations presents a potential risk for the precipitation or
exacerbation of a psychotic disorder. Current trials for psychedelic therapy generally exclude
people with a personal or family history of psychosis, personal history of mania, repeated
violence towards others, and a recent personal history of a suicide attempt serious enough to
require hospitalisation, as well as those with current drug or alcohol use disorders (unless this
is the target for intervention). [2]

• There remain unknown factors and side effects, including long-term side effects, when using
psychedelic substances in trials for psychiatric treatment. Further, different people will
experience varying effects in response to psychedelics. Potential long-term risk factors
following psychedelic therapy, including risks for developing psychosis (hallucinogen induced
psychotic disorder) as well as Hallucinogen Persisting Perception Disorder (HPPD) have not
been investigated. There is an ongoing need to collect adverse event data systematically and
longitudinally in a manner that allows aggregated analyses.

• The selection of appropriate patients requires careful consideration. Patients should have
capacity to understand the risks and benefits of the treatment in the context of their disorder,
duration of current episode, previous treatment history, and ability to provide valid consent. In
addition to these diagnostic considerations, other considerations include medical, psychological
and/or social factors.

• Taking into account recent media attention highlighting the potential therapeutic benefits of
psychedelic substances, broader societal strategies may be required to deter illicit use and
self-medication.

Regulation

• In Australia, the use of MDMA and psilocybin to treat any conditions other than PTSD and
TRD, respectively, remain restricted under the existing Schedule 9 classification. Please refer
to the Clinical Memorandum: Therapeutic use of MDMA for PTSD and psilocybin for treatment
resistant depression for more information. All other psychedelic drugs remain in Schedule 9. In
Australia, outside of clinical trials, it is possible to seek approval to supply psychedelic
substances under the TGA’s Special Access Scheme (Category B) or the Authorised
Prescriber Scheme although, as Schedule 9 substances, additional state or territory
permissions may be required.

• In New Zealand, only ibogaine is registered by Medsafe and can be prescribed as a non-
approved medicine. A psychiatrist wishing to use any other psychedelic substance would need
to comply with the requirements of the Medicines Act and Misuse of Drug Act.

• Regulation governing use varies internationally. Some countries (including Israel, Switzerland
and Canada) have expanded access to allow for MDMA and psilocybin to be used under
expanded access schemes or other regulatory provisions, often on ‘compassionate use’
grounds for example in use in end-of-life depression and anxiety. Breakthrough designation by
the Food and Drug Administration (FDA) in the USA of MDMA for PTSD and psilocybin for

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 treatment-resistant depression indicates that the FDA believes the therapy may offer
substantial advantages over current therapies and is designed to expedite a treatment’s
transition to a prescribed medicine subject to adequate trial results.

• Regulation is subject to change and psychiatrists are advised to check with regulatory
authorities directly to ensure they comply with relevant regulation for psychedelic use.

Considerations for use of psychedelic therapy in treatment

• The clinical use of psychedelic substances should only occur under research trial conditions
that include oversight by an institutional research ethics committee and careful monitoring and
reporting of efficacy and safety outcomes. Active research is encouraged to build on the
current evidence-base.

• More research is needed to examine long term effects of the clinical use of psychedelic
substances. This mandates carefully designed trials within safe and comfortable settings led by
researchers with appropriate training, including specific training in psychedelic psychotherapy,
who understand the importance of maintaining professional boundaries.

• Community and media interest in psychedelic therapy as a promising therapeutic modality in

the face of worsening mental health statistics has led to strong pressure from some advocacy
groups to fast-track, or even bypass, clinical research and rapidly implement psychedelic
assisted therapy in community settings. [29] However, undue haste in translation to community
clinics could compromise essential aspects of efficacy, safety and equity, ultimately threatening
the sustainability of psychedelic assisted therapy. It is critical to avoid the pitfalls of the past,
and give due attention to possible pathways from clinical trials to community clinics. [29]

• Regulatory approval of psychedelic therapy should not pre-empt the adequate evidence-base
of the treatment. In addition, prior to any regulatory approval or movement into use outside of
research trials, there is need for appropriate treatment methodologies, adequate training by
those delivering the treatment, and an ethical and legal framework that provides appropriate
safeguards.

• The RANZCP supports psychiatrists continuing to expand their knowledge and to contribute
within the framework of current research practice to help inform the future use of psychedelic
therapy.

• It is acknowledged that research into the therapeutic potential of psychedelic substances has
been limited by legal restrictions and practical difficulties. Research trials often involve lengthy
ethics approvals and complicated access pathways, which may act as barriers to research. The
treatments can be expensive, and the short timeframes of application (1-2 sessions) puts limits
on the potential profitability of psychedelic therapies; as a result, there are few pharmaceutical
companies supporting research. Accordingly much of the research is funded by privately-
funded research and educational organisations that promote the therapeutic uses of
psychedelics. [5]

• The RANZCP welcomes further research into this area, including through initiatives such as the
MRFF Clinical Trials Activity Initiative in Australia to examine whether substances such as
psychedelic drugs, used in conjunction with psychological/psychiatric care, are effective and
safe for mental illness that has not responded to standard therapies.

Summary
While there is emerging evidence for the use of psychedelic therapies in the treatment of mental
illness in adults, the evidence is still in development. Further research is required to assess the
efficacy and safety of psychedelic therapies to inform future potential use in psychiatric practice.
There may be particular utility in this treatment for people who have not responded to conventional
treatments for mental illness. There are insufficient data on safety for individuals with psychotic

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illness (or vulnerability to it by for example familial risk). Use of psychedelic substances should only
occur under research trial conditions that include oversight by an institutional research ethics
committee and careful monitoring and reporting of effectiveness and safety outcomes. Such trials
should be led by researchers with appropriate training, including specific training in psychedelic
psychotherapy, to ensure appropriate management of risks and side effects.

As the evidence for the use of psychedelic therapies continues to evolve, this memorandum will be
reviewed and revised.

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This information is intended to provide general guidance to practitioners, and should not be relied on as a substitute for
proper assessment with respect to the merits of each case and the needs of the patient. The RANZCP endeavours to
ensure that information is accurate and current at the time of preparation, but takes no responsibility for matters arising
from changed circumstances, information or material that may have become subsequently available.

REVISION RECORD
Contact: Executive Manager, Policy, Practice and Research Department
Date Version Approver Description
05/2020 1.0 B2020/7 R5 New document
12/2021 1.1 PPPC Chair Updated only to include text box note that the CM is under review.
07/2022 2.0 B2022/9 R12 Reviewed and updated
06/2023 3.0 B2023/OOS 22 Reviewed and updated
20XX NEXT REVIEW

© Copyright 2023
Royal Australian and New Zealand College of Psychiatrists (RANZCP)
This documentation is copyright. All rights reserved. All persons wanting to reproduce this document or part thereof must
obtain permission from the RANZCP.

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