Psychedelic-Assisted Therapies: Research Update

Psychedelic-assisted therapies are re-emerging as an option to treat mental illness. This article explores the state of the current research, with a specific focus on psilocybin (also known as “magic mushrooms”).

Introduction

According to the World Health Organization, about 1 in 8 people around the world live with a mental disorder (WHO, 2022a). The prevalence of different mental illnesses varies by country, and with sex and age, but anxiety disorders and depressive disorders are the most common (WHO, 2022b).

The modern era of psychopharmacology, which began in the mid-twentieth century with the discovery of antidepressant and antipsychotic medications, revolutionised the treatment of mental disorders (Braslow & Marder, 2019). However, it soon became apparent that between 20 – 60% of people with psychiatric conditions are treatment resistant, meaning they show limited or no response to these drugs (Howes et al., 2022). For clients with moderate to severe depression, psychotherapies such as cognitive-behaviour therapy (CBT) have similar response rates (Cuijpers et al., 2020). Therefore, new treatment options are urgently needed.

Psychedelic-assisted therapies (PAT), also known as psychedelic-assisted psychotherapies (PAP), have recently emerged as a possibility. These approaches involve the use of psychedelic substances in conjunction with psychotherapy to treat mental disorders and end-of-life distress (Reiff et al., 2020). Clinical research is still in the early stages, and sample sizes are small, but there are indications that PAT may lead to lasting changes in emotional well-being and mental health (Weir, 2020).

What are psychedelics?

Psychedelic substances are a type of hallucinogen. These drugs temporarily induce “non-ordinary states of consciousness” by powerfully altering thought processes, mood and perceptions of reality (Australian Psychological Society, 2021; National Institute on Drug Abuse, 2023; Nichols, 2004). Because they are mind-altering, hallucinogens are also described as psychoactive. When used to treat mental illness, they are considered psychotropic drugs.

Hallucinogens are typically categorised into four classes based on their pharmacological mechanism of action and chemical structure (Table 1). Some hallucinogens, such as psilocybin, are found in hundreds of species of fungicollectively referred to as ‘magic mushrooms’. Other hallucinogens derive from plant sources e.g., mescaline from the peyote cactus, DMT from the Psychotria viridis shrub (a component of ayahuasca), salvinorin A from the Mexican sage Salvia divinorum and ibogaine from the root bark of the African shrub Tabernanthe iboga (Mash, 2023; Schlag et al., 2022; Zawilska & Wojcieszak, 2013). Hallucinogens that are made in a laboratory, such as LSD, MDMA, PCP and ketamine, are referred to as synthetic (Cleveland Clinic, 2023; Johnson et al., 2019).

Table 1. Classes of hallucinogens (Garcia-Romeu et al., 2016; Lodge & Mercier, 2015; National Institute on Drug Abuse, 2023; Nichols, 1986; Tupper et al., 2015).

Class	Mechanism of action	Examples
Psychedelics / classic hallucinogens (drugs that can bring on vivid visions and affect a person’s sense of self).	Serotonin 2A receptor (5-HT2AR) agonists (drugs that primarily influence the way the brain processes serotonin).	Psilocybin, Mescaline, DMT, LSD (‘acid’)
Empathogens or entactogens (drugs which produce feelings of empathy, emotional openness and connection).	Mixed serotonin and dopamine reuptake inhibitors and releasers (drugs that affect both serotonin and dopamine systems).	MDMA (‘molly’, ‘ecstasy’), GHB
Dissociative anaesthetics (drugs which produce feelings of being disconnected from the body and environment).	NMDA antagonists (drugs that primarily affect how the brain processes glutamate).	Ketamine PCP (‘angel dust’), Dextromethorphan, Nitrous oxide (‘laughing gas’)
Atypical hallucinogens (drugs that produce a variety of effects).	Diverse mechanisms of action.	Salvinorin, AIbogaine

While MDMA is often included in discussions of “psychedelic”-assisted therapies, it is important to point out that this substance is a hallucinogen, not a psychedelic. Nevertheless, throughout this article we will adopt the common usage of the terms PAT and PAP to refer to any psychotherapy employing hallucinogens.

Effects of hallucinogens

Unsurprisingly, as pharmacological agents, the effects of hallucinogens depend on the drug (e.g., psilocybin or MDMA), the dose, and the route of administration (e.g., oral ingestion, injection, intranasal, smoking, etc.). What may be more surprising is that extensive experimentation in humans has demonstrated the pharmacology of psychedelics is not solely responsible for determining the subjective effects; these are also uniquely person-dependent.

Factors such as the user’s biology, age, sex, prior drug experiences, personality, current mood, and psychological expectations or mindset (commonly referred to as set) all play a role in the subjective effects of the drug (Garcia-Romeu et al., 2016; Studerus et al., 2012). The experience is also highly dependent on the setting, the social and environmental context in which the drug is taken (Carhart-Harris et al., 2018). This insight about the influence of set and setting helps explain the variability in reactions to hallucinogens across different studies (Garcia-Romeu et al., 2016).

With the above caveats in mind, common effects of hallucinogens include the following acute and transient changes in somatic, perceptual, cognitive and affective processes:

• Hallucinations involving sight, e.g., ‘visions’ involving vibrant colours and scenes
• Hallucinations involving sound, taste and touch
• A blurring of the senses such as sounds being ‘felt’ or colours being ‘heard’
• Reliving vivid memories
• Feeling detached from the body
• Sometimes mystical, ecstatic or spiritual experiences
• Distortions of time, direction and distance, and
• Strong emotions ranging from bliss to fear, anxiety and confusion (Better Health Channel, 2018; Garcia-Romeu et al., 2016; Griffiths et al., 2018; National Institute on Drug Abuse, 2023; Nichols, 2016).

Risks and side effects

When considering the risks and side effects of psychedelic substances, it is important to distinguish between use in clinical and research settings and street use. The street use of psychedelics is fundamentally uncontrolled and the drugs are often contaminated by other substances (Australian Psychological Society, 2021).

In research settings where the substances are of known purity and dose and are administered under controlled conditions, hallucinogens are well tolerated. Clinical trial participants may temporarily experience adverse physical effects such as headache, nausea or changes in heart rate, but these effects are typically not life-threatening. Impaired thought processes and perceptions can cause people using these drugs to behave in unusual and sometimes dangerous ways. Therefore, it is important for another person to be present who can help prevent or respond to an emergency (Breeksema et al., 2022).

However, it should also be noted that research in clinical settings typically screensforand oftenexcludes high-risk individuals such as people with a personal or family history of psychosis or a personal history of mania, violence towards others or acute suicidality. Long-term perceptual disturbances such as hallucinogen persisting perception disorder are also a concern, despite some population studies failing to find a link between psychedelic use and mental health problems (Australian Psychological Society, 2021; Johansen & Krebs, 2015).

The history of psychedelic use

While the use of psychedelic substances for spiritual and therapeutic purposes by Indigenous and First Nations peoples predates recorded history, their use in Western medicine is relatively recent (Nichols, 2016). The potential psychological benefits were first identified in the mid-1940s, with research taking off in the 1950s-1960s. During this period the experiences of more than 40,000 patients were documented in 1,000 academic papers (Grinspoon & Bakalar, 1997).

However, widespread psychedelic use associated with the hippie counterculture movement resulted in growing concerns about potential drug abuse and stigmatisation of psychedelic use that still persists today (Beswerchij & Sisti, 2022). All major psychedelic research programs came to an abrupt halt following the Schedule I classification in the United Nations Convention on Psychotropic Substances in 1971 (Australian Psychological Society, 2022; Carhart-Harris & Goodwin, 2017). Schedule I is the most restricted category, applying to substances considered to have no accepted medical use and which pose a serious risk to public health due to the potential for harm and dependence (Nutt, 2019).

Parties to the UN Convention agreed to:

“Prohibit all use except for scientific and very limited medical purposes by duly authorized persons, in medical or scientific establishments which are directly under the control of their Governments or specifically approved by them… and to require that manufacture, trade, distribution and possession be under a special licence or prior authorization” (United Nations, 1971).

Although access to psychedelics is still highly restricted, there has been a ‘renaissance’ of psychedelic research in the past 15-20 years driven by the need for better mental health treatment options (Hadar et al., 2023; Sessa, 2012).

Psychedelic use vs psychedelic-assisted therapy

Pharmacotherapy refers to treatment using medications. Conventional pharmacotherapy for mental illnesses typically involves a family physician and/or psychiatrist prescribing one or more psychotropic medicines such as antidepressants, antipsychotics, anxiolytics (anti-anxiety medications), sedative-hypnotics or mood stabilisers. Unlike conventional psychotropic pharmacotherapy, PAT includes both a psychotropic medication AND intense psychotherapy sessions in a highly supportive and structured environment (The Royal Australian and New Zealand College of Psychiatrists, 2022).

Studies from the pre-prohibition period that neglected a therapeutic setting and support generally failed to produce positive outcomes (Andersen et al., 2021). In other words, research demonstrates that psychedelics alone are not viable treatments; rather, they are an adjunct tool for psychotherapy. The presence of psychological support is an essential aspect of the psychedelic treatment model (Australian Psychological Society, 2021; Kisely et al., 2023; Rucker et al., 2018). This is consistent with a related finding from a meta-analysis of 101 studies involving almost 12,000 patients with moderate to severe depression that showed patients receiving a combinationof psychotherapy and drug therapy were 25% more likely to respond to treatment compared with drug treatment alone (Cuijpers et al., 2020).

It is currently unclear how much of the therapeutic benefit is due to the psychedelic drug and how much is attributable to the concurrent psychotherapy; this issue needs to be further studied (Kisely et al., 2023; The Royal Australian and New Zealand College of Psychiatrists, 2022). One of the issues complicating PAT research is that the therapy component is not standardised and has been understudied (Browne, 2023; McNamee et al., 2023).

Evidence and current research: Psilocybin

Evidence for the therapeutic benefits of psychedelic-assisted therapies can best be described as emerging, but promising. To date, psilocybin and MDMA have been the most well studied substances.

In this article we will review the evidence for psilocybin, and restrict our discussion to studies employing the ‘gold standard’ of clinical trial designs, randomised controlled trials (RCTs). As of mid-2023, psilocybin has been investigated in eight RCTs (Table 2).

Table 2. RCTs involving psilocybin to treat mental disorders.

Study	Number of participants	Condition	Design and control	Results
Grob et al. (2011)	12	Depression and anxiety in life-threatening disease.	Placebo controlled crossover trial, active placebo = niacin, intervention = single dose of psilocybin 0.2 mg/kg.	Mood improved for 2 weeks after treatment but this was not statistically significant. Improvement in depression scores reached significance at 6-month follow-up.
Ross et al. (2016) and       Agin-Liebes et al. (2020) (follow-up study)	29     15 (sub-set of participants who were still alive and agreed to participate in follow-up study)	Depression and anxiety in life-threatening disease	Placebo controlled crossover trial, active placebo = niacin, intervention = single dose of psilocybin 0.3 mg/kg.	Statistically significant difference from placebo. Improvements in anxiety and depression sustained at 6-month follow-up. Approximately 60–80% of participants met criteria for clinically significant antidepressant or anxiolytic responses at 4.5 year follow-up.
Griffiths et al. (2016)	51	Depression and anxiety in life-threatening disease	Placebo controlled crossover trial, placebo = low dose psilocybin, intervention = single high dose of psilocybin (22 or 30 mg/70 kg).	Statistically significant difference from placebo. Improvements in anxiety and depression sustained at 6-month follow-up.
Carhart-Harris (2021)	59	Major depressive disorder	Comparator controlled, comparator = escitalopram (a selective serotonin reuptake inhibitor), intervention = two 25 mg doses of psilocybin three weeks apart.	No significant difference between psilocybin and escitalopram in the pre-determined primary outcome, although changes in secondary outcomes generally favored psilocybin.
Davis et al. (2021) and Gukasyan et al. (2022) (follow-up study)	24	Major depressive disorder	Wait list control, intervention = two doses of psilocybin (20 mg/70 kg and 30 mg/70 kg) one week apart.	Psilocybin superior to remaining on a wait-list. 75% and 58% of participants respectively showed a treatment response or remission at 12-month follow-up.
Goodwin et al. (2022)	154	Treatment-resistant depression	Placebo controlled, placebo = low-dose psilocybin, intervention = single therapeutic dose of psilocybin (two different doses, 10 mg and 25 mg, trialed).	Psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than placebo over 3 weeks but was associated with adverse effects.
Bogenschutz et al. (2022)	49	Alcohol use disorder	Placebo controlled, placebo = diphenhydramine, intervention = two doses of psilocybin (25 mg/70 kg and 25-40 mg/70 kg) four weeks apart.	Robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy.
von Rotz et al. (2023)	26	Major depressive disorder	Placebo controlled, placebo = mannitol, intervention = single dose of psilocybin (0.215 mg/kg).	A single, moderate dose of psilocybin significantly reduced depressive symptoms vs placebo for at least two weeks.

Psilocybin is generally well-tolerated and there are few reports of adverse events (Carhart-Harris et al., 2016; Grob et al., 2011; Johansen & Krebs, 2015; Kisely et al., 2023). An analysis of 110 healthy participants found no evidence of hallucinogen persisting perception disorder, prolonged psychosis or other long-term impairment (Studerus et al., 2011). However, both acute and longer term effects of psilocybin on psychological functioning appear to be dose-dependent which suggests that care must be taken to ensure the dose is controlled (Griffiths et al., 2018).

In summary, psilocybin-assisted therapy is showing encouraging results for the treatment of end of life distress, treatment-resistant depression, major depressive disorder and alcohol use disorder. Importantly, rapid and sustained therapeutic benefits have been demonstrated from as little as a single dose. On the back of the early trials, the U.S. Food and Drug Administration (FDA) granted psilocybin “breakthrough therapy” status for treatment-resistant depression in 2018 and major depressive disorder in 2019 (Marks, 2021). The breakthrough therapy designation is designed to expedite the development and review of drugs to treat serious conditions where preliminary clinical evidence indicates that the drug may represent a “substantial improvement over available therapy on a clinically significant endpoint” (U.S. Food & Drug Administration, 2018).

From 1 July 2023, Australia will be the first country in the world to make psychedelics nationally available for medicinal use. The Australian equivalent of the FDA, the Therapeutic Goods Administration, will allow authorised psychiatrists to prescribe psilocybin for treatment-resistant depression (Therapeutic Goods Administration, 2023). For this specific use, psilocybin will be listed as a Schedule 8 (Controlled Drugs) medicine in the Poisons Standard. For all other uses, it will remain in Schedule 9 (Prohibited Substances) which largely restricts its supply to clinical trials.

Limitations of current evidence for psilocybin-assisted therapies

There are many limitations of the current evidence for psilocybin including:

• Variations in the dose between studies making it unclear what constitutes a therapeutic dose.
• A lack of consensus and standardisation of the psychotherapy component of the intervention.
• Sample sizes remain small as there have been no Phase III multi-center clinical trials.
• Treatments have rarely been compared to existing first-line pharmacotherapies.  
• Few longitudinal studies to assess long term effects.
• Strict eligibility criteria have resulted in highly selected and homogeneous samples which makes generalizability to more typical clinical populations unknown (Ledwos et al., 2022).
• PAP studies are functionally unblinded as both the researchers and participants are aware of the absence or presence of psychoactive effects, leading to a high risk of expectation bias and nocebo effects (Ledwos et al., 2022; Mertens et al., 2022).
• Adverse events have not been systematically addressed in all studies (Breeksema et al., 2022).

A recent critical appraisal of evidence on the efficacy and safety of serotonergic psychedelic drugs as emerging antidepressants concluded:

“Given the methodological limitations of published RCTs, the evidence supporting the efficacy and safety of serotonergic psychedelics for depression is currently of low level. Future research should assess the role of expectancy and psychedelic effects in moderating and mediating treatment response. Innovative trial designs are needed to overcome functional unblinding. For now, psychedelics should remain experimental interventions used within clinical trials” (Ledwos et al., 2022).

Further randomised control trials (RCTs) with larger populations that evaluate the safety, tolerability and efficacy in clinically representative populations are thus warranted (Gill et al., 2020).

In a follow-up article we take a closer look at the ‘therapy’ component of PAT, consider how PAT works by exploring the neurobiological mechanisms, and finish with the legal status of psychedelic-assisted therapies across the globe.

Key takeaways

• Because many clients do not respond to conventional drug or psychotherapies for mental disorders, alternative treatment options are urgently needed.
• Psychedelics were widely studied as treatments for mental health conditions in the 1950s–1960s. However, their use was prohibited around the world by the early 1970s. There has been a renaissance of research interest in the past two decades.
• Hallucinogens include psychedelics, empathogens/entactogens, dissociative anesthetics and other hallucinogens. These drugs temporarily induces non-ordinary states of consciousness.
• The effects of hallucinogens are dose-dependent. The effects are also strongly influenced by the mindset (‘set’) of the user and the setting in which the drug is taken.
• The current research evidence indicates psychedelics are only effective for the treatment of mental health conditions when combined with psychotherapy. The therapy component varies between studies.
• There is emerging evidence for the efficacy and safety of psilocybin in the treatment of end of life distress, treatment-resistant depression, major depressive disorder and alcohol use disorder.
• Until larger scale Phase III trials have been conducted, psilocybin remains an experimental treatment despite ‘breakthrough therapy’ designation by the U.S. FDA for treatment-resistant depression and major depressive disorder.

Useful links

• Multidisciplinary Association for Psychedelic Studies
• Australian Multidisciplinary Association for Psychedelic Practitioners
• Psychedelic-Assisted Therapy (Resources)
• Psychedelics 101: Books, Documentaries, Podcasts, Science, and More
• How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks
• The Science of Psychedelics for Mental Health

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