The promise and perils of psychedelic-assisted therapy

By Dr Jeremy Tannenbaum, Pain Specialist & Psychiatrist, West Perth

Psychiatric research has seen a resurgence of interest in psychedelic-assisted therapy (PAT) over the past two decades. The US Food and Drug Administration designated MDMA and psilocybin as ‘breakthrough therapies’ for post-traumatic stress disorder (PTSD) and treatment-resistant depression (TRD), respectively, in 201819, in a field where response and remission rates have been stagnant for decades.

From the 1950s until criminalisation and the ‘War on Drugs’ in 1970, over a thousand clinical papers on the therapeutic uses of psychedelics (mainly LSD and psilocybin) were published, and several international conferences held. Psychiatrists prescribed and often conducted treatment, including group therapies. Common indications were ‘neurosis’, OCD and alcoholism. Many psychiatrists had personal experience with psychedelics as part of their training.

In February 2023, the TGA surprised the clinical and research communities as it responded to lobbyists and rescheduled MDMA and psilocybin, going against the recommendations of leading experts in the field and undermining the scientific process. There are widespread concerns about the role lobbying, political and community interests played in the decision.

Rescheduling allows authorised psychiatrists to prescribe MDMA and psilocybin, in conjunction with psychotherapy; so-called MDMAassisted therapy (MDMA-AT) and psilocybin-assisted therapy (PsilAT). MDMA-AT will be indicated for PTSD and Psil-AT for TRD and must be supervised by the psychiatrist and conducted in controlled clinical settings.

From July 1, psychiatrists can apply, on a case-by-case basis, to a human research ethics committee and then the TGA to become an authorised prescriber. Authorised

Key messages

Research in psychedelics has been resurgent

From July 1st 2023, psychiatrists can apply to be authorised prescribers of MDMA and psilocybin therapy. However, there are concerns regarding the potential risks of MDMA, including neurotoxicity, medication interactions and cardiovascular effects. Concerningly, there have already been reports of patient-therapist boundary violations in clinical trials. prescribers must have experience, which at this stage is likely only accessible through participation in clinical trials. Therapists must also have additional training. New groups are vying to be the first to establish professional standards and accredited training organisations.

Hype needs to be tempered but there is genuine promise.

Psil-AT for TRD has also shown promise in recent clinical trials, with some studies showing significant improvements in symptoms lasting up to six or more months posttreatment.

Several phase 3 randomised control trials of MDMA-AT for PTSD have been conducted in recent years, with initial results indicating higher rates of response and remission compared to placebo. MDMA, a ‘serotonergic amphetamine’, induces mood elevation, fear extinction and pro-affiliative social behaviour, which can enhance the patient-therapist relationship.

MDMA may reduce adverse physiological, cognitive and affective responses in patients with PTSD, enabling them to revisit and work through traumatic experiences in

Partial or full agonism at the post-synaptic 5-HT2A receptor, characteristic of psilocybin and the other ‘classic’ psychedelics, induces neuroplastic changes and may destabilise the usually rigid, negative thought patterns characteristic of depression (and perhaps other mental disorders). Psychotherapy may harness transient neuroplasticity and cognitive shifts to allow patients to develop insights, change behaviour and hopefully enable recovery. Ketamine, a dissociative anesthetic, is increasingly used off-label for TRD and acute suicidality. Many trials are underway investigating ketamineassisted therapy (KAT) for psychiatric and non-psychiatric indications. Ketamine’s antidepressant effects have been attributed to NMDA receptor antagonism and other multimodal effects of the r and s-ketamine entantiomers and various active metabolites.

Unfortunately, relapse typically occurs after 7-10 days following a single dose, so repeated dosing may be required to see a benefit and to maintain effectiveness. The widespread emergence of unregulated ketamine clinics managed by health professionals without psychiatric expertise raises many concerns.

Psychological risks of psychedelics include 'bad trips’, flashbacks, and deterioration of mental state, for example, psychosis, or complications from withdrawing medications due to a potential drug interaction with psychedelics. Medical risks may include cardiovascular toxicity (MDMA and ketamine), and hepatotoxicity, bladder injury and cognitive impairment with ketamine.

Many of these risks are established in long-term recreational users, although the risks within therapeutic contexts are poorly understood. These risks may be minimised with robust screening, psychotherapy, safety and monitoring processes.

PAT trial results must be interpreted cautiously in confronting unrealistic expectations amplified by media hype. PAT trials are typically limited in size, scope, and duration. Participants may not be representative of clinical populations, and maintaining the blinding of participants and researchers has been challenging, introducing significant bias. Further, PAT trial therapy protocols are unrealistically intensive and usually involve two clinicians.

Crucially, significant challenges remain in translating PAT trial protocols into clinical services. These protocols are incompatible with the conventional, individual psychiatric/psychotherapy practice, and most other existing clinical services and funding models. There is no clarity on training requirements for clinicians. We have already seen the exploitation of vulnerable patients in clinical trials, and there are significant medicolegal risks for clinicians. Rigorous safety protocols and clinical guidelines do not exist, and peak bodies are yet to release updated position statements.

Having two therapists per patient in a dosing session is not feasible from a workforce or payer perspective and, therefore, is not viable as a business model. Dosing sessions alone can last half a day or more, which is exhausting for patients and therapists. This would reduce therapy access for other patients, and is a financial opportunity cost for therapists, and psychiatrists depending on the level of supervision required of them by regulators.

In my opinion, MDMA and psilocybin rescheduling was premature. Nevertheless, this reality is fast approaching.

While PAT offers exciting opportunities for treating psychiatric disorders, it is important to approach these treatments with cautious optimism, given the potential risks and challenges involved in translating these therapies into clinical services. This will require large-scale accredited training and education programs, the development of clinical guidelines, clinical service restructuring and digital transformation, a national framework for monitoring and outcome evaluation, and a commitment from payers to develop adequate funding models. Despite these challenges, I remain hopeful that person-centred care principles are compatible with sustainable and accessible PAT programs and that we will see these treatments integrated safely and effectively into mental health services.

– References provided on request. Author competing interests - Dr Tannenbaum has consulted for Emyria and Reset Mind Sciences and is engaged in several industry-sponsored clinical trials of psychedelic-assisted psychotherapy.