Psychedelics: unravelling the science and the hype

REGULATORS are under increasing pressure to expand access to psychedelic drugs for the treatment of mental illness. Experts say that although the science is promising, the hype is unhelpful.

In December 2021, the Therapeutic Goods Administration (TGA) rejected an application to down-schedule psilocybin and MDMA (3,4-methylenedioxymethamphetamine) from Schedule 9 (prohibited substance) to Schedule 8 (controlled substance). The move would have enabled patients to access the drugs through pathways such as the Special Access Scheme.

In its decision, the TGA cited expert advice that although psychedelics showed promise in highly selected populations as a psychotherapeutic treatment, this was only in the context of closely clinically supervised settings, with intensive professional support. More high quality research using larger scale studies were needed to determine the drugs’ safety and efficacy, the TGA said.

In January 2022, then federal Health Minister Greg Hunt announced that more trials were coming – $14.8 million of government funding was awarded to seven studies of innovative therapies for mental illness. These include studies using MDMA-assisted psychotherapy for treatment-resistant social anxiety in young adults with autism spectrum disorder, psilocybin-assisted psychotherapy for anorexia nervosa and treatment-resistant depression, and MDMA-assisted exposure therapy for comorbid alcohol use disorder and post-traumatic stress disorder (PTSD).

Leading psychiatrists have commended the government for investing in the science while resisting pressure to make the drugs more widely available.

Professor Ian Hickie, Co-director of Health and Policy at the University of Sydney’s Brain and Mind Centre, is a researcher on the MDMA study involving young people with autism. “This is important research and there’s an opportunity here; these drugs are different from what’s been available and there are a lot of people in need who don’t respond to conventional therapies,” Professor Hickie told InSight+.

“We need the science to answer the questions of which patients could benefit, at what dose, over what period and under what circumstances, and what the long term effects are.”

Associate Professor Vinay Lakra, President of the Royal Australian and New Zealand College of Psychiatrists (RANZCP) told InSight+ the science provided grounds for optimism.

However, he added: “Interest in psychedelics and advocacy for them is way ahead of where the science is – good science keeps the enthusiasm and the rhetoric outside”.

MDMA- and psylocibin-assisted psychotherapy

Melbourne psychiatrist Dr Nigel Strauss has been at the forefront of efforts to bring psychedelic medical research to Australia. He is personally helping fund a trial at Monash University using MDMA-assisted psychotherapy for treatment-resistant PTSD.

He is also involved in a trial at St Vincent’s Hospital Melbourne using psilocybin-assisted psychotherapy for end-of-life anxiety, and another at Swinburne University of Technology of psilocybin-assisted psychotherapy for treatment-resistant depression.

Dr Strauss said he was optimistic that the recent federal funding would help legitimise research in the sector, which has been stigmatised because of the history of recreational psychedelic drug use.

“There is probably enough soft evidence from the early era of psychedelics back in the 1970s to suggest these drugs are going to be effective,” he told InSight+.

“They’re not going to be a panacea; even though I hear certain organisations overexaggerating their potential to solve the mental health crisis, careful patient selection is crucial.”

Dr Strauss said psychedelic-assisted therapy typically involved a patient being administered the substance in a treatment session lasting up to 8 hours. The patient wears an eye mask and listens to gentle music under the supervision of two therapists. Depending on the condition, psychotherapy can be done during the dosing session or afterwards, in what is described as integration work.

“It works by enabling neuroplasticity,” Dr Strauss said. “People see things in a different way, and that helps in psychiatric conditions characterised by rigidity of thought.”

In relation to the treatment of PTSD with MDMA-assisted therapy, Dr Strauss said psychiatric and psychological treatments in the past have not always been effective.

“MDMA allows patients to go back into those frightening experiences and reprocess those events,” he said.

Dr Strauss said MDMA-assisted psychotherapy for PTSD was the frontrunner to become the first approved psychedelic medicine application in the world.

The US Food and Drug Administration could approve the indication as early as 2024–25, he said, based on the fact a phase 3 trial of it had been successful, and a second phase 3 trial will soon be completed.

The successful 2021 phase 3 study included 90 patients with severe PTSD, and found manualised therapy with MDMA was associated with “significant and robust” attenuation in PTSD symptoms compared with manualised therapy plus placebo. No major safety issues were reported in the MDMA arm of the study.

Addressing the limitations of blinding, the authors said it was reassuring that anecdotally, at least 10% of participants had inaccurately guessed their treatment arm.

The study was sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS) and its protocol and statistical analysis plan were developed in conjunction with the FDA. In 2017, MDMA-assisted therapy for PTSD was granted an FDA “Breakthrough Therapy” designation, a process designed to expedite the development and review of certain drugs.

Still, Professor Hickie said most research into MDMA- and psilocybin-assisted therapies was “in its very early stages”.

“Most respectable centres are engaged at looking at who may benefit in what way and trying to conduct comparisons with existing treatments and are looking at not just short term but long term effects,” he said.

“Establishing the efficacy of these compounds is really difficult because of the theatre that surrounds the situation – the setting, expectation, psychological therapy, being escorted through the trip,” he said. “That’s why functional [magnetic resonance imaging (MRI)] studies looking for independent brain markers are so important, so we can assess the treatment more objectively and compare with other treatments.”

Professor Hickie said another important issue to consider with psychedelic therapies was the “very vulnerable state” patients were in when they were under the influence.

“They are open to exploitation,” he said.

A recent ABC Four Corners episode included an interview with a patient who accessed MDMA-assisted psychotherapy in Canada as part of a MAPS trial. The patient claimed her therapist sexually assaulted her after the therapy session had ended. The trials are now being reviewed by Health Canada.

“These drugs do make people very suggestible, and this is why we have to be very careful about who is providing the treatment and under what conditions,” Dr Strauss said.

Dr Strauss urged RANZCP to establish a psychedelic medicine interest group and education programs for psychiatrists now to ensure they were ready for the arrival of psychedelic-assisted psychotherapies in the near future.

Ketamine: a different drug

The anaesthetic ketamine – and its components esketamine and arketamine – is sometimes referred to as a psychedelic, although it tends to induce a dissociative state rather than hallucinations.

There are several ongoing studies of ketamine infusions for major depression in Australia. Last year, the TGA also registered the first ketamine product for mental illness: esketamine hydrochloride nasal spray (Spravato, Janssen-Cilag). The product is approved as adjunct therapy for treatment-resistant depression – the first new class of drug to be approved as an antidepressant in Australia for 30 years.

Professor Hickie, who is involved in Australian Spravato trials, estimated around 300 Australians were now accessing the product for treatment-resistant depression. The spray is given twice per week in conjunction with a newly initiated oral antidepressant.

“One of the most promising features of esketamine is its rapid onset,” Professor Hickie said. “It works quickly, unlike existing antidepressants, which causes its reported effect on reducing suicidal behaviour.”

However, the effect generally lasts less than a week following a single dose, and at hundreds of dollars a dose, cost is prohibitive for patients not enrolled in clinical trials.

Professor Hickie stressed that unlike MDMA and psilocybin, ketamine was not used to guide psychotherapy.

“The patient just sits quietly and passes through the dream-like experience and 90 minutes later they report how they feel,” he said. “People who take it seem markedly less depressed, but they don’t report that their whole life has changed in its outlook – nothing like the hype that surrounds psychedelics like MDMA and psilocybin.”

The drug’s precise mechanism of action is not fully understood, although it has effects on the glutamatergic system as well as monoamine, cholinergic, opiate and cytokine systems.

An observational study published in 2022 found that out of 537 patients with depression who received a series of ketamine infusions at US clinics between 2016 and 2020, around half had at least a 50% reduction in their depression symptoms.

Among patients with suicidal ideation, 73% had a reduction in those symptoms. However, a subset (8.4%) of patients experienced an increase in depressive symptoms after induction, while 6% of patients reported increased suicidal ideation, the study found.

Professsor Hickie said further studies into ketamine’s long term effects were needed, including investigation into whether it causes dependency.

RANZCP has prepared detailed clinical memorandums on the therapeutic use of psychedelic substances and the use of ketamine in clinical practice (here and here).

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