Psychedelic research renaissance: The urgent quest for new mental health medicines

There’s a story from way back in Australian scientific history about the Melbourne psychiatrist, Dr John Cade. He was the one to first discover the mood-stabilising effects of lithium in 1949, a breakthrough that has great resonance today, given the urgent quest for new mental health medicines.

Lithium remains one of the most prescribed medicines in mental health, for bipolar disorder. But it’s one of very few of the “old” psychiatric drugs that still work well for most people most of the time.

Ambitious new science for treating poor mental health, like Dr Cade’s, is fast emerging.

Cade was the son of a doctor, born in the Victorian wheat town of Murtoa. At the time of his earliest discoveries, the only Western treatments for mental illnesses were a lobotomy or electric shocks. His singular finding – that lithium carbonate worked on bipolar – meant it became the oldest mental illness medicine still commonly used.

He was already practising before World War II, in Melbourne, then went to war in Singapore with a field ambulance unit. He was captured and sent to Changi prison for three years, but was able to keep observing patients in a prison hospital, and began to conduct experiments on nutrition, but also “mania” (as it was called then) via patients’ urine.

After the war and safely back in Melbourne, he began working at a repatriation hospital, and continued his experiments using a disused kitchen as a makeshift lab.

He eventually published his findings on 10 patients with “psychotic excitement”, “mania” or “manic depression” – what we now know as bipolar disorder – in the Medical Journal of Australia.

According to Nature, the paper “went largely unnoticed at the time”, but after more detailed work by two Danish psychiatrists through the 1960s – with data published in 1971 – Dr Cade’s formative role was finally appreciated.

The times are changing in mental health research

While far from a cure, lithium remains one of the more effective psychiatric medications, particularly in the treatment of the manic phase of bipolar.

However, most available psychiatric treatments aren’t able to adequately treat about one-third of people with a mental illness – and present with substantial side-effects. Most, also, take up to a month to begin working.

As rates of mental health disorders in the community continue to climb, the early promise of psychiatry as a brain-based solution to mental distress hasn’t been fulfilled.

But times are changing. In March this year, Australia’s federal government committed $15 million to explore a new frontier in mental health research – psychedelics, and their use in facilitating psychotherapy for common mental illnesses.

A month before the landmark government funding announcement, the Royal Commission into Victoria’s Mental Health System highlighted the severity of the mental health crisis, and the lack of new and effective medicinal treatments.

These milestones represent a seismic shift in both research potential and traditionally conservative thinking regarding the possibilities of compounds such as psilocybin (the psychoactive substance in “magic mushrooms”) and MDMA (the active substance in some street “ecstasy”), the likes of which have remained prohibited – except for very limited research purposes – since former US president Richard Nixon’s “War on Drugs” in the 1970s.

Heading into 2022, Melbourne is again at the forefront of new mental health research. Monash University has embarked on cross-faculty psychedelic research, which includes the country’s largest clinical trial, led by Dr Paul Liknaitzky.

Results from small clinical trials internationally are so far overwhelmingly positive. A few mostly small hospital or university trials are also underway (or approved) elsewhere in Australia, looking into psilocybin in the treatment of end-of-life distress, depression, and methamphetamine use disorder.

“Monash has a deep breadth of expertise in medicinal chemistry, pharmacology, psychiatry and psychology, as well as our ability to draw on leading experts in the neuropsychopharmacology field through our global networks,” says the Dean of the Faculty of Pharmacy and Pharmaceutical Sciences (FPPS), Professor Arthur Christopoulos.

“The bottom line for me is that mental ill-health was always a big problem before COVID, and it’s only getting worse. The time is right to link up these activities and drive novel neuromedicine research for psychiatric illnesses.”

The role of psychedelics throughout history

In many ways, it’s a case of back to the future. Cultural histories suggest that many ancient civilisations in Mexico, South America, Siberia and Europe utilised the effects on consciousness of some psychedelic fungi and plants.

The nexus between mental health treatment and psychedelics goes back to the 1940s, but it later effectively stopped after the drugs became increasingly researched by scientists but also used in the wider community, out of scientific hands. The result was a politically-driven moral panic and bans.

“The problem,” says Monash’s Department of Psychiatry head, Professor Suresh Sundram, “is that despite the insights we’ve seen, we haven't had any major improvement in their development.

“We want to subject psychedelics to the proper rigour that should have been done back then. From these data we want to see if we can establish a paradigm shift towards a new, precision approach to the treatment of psychiatric disorders.”

Clinical trials and specialist training

In the spirit of Dr John Cade, a number of psychedelic studies are underway at Monash with funding from a variety of sources, including industry, philanthropy, government, and the University.

The Clinical Psychedelic Research Lab at Monash, the first psychedelic medicine lab in Australia, is establishing several clinical studies.

One of these trials will investigate whether psilocybin-assisted psychotherapy can safely and effectively treat severe and entrenched anxiety; another will look at a form of psychotherapy facilitated by MDMA – an “entactogen” rather than a classic psychedelic – in the treatment of severe PTSD.

These drug treatments are delivered alongside psychotherapy, and trial therapists have undergone specialised training to facilitate the long sessions.

The group’s leader, Dr Liknaitzky, is a research fellow at the Turner Institute for Brain and Mental Health, and Department of Psychiatry. His group has also developed and delivered the first applied psychedelic therapist training in Australia, obtained the first industry funding and partnership for clinical psychedelic research, and has numerous local and international collaborations with leading experts in psychedelic science and treatment.

“The bottom line for me is that mental ill-health was always a big problem before COVID, and it’s only getting worse. The time is right to link up these activities and drive novel neuromedicine research for psychiatric illnesses.” – Arthur Christopoulos, Dean, Monash Faculty of Pharmacy and Pharmaceutical Sciences

Another of Monash’s psychedelic trials, PSICONNECT, in a healthy population, will be led by Associate Professor Adeel Razi. This trial will use brain imaging to record, in real time, the peak effects of psilocybin on the brains of healthy subjects. This trial is looking to decipher the connection between the psychological and neurological effects of psilocybin (that is, how it works) in a normal functioning brain. This is a poorly-understood area.

Other Monash groups are investigating the use of psilocybin in preclinical studies, and conducting survey and qualitative research on psychedelic use.

A multidisciplinary approach

Further trials and translational research studies are in advanced planning. Monash experts from across the pharmaceutical sciences, psychiatry, psychometrics, psychotherapy, risk mitigation, governance, behaviour change, computational neuroscience, and mental health are involved.

Some of the central questions are:

• Can these prohibited substances, combined with psychotherapy, dramatically improve outcomes across a range of poorly-treated mental health disorders?

• Can a better understanding of the causes of mental ill-health be found? Will a process of potentially addressing more fundamental causes of psychological distress than surface symptoms show us more about the illnesses themselves

• Can we discover more about what happens at a molecular and cellular level in the brain after taking psychedelic substances, and can that knowledge help those who suffer?

• And, do psychedelic-assisted psychotherapies represent a new form of treatment that can directly and effectively target both the brain and mind simultaneously? Will this allow mental health treatments to finally catch up to those available for other diseases, such as cancer and heart-disease, which now have new science and more targeted therapies?

These studies appear crucial in an ongoing mental health crisis, with mental illness being this century’s leading cause of disability.

“There is a vast unmet need for safe and effective medicines for mental health disorders,” says Dr Chris Langmead, of FPPS’s Monash Institute of Pharmaceutical Sciences (MIPS).

Dr Langmead is co-lead of the Neuroscience and Mental Health Therapeutic Program within MIPS.

“Poor mental health represents a growing problem in our society, and it’s being increasingly recognised as such,” he says.

“There’s been rising expenditure in programs trying to address mental health, but the extra spending is not addressing the rates of disorders that we see.”

Statistics tell the story

The numbers are unequivocal. One in eight Australians are on antidepressants (including one in four older Australians), yet at best only about half report adequate improvement.

Psychotherapy alone, too, has mixed results. The Australian Institute of Health and Welfare says nearly half of all Australians (aged 16-85) experience a mental health disorder during their lifetime, most commonly either anxiety or depression, or both. Eight Australians take their own lives each day.

The public health burden is huge – the Productivity Commission estimates mental illnesses cost the economy $A220 billion a year.

Read more: Acting early to break the cycle of family mental illness

Professor Christopoulos recently told the landmark Royal Commission into Victoria’s Mental Health System that there’s been no real innovation in psychiatric medicine discovery for nearly 50 years.

“My passion has always been the desire for better treatments of mental illness,” he says now.

“For decades, our medicinal armamentarium has comprised medicines that are often taken long-term, aren’t effective for a large portion of patients, and are associated with significant adverse effects.

“Addressing this impasse is what drives me. There’s a missing piece of the puzzle, and it’s possible that we have ignored this for a very long time.

“We need to focus on the neuromedicines of the future.”

Realising this “future”, however, requires appropriately designed and validated basic, preclinical, and clinical research.

“When it comes to psychedelic medicines, it’s important to understand that you’re not going to be going to a GP, getting a prescription, then walking into a pharmacy to get them,” says Professor Christopoulos.

“These medicines should only be used under clinical supervision to assist psychotherapy. Understanding how to deliver the appropriate therapy, in parallel to investigating how these drugs work, is thus going to be vital – particularly for registration and regulation purposes.”

The field is booming. As well as scientists and therapists, investors and industry are very excited by the possibilities.

“There’s been a resurgence in research and interest in psychedelic medicine over the past two decades, and particularly so over the past five years,” says Dr Liknaitzky.

“I’m heartened to see a generational shift in perceptions, and an increasingly productive and insightful scientific field – this is now one of the fastest-growing areas of biomedicine globally. The misunderstandings around safety have already shifted; that narrative has already transformed.

“In fact, I’m now less concerned about old-world conservatism blocking important research, and more concerned about a new-world evangelism running it off the rails, again.”

The promise of psychedelics, he says, has also “attracted those in a rush to dominate a new opportunity at the expense of rigorous science, adequate training, and a therapeutic approach that is informed by the evidence-based best-practice of the field”.

“So much remains unknown about how these treatments work, how best to deliver them, and what some of the potential drawbacks might be,” Dr Liknaitzky says.

“In our clinical trials and related projects, we’ll also be asking questions such as: Who responds to which therapies, and why? How can we sustain the benefits over the longer term for more people? What aspects of the treatment are doing the heavy lifting? And how do we develop a viable collaborative care model for future service delivery?”

Stigma remains a hurdle for research

Times are changing, says the leader of the Reason Party and Victorian Legislative Council member Fiona Patten, who enjoys support from all sides of Victorian politics. But, she adds, they’re changing slowly. Medicinal cannabis, she points out, is still hard to access in Victoria.

“The stigma of all these substances, because of their recreational use, sets up very difficult barriers for researchers and regulators,” she says. “But I like the confidence of the scientists, and I like the results I have seen so far. It’s excellent to see Monash in the game.”

“Some of the results are spectacular, and the opportunity is enormous.” – Dr Chris Langmead, Monash Institute of Pharmaceutical Sciences

It’s been a very long road to this point, and researchers still face significant regulatory hurdles to make it happen. The “prohibition” began with Nixon – not known for his governance or political character – and his “War on Drugs” has prevented institutions from being able to research and understand certain psychoactives; psilocybin, MDMA, LSD, DMT, and related substances.

Psilocybin mushrooms may have been used by ancient peoples in both spiritual rituals and treatment from as long as 6000 years ago.

MDMA was first made in Germany in 1912, when scientists were trying to make precursor chemicals for treating bleeding disorders. It was used with psychotherapy (as were psilocybin and LSD) in the US in the postwar era to treat a range of psychological maladies, and in couples counselling, but was subsequently banned.

All these compounds, however, have remained in widespread underground use within recreational, ceremonial, and therapeutic contexts.

Psychedelics research has gone global

There are now about 100 studies worldwide looking into psychedelic psychoactive substances for use in mental health therapy.

This year alone, important findings have been published. A team from the Multidisciplinary Association for Psychedelic Studies (MAPS) in California, in an advanced phase three trial, found that 67% of participants who received three MDMA-assisted therapy sessions for severe and protracted PTSD no longer had PTSD at the end of the study. Close to 90% reported a significant reduction in symptoms.

The study found no relationship between onset or duration of PTSD and how well the treatment worked. Other studies show that few participants seek to find the drug outside of the clinical therapy sessions.

Meanwhile, the Psychedelic Research Centre at London’s Imperial College found psilocybin acted on treatment-resistant depression faster than a current standard-of-care antidepressant.

Dr Liknaitzky describes what the patients get as “therapy with feelings”. They potentially get a “more expansive or flexible or compassionate” view of themselves and the world.

“A wider aperture,” he says.

Read more: Double trouble: How severe lockdown restrictions have taken a toll on population mental health

A smaller study late last year, led by the storied Johns Hopkins School of Medicine in Baltimore, found participants with major depressive disorder who received immediate psilocybin-assisted therapy, compared with delayed treatment, showed improvement both immediately and one month later.

“Frankly,” says Monash’s Dr Chris Langmead, “some of the results are spectacular, and the opportunity is enormous,”

“How do we now use that information and then take it in a comprehensive, research-orientated manner to find the best way forward, to find the right therapeutic with the right psychotherapy for the right patient with the right disorder?

“Once we do this, we can make recommendations to healthcare policymakers in government to move it from promising research into a new generation of therapeutic options for patients.”