As Australia became the first country in the world to classify psychedelics as medicines last week, major health organisations have urged caution, even as some experts and patients have hailed the landmark moment.
The decision, which follows the medicines regulator, earlier this year, approving the use of psychedelics to assist therapy sessions, will see psilocybin, found in magic mushrooms, being used for treatment-resistant depression, and also allow MDMA, known as ecstasy in tablet form, for post-traumatic stress disorder (PTSD) treatment.
The BBC reports that Professor David Nutt, head of neuropsychopharmacology at the UK’s Imperial College, congratulated Australia on “leading the world in this vital treatment innovation”, while psychedelic researcher and psychiatrist Dr Ben Sessa described the approval as pioneering.
“This is where the global psychedelic spotlight now shines,” he said.
Other countries have explored psychedelics for compassionate use, including Switzerland, Canada and Israel, where regulators have made similar decisions, although not nationally, like Australia. Psychedelic clinics also operate legally in countries including Jamaica and Costa Rica.
But how Australia rolls out clinical prescriptions for both drugs, and at what price tag, will be closely watched, reports the BBC.
First developed as an appetite suppressant in 1912, ecstasy was used in therapy sessions in the US until the mid-1970s when it was outlawed. It entered Australia in the 1980s as a party drug due to its reported effects of increased energy, empathy and pleasure, and was criminalised in 1987.
In the 2000s though, research slowly started up again, with recent trials finding that both MDMA and psilocybin can quickly improve symptoms of severe depression, though little is known about how they do this.
Mind Medicine Australia (MMA), a charity which lobbied for psychedelic treatments, is helping to train health professionals tasked with procuring and prescribing the drugs.
To become an authorised prescriber, psychiatrists must apply to an ethics committee and to Australia's drugs regulator the Therapeutic Goods Administration (TGA); and then source and supply both MDMA and psilocybin.
Once all expenses are factored in, including the drugs themselves, supervision from multidisciplinary teams, psychiatrist sessions and hiring a private clinic, costs could spiral to about $15 700 to $20 000 per treatment, according to one psychedelics expert.
Due to the price tag, Dr Stephen Bright, senior lecturer at Edith Cowan University, says he doubts these treatments “will be very widely available at all” for the first 12-18 months.
With no planned government subsidies, the five-figure treatments are expected to remain unaffordable for most patients.
‘Not a miracle cure’
On the other side of the fence, Australia’s major medical and mental health bodies are pushing back against psychedelic treatments.
“There’s been considerable caution from the scientific and medical community,” said Kristen Morely, a professor of addiction medicine at the University of Sydney.
According to MMA, the “weight of submissions from thousands of Australians whose current mental health treatments just aren’t working” helped get the TGA approval over the line.
The Australian Medical Association (AMA) and the Royal Australian and New Zealand College of Psychiatrists (RANZCP) have also expressed serious concerns, both groups calling for larger-scale studies and better research into psychedelic treatments, warning of unknown risks, long-term side effects and “potentially very limited benefits: from their use in therapy.
“Psychedelic-assisted therapy may offer hope to a small number of people where other treatments have been attempted without success. But it’s not a miracle cure,” warned Professor Richard Harvey, who chairs the RANZCP’s Psychedelic-Assisted Therapy Steering Group.
He urged a “cautious, considered and informed” approach, due to the “potential for psychedelic substances to cause fear, panic and re-traumatisation”.
“Vulnerable people can understandably feel distressed if their experience doesn’t match their expectations of this therapy,” he said.
It’s also unclear, he argued, whether the results from psychedelic treatments stemmed more from the substances themselves, or the psychotherapy.
“Put simply, psychedelic-assisted therapy is in its infancy. There is more we need to know.”
Theories on how psychedelics work
In the United States, the founder of Field Trip, a chain of shuttered ketamine clinics currently facing insolvency, last month put forward an unexpected theory of how psychedelics work to treat depression.
“The truth is, almost all of the effect of psychedelic-assisted therapy could be placebo,” said Ronan Levy, speaking at a five-day conference on the emerging field of psychedelic medicine.
“Personally I don’t have a problem with that. The outcomes are the outcomes, and that’s really what matters in my view.”
Some researchers attribute a therapeutic effect to a combination of physical changes in the brain – though where, exactly, is still uncertain – plus personal experiences while high and in the days after psychedelic treatment. Or maybe the strength of the mystical experience while on psychedelics determines the psychological response. Or, it could be entirely biochemical.
“How do you make sense of it?” said Boris Heifets, anaesthesiology professor who studies ketamine at Stanford University. “Some of it just has to be wrong.”
The confusion and combination of evidence presented at the conference reflects a field still in the early stages of trying to disentangle a potential medical treatment, reports STAT.
Many types of psychedelics – both traditional drugs, like MDMA and psilocybin, and newer, modified versions – are under investigation as treatment for a range of mental health conditions, including depression and post-traumatic stress disorder.
Though there are plans to submit trials on MDMA for PTSD to the US Food and Drug Administration for approval later this year, none of the medications has yet been definitively proven to work. And the question of how they work is very much up for debate
“There’s an awful lot of uncertainty,” said Fred Barrett, cognitive neuroscientist and director of Johns Hopkins Centre for Psychedelic and Consciousness Research. “Part of that uncertainty comes from the very small amount of data that exists.”
The research to tease out the mechanisms of psychedelics is based on animals or studies of humans with small sample sizes, meaning there’s no definitive evidence yet.
The divergence of theories and lack of clarity receives little attention in journal press releases and media coverage of psychedelics, which often portray these drugs as transformative agents that work by enhancing “neuroplasticity”, rewiring the brain and creating a child-like state of learning. The concept of “neuroplasticity,” though, is too general to be meaningful.
“Anything you do, any change in behaviour is nominally plasticity,” said Heifets. “It’s a very broad statement.”
Some of the earlier work on how psychedelics affect the brain was led by psychologist and neuroscientist Robin Carhart-Harris, who started his investigations at Imperial College London and is now a professor of neurology and psychiatry at the University of California, San Francisco.
According to Carhart-Harris’ research, which uses fMRI imaging to track brain activity, psilocybin disrupts the typically organised activity in the default mode network, an area of the brain associated with introspection, making existing thought patterns less dominant and creating the opportunity to develop new perspectives.
“It starts with breaking down habits of mind and brain and behaviour,” he told STAT. “In psychopathology of mental illness, it would be excessive order: getting stuck in a rut in depression, getting stuck on a feeling of relief and addiction.”
Carhart-Harris said he is 80% confident in his theories, which have the intuitive appeal of combining neuroscience and psychology.
Even if they are right, though, he acknowledges there’s still more to uncover. “If you were to say to me, ‘Do you know it all about how psychedelics work in the brain,’ I would say very quickly, ‘Absolutely not’.”
Others do not share Carhart-Harris’s certainty, arguing the limited data and specificity make it difficult to test. “It’s not quite well enough specified to be a model that you can interrogate reliable brain circuits with in a well-disclosed fashion,” said Barrett.
Barrett has published work showing that psychedelics reduce activity in the claustrum, a brain area called “the seat of consciousness”, which helps people switch between mental states (for example, from calm to urgent action), and was also a researcher on separate studies showing they could be disrupting the thalamus loop, a brain region that provides a filter for sensory information going to higher levels of the brain for decision-making.
Meanwhile, research from Gul Dölen, a neuroscience professor at Johns Hopkins University, highlights psychedelics’ impact on an area of the nucleus accumbens that is associated with social reward learning. Dölen finds mice are more sociable after being given MDMA, suggesting the drug creates a state where there’s an increased sense of reward from social experiences.
“I don’t think these are blatantly contradictory theories, but they do make different predictions,” said Barrett.
The question of where and how psychedelics create changes is crucial, Thomas Insel, former head of the National Institute of Mental Health, told STAT.
“Neuroplasticity is a very vague concept. It means a lot of different things, and when we’re talking about neuroscience and behaviour, it matters where things are happening,” he said.
These theories all share a sense that both the subjective experience of tripping while taking psychedelics and biochemical changes in the brain work together to create a therapeutic effect. Patients can have hallucinations and intense emotional experiences, such as confronting past trauma, that can be psychologically beneficial, and any subjective experience will be reflected in physical changes in the brain.
There’s no certainty, though, of what comes first or how the two interact. Plus, psychedelics are being studied as treatment alongside psychotherapy, meaning two treatments are being evaluated in conjunction, and there’s debate over which is the most effective.
“I think from immediate effect, that’s almost 100% from the drug,” said Srinivas Rao, chief scientific officer at Atai Life Sciences, a for-profit psychedelic drug company.
Patients haven’t had much therapy at that point, so 24 hours after treatment, any reduction in symptoms likely comes from the psychedelic. But for patients who do well longer term, Rao attributes that to therapy. “If you’ve been through therapy and, a year out (from the psychedelic experience), you’re still doing well, it’s unlikely it was the drug to me,” he said.
Then again, all these ideas could end up being dismissed. There are researchers studying psychedelics without the high, effectively trying to determine whether any therapeutic effects are entirely down to changes in brain chemistry.
And Heifets recently posted a preprint (still in the process of peer review) describing a study that gave participants ketamine while they were under general anaesthesia. They saw a drop in their depression regardless of whether they were given ketamine or placebo, suggesting it’s the experience of going through the trial that addresses symptoms rather than the drug itself.
Many of these questions mirror those around other mental health treatments.
Prozac was released 35 years ago and there’s still no consensus on how such SSRI antidepressants work or if their effects can be disentangled from placebo.
A number of scientists compare the idea that psychedelics work by “increasing neuroplasticity” to the now-disproven theory that antidepressants work by changing chemical imbalances: both suggest a straightforward mechanism for a pill to change well-being, but don’t come close to capturing the complexities and uncertainty.
Currently, explanations about how psychedelics work should be taken with more than a pinch of salt, said Insel. “I think it’s a whole shaker of salt.”
MedRXiv preprint Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients (Open access)
BBC article – MDMA: Australia begins world-first psychedelic therapy (Open access)
STAT article – As psychedelics near approval, there’s no consensus on how they work (Open access)
See more from MedicalBrief archives:
Study shows how psychedelics work on the brain to relieve depression
Largest study finds psychedelic ‘highly efficacious’ in serious depression — COMPASS 2b trial
New research propels psychedelics into the mainstream
Psychedelic mushrooms can help depression, anxiety, addiction