In June 2021, 32-year-old actor Kate Hyatt travelled to a farmhouse near Great Malvern in Worcerstershire for a plant medicine retreat that she hoped would improve her mental health after a difficult time during the pandemic lockdowns. While there, she is believed to have taken a substance called wachuma, or San Pedro cactus, a powerful hallucinogen used by Indigenous people in the Andes for thousands of years.
But Hyatt did not experience relief; instead, her mental health worsened. Three months later, she described being in “some sort of psychotic break” and feeling as if her brain was going to explode. Later that autumn she took her own life. At the subsequent inquest, the coroner’s report linked her worsening symptoms to the hallucinogens she had consumed.
Such tragedies represent the darker side of the psychedelics renaissance. These cases are often forgotten amid the feverish anticipation surrounding the therapeutic potential of these drugs, combined with exhaustive media coverage, the rapid rise of a billion-dollar industry – ranging from venture capital-backed startups to wellness retreats – and the hype around last year’s Netflix series How to Change Your Mind (based on Michael Pollan’s bestselling book).
Yet without careful monitoring and scrutiny of who receives them, this class of drugs – which includes LSD, MDMA (commonly known as ecstasy or molly) and psilocybin (the active ingredient of magic mushrooms) – can be dangerous. There is evidence that they can destabilise vulnerable individuals who have experienced a previous psychotic episode or have a family history of psychosis. The substances are illegal to distribute and possess in the UK, although they are often obtained on the hidden market. Scientific researchers and biotechnology companies are able to use them in clinical trials only after obtaining a Home Office licence and applying extensive security arrangements.
“Psilocybin affects serotonin and it’s been known for some time that drugs which do this can set off a manic episode in people with bipolar disorder,” says Andrew Penn, a psychedelics researcher at the University of California, San Francisco. “What we worry about with somebody with underlying psychotic illnesses is that the drug might wear off, but the illness symptoms persist, or even that the drug has helped them emerge.”
Self-medication is a particular concern, encouraged by the relentless promotion of the possible benefits of psychedelics. While clinical studies will use precisely controlled doses and patients will be supervised by trained staff, this does not necessarily happen when people take psychedelics alone or at retreats. “People using it out there in the wild, as we say – that’s rapidly increasing,” says Haley Dourron, a researcher at the University of Alabama at Birmingham. “We’re seeing more instances of people having bad experiences, especially those with questionable mental health histories, or use in unsafe circumstances.”
Scientists feel that the popular discussion of psychedelics often downplays the importance of psychotherapy in clinical studies, before and after the drugs are administered. The therapist’s role is not only to help the patient process and learn from their experience, but to keep them safe.
“People with depression tend to have profound guilt about many different things and on these drugs that might get put on blast,” says Penn. “In trials, they go home with a trusted person who keeps an eye on them. Then the next day we start to talk about the experience, and as part of our protocol we’d be assessing that person for suicidal thoughts.”
When Compass Pathways, a London-based biotechology company, published the results of a phase 2b trial of psilocybin for treatment-resistant depression, it reported that three patients demonstrated suicidal behaviour for at least a month after receiving the drug.
Penn has heard first-hand how tragedy can happen when the drug is taken in the wrong settings. “One recent case was very concerning,” he says. “A 21-year-old woman tried to treat her own depression through self-medicating with a high dose of psilocybin. She got very distressed, and apparently tried to go to the office the next day before deciding she wasn’t in a fit state to work. She turned around, stopped in the middle of the Golden Gate Bridge [in San Francisco] and jumped off.”
Preventing harm and understanding more about why some patients respond well while others do not are two big concerns for scientists as psychedelics move closer to mainstream medicine. Earlier this year, the nonprofit Multidisciplinary Association for Psychedelics Studies in San Jose, California, completed a successful phase 3 trial of MDMA to treat post-traumatic stress disorder (PTSD), meaning it can now apply for regulatory approval.
In the Compass Pathways study, 29% of patients with treatment-resistant depression were in remission after three weeks and a phase 3 trial is under way. “We think this is extremely good,” says Guy Goodwin, chief medical officer at the company. “These patients have got treatment-resistant depression where they’ve had at least two failures with antidepressant treatments previously.”
While independent researchers are optimistic, they still urge caution. Dourron feels that there needs to be a more concerted scientific effort to look for potential risks in the wider population, particularly in vulnerable patients.
Matt Butler, an academic psychiatrist at King’s College London, is concerned that the substantial commercial interest in psychedelics will lead to them being ushered into the mainstream prematurely.
“There are pressures to get things pushed forward,” he says. “The results are promising, but I think we need to do more research. There are lessons from the 50s, 60s and 70s, when psychedelics were pushed through quite quickly and things didn’t end well.”
The placebo problem
The psychedelics revolution is progressing at pace. Regulators in Australia gave psychiatrists the green light from last month to prescribe MDMA and psilocybin for PTSD and depression.
“Maybe it’s a decision based on their perceived lack of risk versus the potential for usefulness,” says Rachael Sumner, a pharmacy researcher at the University of Auckland in New Zealand. “But there are these issues that are well known.”
Sumner’s surprise stems from the question marks that still exist regarding how to measure the benefits of psychedelic-assisted treatment. Most medicines are assessed by giving one group of patients the active drug and another a placebo, before comparing the two. Ascertaining whether a new drug performs better than a placebo is particularly imperative in depression, where patients commonly experience a short-term psychological boost from receiving a new treatment.
But this works only if patients cannot guess whether they have received the drug or not, and with psychedelics, most can tell. While scientists have tried various placebos – from the vitamin supplement niacin, which causes flushes, to the sedative remifentanil – Sumner says that in her experience the majority of participants can guess.
This can cause an additional problem. The crushing disappointment from realising they have not received the psychedelic can cause a patient’s condition to deteriorate. Both Butler and Sumner have published papers speculating that some of the large differences between psychedelic and placebo groups in trials is not just because patients on the drugs have improved, but because those on the placebo have worsened. “I think we’re probably overestimating how effective they are at the moment,” says Butler.
So what can be done? One possibility is to use augmented or virtual reality to simulate a hallucinogenic trip. Compass Pathways ditched the placebo altogether in its recent psilocybin trials, attempting to show efficacy by comparing patients given three different doses – from low to high.
However, Sumner feels that the hype around psychedelics should be tempered until regulators have agreed on a method of accurately assessing them. “People should treat the drugs with caution until this is worked through in some way,” she says.
How many patients will benefit?
The other question is how many patients will actually benefit from psychedelic-assisted treatment, even if regulators grant approval. The full psychedelic experience for psilocybin lasts between six and eight hours, limiting the number of patients who could be treated in one day.
Combined with the need for trained therapists, of which there is a significant paucity, according to the UK Council for Psychotherapy, the psychedelics industry has significant scalability problems, not least because long-term benefits may require many treatment sessions. Last year, two private psychiatrists in Switzerland, who have used psychedelic-assisted therapy for decades, published a paper suggesting that effectively treating PTSD could require as many as nine applications of MDMA, or 12 applications of LSD.
Kabir Nath, chief executive of Compass Pathways, explains that the company’s phase 3 trial of psilocybin for treatment-resistant depression will indicate how many doses will probably be required in a year to maintain remission. “In the phase 2b, we saw that more than 20% of patients were in remission after 12 weeks,” he says. “If you asked us to guess, we would say somewhere between one and four doses a year.”
He points out that this compares favourably with other treatment regimes such as transcranial magnetic stimulation, which requires somewhere between 35 and 50 procedures over several weeks to have an impact.
One solution for addressing the shortage of therapists could be to involve other medical personnel in the treatment process. “I think you will see a lot more experimentation with who actually needs to be in the room with the patient for psychological support,” says Nath. “Can it be a nurse or some other kind of healthcare worker?”
The length of the psilocybin experience also makes it relatively expensive. Cost estimates from Australia are far from cheap. Peter Hunt, chair of the mental health charity Mind Medicine Australia, says that patients should expect to pay between A$10,000 (£5,215) for two psilocybin-assisted therapy sessions and A$15,000 (£7,823) for three MDMA-assisted sessions.
Will insurers or the NHS be willing to stump up such money? Goodwin argues that these patients cost the public healthcare system far more because they are often hospitalised. “Their lives are very curtailed, their opportunities are restricted and they cost a lot of money,” he says. “They’re at high risk of suicide and we’re definitely not serving them very well at the moment.”
Other companies are exploring “second-generation” psychedelics, which could possibly prove more cost-effective by reducing the time of the trip. London-based Small Pharma, for example, is researching the compound DMT for use in major depression, for which the hallucinogenic experience lasts 30 minutes.
Penn says that despite the concerns, he remains excited about the potential of psychedelics, but that the discussion of them needs to be tempered by responsibility.
“In the media, a lot of ink gets thrown about this topic,” he says. “People read that and say: ‘I have depression and my buddy grows mushrooms. Maybe I’ll just take this and see if it makes me better.’ But what those narratives are overlooking is that there’s a lot more to psychedelic treatment than just the drug, and there’s this whole context and safety container that makes it safer.”
