The idea behind psychedelic therapy is that the receptive state that the drug confers opens the door to fresh ideas about how to think about the past and future, which the therapist can reinforce.

“There is a growing evidence base to the principle that this is very much about a synergy between drug-induced hyper-plasticity and therapeutic support,” says Carhart-Harris, who trained with Nutt.

Kirk Rutter, a patient, says his journey to treating depression with Carhart-Harris was focused, but flexible. When Rutter first removed a pair of eye shades after the drug took effect, the therapist appeared “fractured” and seemed to have another eye in the centre of his forehead.

“I should imagine I look quite strange to you now,” Carhart-Harris said. Rutter burst out laughing and Carhart-Harris joined him. When the laughter stopped, the two men started talking. Rutter wanted to discuss his resentments, which led to pondering about the word ‘relent’ and its etymology. Carhart-Harris looked it up for him on his laptop.

“That was a lovely moment, actually,” Rutter says. He returned for a second session with a stronger dose of the drug, followed by a second MRI and an ‘integration’ session, to discuss the experiences.

The treatment “made me look at grief differently”, Rutter says. “It was a realisation that actually it wasn’t helping and letting go wasn’t a betrayal.”

Testing these drugs effectively and translating the clinical research into actual treatments will prove challenging, however. Two of the most closely watched studies have grappled with this. One is the recently completed MDMA trial, which was testing the approach in people with severe PTSD.

It was a phase III study, usually the final stage before drug regulators decide whether to approve a treatment, and it involved 90 participants at 15 sites around the world. The Multidisciplinary Association for Psychedelic Studies (MAPS), a non-profit organization in San Jose, California, sponsored the study, but has not so far released the results.

Meanwhile, the mental-health-care company COMPASS Pathways in London is running a phase IIb trial — testing different dosages of psilocybin for treatment-resistant depression.

Evaluating the results won’t be simple. One concern revolves around controls. Most individuals given a placebo will know that they are not receiving a powerful hallucinogen. Some studies evaluating psychedelics have attempted to address this by giving people in the control group a pill containing niacin, which elicits a physical sensation — usually a flushing response in the skin. Mitchell says that some participants in her MDMA study who’ve been given the drug thought they received the placebo, while some taking the placebo believed that they had been given the drug.

The studies’ designers must also tackle how important the non-drug aspects of the trial are to the results. These include the mindset of the individual going into the experience, and the environment in which it takes place.

The vibe is definitely hotel spa at the treatment rooms for the COMPASS study at Utrecht University Medical Centre in the Netherlands. There’s a Mexican-style blanket folded at the foot of a twin-size bed. Beanbag chairs hug a potted palm in the corner. And a poster of Van Gogh’s Almond Blossom adorns one wall. All 24 sites in the study are similarly decorated.

Then there’s the training and experience of the therapists guiding both the dosing sessions and the drug-free integration sessions. COMPASS, which became a public company in September and earned a stock-market valuation exceeding $1 billion, developed a five-tier training programme for therapists in its trial. Company co-founder and chief innovation officer Ekaterina Malievskaia says site investigators must adhere to the training if the company expects to win regulators’ approval.

Madras goes further to say that the conditions of the trial will have to be replicated for any wider roll-out of the drugs. They “have to be approved under the stringent conditions in which they were investigated”, she says. But the path forward for mandating such conditions is unclear. For the US FDA, there is a mechanism to ensure that drugs are administered in a specific way: Risk Evaluation and Mitigation Strategies, or REMS.

Through REMS, the agency can require prescribing physicians and pharmacists to be certified for a treatment strategy designed to mitigate the risks associated with a drug — such as addiction and dependency for opiate prescription. REMS could be used with psychedelics, Dunn says.

The effect would be to bundle the delivery of the drug with the therapy component, and potentially certify practitioners. A source working on one of the trials says that discussions are under way with the FDA over whether therapists who administer the drugs ought to be trained, what that training might involve and whether therapist certification should be required.

Certification could mean legitimizing therapists who have been ‘treating’ individuals with the drugs illegally for as long as 30 years. But some of these therapists might resist the advice, or the involvement, of a government that has driven them underground.

Approvals still have a long way to go. Towards the end of 2020, MAPS reported in a news release that there are statistically significant differences in the response between the control and placebo groups in its MDMA trial. But the company won’t say more about the results until it releases the full data sometime this year.

It is also recruiting for a second phase III study using MDMA therapy for people with moderate-to-severe PTSD, which it aims to complete before the end of the year. COMPASS expects to have results from its phase IIb study on psilocybin by that time, and the company says it is planning a phase III study.

Robert Malenka, a psychiatrist and neuroscientist at Stanford University in California who has studied MDMA’s effects on rodents, says he thinks that some psychedelic drugs will eventually earn approval as treatments for certain conditions.

“They have potential to be — I want to use the right analogy — a part of our toolset for treating patients,” he says. But he warns against overzealousness, particularly a brand of evangelism he’s seen among some of the underground purveyors of psychedelic-assisted psychotherapy. “I don’t think they’re going to be miracle cures,” he says.

He argues that the hypotheses for how the drugs might be working in the brain still need further research, and that investigating compounds that provide the same benefits without the hallucinatory effects could prove worthwhile in the long run. Others point out that SSRIs work for many individuals without clinicians fully understanding their mechanism.

Regarding the clinical work, however, Madras says she’s concerned by the studies’ size and design. She noted that many of them recruit people who have had previous experience taking psychedelics. Those who are attracted to this type of experience, she argues, might be more likely to say positive things about it.

Nutt has said that working with experienced users of the drugs minimizes the chance of adverse events. But there are other potential confounders, according to Madras. “The consent forms tell you what the expectations are,” she says. “So there’s bias on the part of the subjects.”

Rutter says that despite all that, he is convinced that the treatment he received in 2015 changed his life for the better. In the weeks after his sessions, he found himself wondering whether the automatic circuit would return. “I was terrified,” he says, “and I realized I’ve got a little bit of control over this, right?” The thought had never occurred to him before.

A week or so later, he was out with friends at a shopping centre and sensed the return of optimism and openness. “It felt like somebody had opened a window in a stuffy room.” Five years later, his depression has not returned.

• A Nature magazine report