In a recent UK trial, 12 patients with major depression took a pill quite different to commonly prescribed antidepressants: 25mg of psilocybin, the psychedelic compound found in magic mushrooms.
Though it's early days (the study is the first of its kind), the results of the trial are promising.
In a feasibility study published today in The Lancet Psychiatry, the researchers reported that the drug was well-tolerated by the patient group. What's more, the results have given researchers cause for optimism about the drug's efficacy.
"The main takeaway is that the effects are well-tolerated in this population, and not just that—the antidepressant potential of the treatment seems to be pretty considerable," Robin Carhart-Harris, a psychopharmacologist at Imperial College in London and the lead author on the study, told me in a phone call.
All 12 of the patients reported a reduction in the severity of their depression for one week after the psilocybin experience, and for most this was true after three months. At week one, eight patients met standard criteria for remission, with five remaining in remission at three months.
"It's hard not to get excited about the results," said Carhart-Harris. "I keep issuing these cautionary notes about the study, encouraging people not to get carried away, and in a way that's a note to myself as well not to get carried away, because on another level the results are pretty exciting and they kind of endorse what we're doing and what we've been working on for so long."
The trial took place in 2015, but preparations started well before then. When dealing with regulated substances such as psilocybin, it's notoriously difficult to get approval and funding for research, and even just to get hold of the drug to the required quality (it has to be produced and prepared to exacting standards). This study was funded by the Medical Research Council with support from the Beckley Foundation.
The participants, six men and six women between the ages of 30 and 64, were carefully screened for suitability. All had major depression classed as either moderate or severe and had previously tried at least two other treatments—such as conventional antidepressants like SSRIs—and not responded.
Participants were given a safety dose of 10mg seven days before receiving the treatment of 25mg. Carhart-Harris explained that this dose was decided on in correspondence with Johns Hopkins University, which has done a lot of work in this area.
The patients were given the drug in a treatment room designed to be calming.
They relaxed on a bed with a psychiatrist on either side, and carefully-selected music playing throughout the six to seven hour trip. The psychiatrists "checked in" with the patients at regular intervals, but participants were largely left to experience their own "inner journey." The researchers also measured physiological effects such as heart rate and blood pressure. The patients completed assessments at various points after the experience to track their response.
When I asked Carhart-Harris how it went, the first thing he said was that it was really hard work.
"[It was] quite a heavy burden to carry. I don't think it's too much to compare it to the ring in Lord of the Rings"
"It was a gruelling 10 to 12 months," he said. "It was a demanding schedule; you're dealing with a lot of souls. And I mean it when I say it that way, because you're not just dealing with people on a superficial level; you're really dealing with them on the deepest possible level. They're bearing their souls to us, and then we're introducing a drug which puts them in a very vulnerable state where even more of their soul is revealed."
"That's quite a heavy burden to carry," he added. "I don't think it's too much to compare it to the ring in Lord of the Rings; it's something that has an incredible power that's recognised. This isn't to imbue any magic into the psilocybin, but in terms of the effect, psychedelics have this immense power; they can change people, and so there was an immense burden of responsibility to do this properly."
He said the experience was emotionally challenging, especially given patients were suffering to begin with.
In the end, Carhart-Harris said feedback from participants was mixed. "But sometimes emphatic gratitude—I've got quite a few new presents on my windowsill in the office at work."
Moving forward, he said that one area the team would focus on was the aftercare for patients following the experience. The researchers have been continuing work beyond the participants described in this study and have now worked with a total of 20 patients. They have now been following up with participants for six months, and hope to publish further findings later this year.
The effects of psychedelics
Psilocybin is of therapeutic interest in the context of depression because it affects serotonin receptors in the brain. In their paper, the researchers explain that it "has a novel pharmacology in the context of currently available antidepressant medications" because it directly affects a specific serotonin receptor (5-HT2A) which SSRIs do not. LSD also affects this receptor.
Carhart-Harris, who has recently published work on LSD in human subjects, said that psilocybin was used in this study instead of another psychedelic for a few practical reasons. The trip lasts around five to six hours—shorter than LSD—which fits well into a work day. It's also quite easily metabolised and is not as toxic as some other similar drugs. He also thinks it is more appealing both to participants and to those approving research than something like LSD, which perhaps has a more provocative reputation. The fact that psilocybin is naturally occurring, and has been used as a medicine since ancient times, may add to this appeal. More recently, a 2011 US study found that psilocybin can help with end-of-life anxiety.
"I don't think it's got any edge in terms of its classic psychedelic effects, but in my view it's no less a psychedelic than LSD or DMT, ayahuasca—it's very much a classic psychedelic," he said.
Using psychedelics as a treatment is particularly compelling, because the current model researchers are pursuing is to give patients the drug (in carefully orchestrated circumstances) just once, or on a few occasions.
The idea is to induce a profound psychological experience, sometimes referred to as a "peak" experience that Carhart-Harris described as a "rebooting of perspective."
In that way, the experience is more important than the drug itself. "But the experience doesn't happen without the drug," he said. "Certainly something's happening on a chemical level."
Caveats and cautions
The findings of the new study are promising. For those struggling with depression for many years with little relief, the possibility of a new treatment that works differently to conventional methods is bound to be met with excitement.
However, the authors warn against getting over-enthusiastic at this stage. There are important limitations to their results that mean we can't draw too many conclusions just yet.
In a comment piece published alongside the study, University of Oxford psychiatrist Phil Cowen, who wasn't involved in the work, characterises the results as "promising but not completely compelling."
He told me in a phone call that he supported the idea of researching the therapeutic potential of psilocybin to treat depression. "I think it's an idea worth pursuing, particularly since psilocybin's been used in the treatment of other rather refractory disorders, for example post-traumatic stress disorder," he said.
But he explained some of the caveats to the work so far. The authors make a good case for the safety of using the drug, he said—"But at the moment you couldn't really conclude much about its efficacy."
For a start, the study uses a small sample size and is "open-label," meaning there was no placebo or other control for comparison.
Cowen explained that, as the treatment also involved other elements of psychiatric support, it's hard to conclude what effect is attributable to the psilocybin. "People get a lot of looking after and very good care, and that's important—it's known to have a placebo effect, even in patients who have been depressed for a very long time," he said.
He also noted that as most of the patients self-selected for the study, and as five of the 12 had previously taken psilocybin, they would likely be expecting a positive response. He drew parallels to previous touted treatments that have appeared effective before failing to produce significant results in control studies, such as insulin coma therapy.
Carhart-Harris said it was possible there was a "placebo effect" at play, but that this was unlikely because the magnitude of the results was significantly higher than you'd usually expect in this case.
"I don't think people should extrapolate from this that they can go out and find some mushrooms and cure their depression"
Cowen would like to see a more controlled study where patients don't know in advance if they've taken psilocybin or another drug. The 2011 study that posited psilocybin as a treatment for anxiety in late-stage cancer patients was a double-blind, placebo-controlled trial, meaning patients received psilocybin on one occasion and a placebo on another, without knowing which to expect first.
Cowen also said he'd be interested to get further information on the patients' condition after a longer interval.
"I'd like to see more coming out about what the experience of taking the drug was like for the patients, what they thought about it, and I'd really like to see a six-month and year follow-up—a detailed assessment, not just the rating scales which I'm sure will be done; something more qualitative," he said. "What's life like for them now? What's changed?"
Carhart-Harris agrees that a control study should be the next step. "I think we're a long way from convincing people," he said. "I don't think anyone should feel convinced after looking at these findings."
He suggested they would do well to pit psilocybin against an established treatment such as SSRIs (antidepressants such as Prozac) or ketamine.
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"If we were to find that actually psilocybin has advantages over SSRIs and—this is hypothetical, but if we were to find that it's more effective and better tolerated than SSRIs, that would be a major outcome."
He said the next stage was to do a placebo-controlled trial in order to standardise the level of psychological support given to patients and show that the effect isn't just down to caring for people.
There is a limit to the usefulness of placebo trials when studying psychedelics, however: Frankly, it's pretty obvious to people whether they've taken magic mushrooms or a sugar pill.
Carhart-Harris added that there were also benefits to a more "naturalistic" trial. "At the end of the day, when a patient comes in for a treatment, they know what they're going to get," he pointed out. "So what we've done is actually more realistic relative to what people do ordinarily when people give a treatment. There's something about a randomised control trial that's actually a bit artificial."
He also emphasised that the treatment was carried out in a carefully prepared context with the help of mental health professionals. "I don't think people should extrapolate from this that they can go out and find some mushrooms and cure their depression," he said.
Nevertheless, with the right research he foresees a time when psychedelics could find themselves among regular treatments for depression. When I asked him if he thought psychedelics could one day be a first treatment option, he said it would be worth considering. He noted that not all people want to take antidepressants, and that regular therapy can be expensive, time-consuming, and hard to get.
"If you can improve the efficiency of things by offering a more accentuated kind of psychotherapy that's sort of 'sped up' in a way by the psilocybin, that could be quite appealing not only to patients but to people managing mental health," he said.
"I think that for some people they would actually prefer to have an experience with magic mushrooms, say—in the right kind of controlled way—than to try some Prozac or to go on a course of CBT, for example."