Johns Hopkins psychedelic researchers continue to find evidence supporting the effectiveness of psilocybin-assisted therapy at treating depression, with a new follow-up with past study participants showing persistent antidepressant effects one year later.
Earlier studies had shown rapid antidepressant effects from psilocybin, but how durable such improvements would prove to be over time has remained an open question.
The new findings are promising given that the participants only received two doses of psilocybin, one and a half weeks apart but they’re also complicated by several factors. Some of the study participants took part in additional forms of therapy after completing the study, and some even began taking traditional antidepressant medications during the 12 months since their last psilocybin session.
The researchers also found that the intensity of the subjective psilocybin experience did not correlate with decreases in depression symptoms, but did have an impact on how participants rated their overall wellbeing.
“It’s not exactly a clear cut picture,” said Dr. Natalie Gukasyan, an assistant professor of psychiatry at Johns Hopkins and lead author of a new paper presenting the follow-up data in the Journal of Psychopharmacology. “This is our best assessment of how people are doing in general, but many things might have contributed to that improvement.”
The new follow-up study builds on a randomized clinical trial Johns Hopkins researchers completed in 2020, publishing the initial results in the Journal of the American Medical Association. The trial took 27 participants with a major depressive disorder diagnosis and gave them two doses of psilocybin following eight hours of supportive psychotherapy in preparation for their first dose, and two to three hours of psychotherapy after their last dose.
At one week after their last psilocybin treatment, 17 of the 24 participants, or 71%, saw a clinically relevant reduction in depression symptoms scores, and 14, or 58%, were considered to be in remission.
In the new, 12-month follow-up study, 75% of the participants showed a clinically relevant response one year after treatment, and 58%, again, were considered in remission. No safety concerns appeared at any point in the study, and no participants showed an increase in depression scores following psilocybin, though three participants showed no response to the treatment.
Taken with the mixed results from recent commercial clinical trials with psychedelics, it’s yet another indication that successful therapies involve more than psilocybin alone, and that therapy protocols and other factors are also important to positive treatment outcomes. This is not to say that psilocybin therapy is ineffective, as a 71% response rate is very good. But there is not yet evidence to say that psilocybin therapy alone reliably produces durable effects one year later.
The persistent antidepressant effect wasn’t entirely unexpected given other published work on psilocybin and depression, Gukasyan said, but the longest follow-up conducted by other researchers so far was just six months after treatment. That follow-up was part of an open label trial conducted by UK psychedelic researchers Robin Carhartt-Harris and David Nutt on a different patient population, those who had failed at least two other forms of treatment and were therefore diagnosed with treatment resistant depression.
The open label trial was also notable, Gukasyan said, because some of the participants took psilocybin on their own outside of the trial before the six-month follow-up, somewhat clouding the results.
None of the participants in Gukasyan’s study reported using psychedelics outside of the study, but they did introduce a different complicating factor to the results. By the 12-month follow-up, eight participants, or 33.3%, reported starting or returning to daily antidepressant medication use. All eight of those participants had scored higher on depression measures at the beginning of the trial.
It’s not entirely clear what motivated the study participants who began taking antidepressants — or began taking them again — during the 12 months following the initial study, Gukasyan said, but she suspects a person taking antidepressants “probably did have some symptoms that were interfering with their function more so than the person who didn’t have to go back on medication.”
All the initial study participants had cycled off any antidepressants before beginning the study, Gukasyan said, a standard requirement in psychedelic studies. Not only are there some safety concerns, but the most common antidepressant medications — Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Norepinephrine Reuptake Inhibitors (SNRIs) — seem to interfere with the subjective effects of psychedelics.
“It actually seems that being on an antidepressant, or any drug that affects serotonergic function the way that an antidepressant does, actually ends up blunting the effects of psychedelics,” she said. “It actually interferes with the action of psilocybin, probably in an indirect way.”
But while psychedelics and antidepressants may remain contraindicated even if psilocybin and other psychedelics win FDA approval, psychotherapy could remain a common adjunct to psychedelic therapies. In that sense, study participants seeking therapy after their psilocybin treatment may be indicative of how psilocybin assisted therapy would work in real-world clinical practice.
“It might be a very healthy thing to pursue therapy to talk out some issues that have become apparent to you, for example, after this psychedelic experience,” Gukasyan said. “I wouldn’t necessarily even see it as a marker of treatment failure in any sense.”
She added that therapy was very liberally defined for the new paper, noting that “one person did a couple of sessions of couples counseling with their partner. And so it’s not necessarily some sort of marker of worsened depressive mood.”
One other finding in the new study complicates the understanding of how psilocybin assisted therapy may function in people, namely that measures of the intensity of the subjective, mystical experience component of the psilocybin session did not correlate with reductions in depression. That is, a more intense trip did not predict changes in depression scores at any point, one week, one month, or one year after treatment, as previous research has indicated.
But participants’ scores on the Mystical Experience Questionnaire, which researchers use to quantify the subjective experience of psychedelic sessions, did predict participants’ self-reported ratings of overall wellbeing.
“It’s not a measure of change, per se, it’s just an absolute measure taken at each follow-up point,” Gukasyan said of the measures of wellbeing, which are assessed through a questionnaire. “It asks things like, would you say that you’ve had good changes in your relationships with other people as a result of your psilocybin experience?”
That the sometimes intense, mystical experiences engendered by psilocybin might affect how people view their lives certainly fits with the anecdotal reports of psilocybin users. But, Gukasyan said, they are intrinsically more difficult to study than, say, depression symptoms, since “it’s not something you can go in and see there in the screen of their mind’s eye.”
But with researchers and some psychedelics companies working on compounds they hope will carry the antidepressant effects of a drug like psilocybin, but without the trip, understanding how the subjective psychedelic effects impact people over the long term could be important.
“I find it just kind of hard to believe that that is not an important component of why people seem to have some longer term effects from this,” Gukasyan said, even as the new findings suggest that at least some of the rapid antidepressant effects of psilocybin do not stem directly from the subjective psychedelic effects.
It could be that the subjective effects of psilocybin are important to non-clinical applications for the drug, she suggests, including the personal development and spiritual growth more typically associated with therapy and spiritual practices.
“I think a lot of people are hopeful that this might have applications for people, even beyond those who are suffering with depression,” said Gukasyan, suggesting that psychedelic-assisted therapy could be “a method of improving people’s lives, even if they’re not suffering with a clinical diagnosis or something. But that, I think, is a little bit away from where we’re at.”