Psychedelics for depression: Clinical trial finds “rapid and robust response” with psilocybin

06 Sep 2023 --- Psilocybin treatment was found to clinically and significantly reduce depressive symptoms and functional disability without serious adverse events in a new randomized, placebo-controlled clinical trial. Study participants received one dose of the psychedelic and psychological support before, during and after dosing. 

“The psilocybin produced a rapid, robust and sustained antidepressant response,” says lead author Charles Raison, director of clinical and translational research for the Usona Institute, which explores consciousness-expanding medicines to address mental health conditions, in a recent JAMA author interview. 

“From where they started at baseline to six weeks later, the folks that got a single 25 mg dose of psilocybin on average had a 19.1 point drop in the Montgomery-Asberg Depression Rating Scale (MADRS).” MADRS is a standard scale to rate depression. 

People who received the placebo – 100 mg of niacin – had a 6.8-point drop, a difference of 12.3 points. 

“Most of the antidepressant effect was apparent within a week after dosing, but the effect did not decay over the subsequent five weeks,” Raison continues. Of the people who took psilocybin, 41% were in remission a day after receiving the dose, compared to 11% of those who received niacin. 

Dr. Rachel Yehuda, from the James J. Peters VA Medical Center in the Bronx, New York, comments on the study’s findings: “The important question is, should we continue to invest in this approach? Are we getting a strong enough signal? Is it promising enough? Should we invest our time in learning more about this?” 

“I think the conclusion from this study is yes. Let’s invest our time to see what this is all about because this might herald a new way of dealing with an intractable problem.”

The participants received psilocybin in combination with psychological support.Study set-up 
The study, published in JAMA, included 104 participants between 21 and 65 years old diagnosed with major depression disorder for at least 60 days and with a moderate or greater symptom severity. 

People were divided into an intervention and a control group, which received niacin in identical-appearing capsules. Niacin has been used in psychedelic research to help assist in blinding participants because it produces a physiologic response. 

Raison highlights that the study included psychoeducation, where facilitators spent six to eight hours getting to know a patient, reviewing a patient’s history with depression and establishing if they feel safe to deliver psilocybin to these patients because it is very potent. 

“On the dosing day, subjects came in and had a 50-50 chance of getting either a 25 mg psilocybin tablet or capsule of niacin. They swallow it. We encourage them to lay down and to wear eye shades, so they’re not distracted by things in their environment.”

“The dosing session lasts between six and eight hours. When it’s over and people are safe, they go home. We see them the next day. We offer them what’s called an integration session, meaning that we spend two hours with the participants to discuss – what did the experience mean to them, what stood out and what didn’t stand out?” 

The researchers assessed outcomes the day after a dosing session, plus two, four and six weeks later. 

“Psyche back in psychiatry” 
Raison underscores a need for new antidepressants as many people do not respond adequately to currently available drugs, and “when they get it, they tend to lose it.” In earlier research, psilocybin outperformed antidepressants as well. 

However, treatment with psilocybin is challenging as it is a federally illegal substance. Raison expects that “we’re a few years away from it being FDA approved and available.” 

New antidepressants are key as many people do not respond adequately to currently available drugs.In her comments on the study, Yehuda highlights that it “brings the psyche back in psychiatry.”

“One of the things that’s radically new about this approach is that it is combining the power of a pharmaceutical, a drug that can change the brain and activate receptors and bring about a lot of different neurochemical events.” 

“We’re harnessing it with being in the right frame of mind, having an intention to deal with your mental health problem and using the altered state to gain an insight, to embark on introspection.”

Yehuda underscores that the changes that occur when you take a psychedelic also help patients open up to the possibility of change instead of feeling that it won’t be different tomorrow. 

“That’s where some of the treatment resistance may also find itself just in this idea that tomorrow is going to be the same as today and that there’s a little hope.”

“One of the most exciting features of psychedelic-assisted therapies is that they are transdiagnostic. Transdiagnostic for not only mental health, but they may even reach into some psychosomatic medical illnesses.” 

Limited adverse effects 
Since psilocybin doesn’t produce as long or intense a psychedelic experience as, for example, LSD, it is more user-friendly, notes Raison. Moreover, as psilocybin is only in the body for six to eight hours, side effects were time-limited. 

“Almost all the side effects occur on the day of dosing, and they’re mostly resolved within a day. The most common side effects were nausea, headaches and visual effects where people see hallucinations or patterns.”

“There were some people that had anxiety. That is not uncommon also because this experience is so intense.” 

Better-designed, larger-scale and long-term research are the keys to verifying the study’s outcomes.He adds that there were no serious adverse events, though a few people reported visual disturbances that would carry over for several days after dosing. However, this was not significant enough to require interventions. 

At the same time, as the research field expands to more trials on larger groups of people, Raison cautions that more adverse effects may arise. 

Future research 
Yehuda and Raison underscore a need for better-designed, larger-scale and long-term research. Though there have been many studies on the substance, these were small. The current study is the first large FDA-type study, notes Raison. 

“Blinding is a real challenge,” explains Raison, “There may not be a way in these sorts of trials to stop that other than noting it and seeing what the association is between correctly guessing what you got and how large a response you get.” 

“As a field, we must diversify our participant ethnicity and racial makeup. We’re deeply committed to doing that. I know the other entities in the field are also very deeply committed. That’s part of what we and others will work on assiduously as we move into phase three.” 

Long-term studies are missing, Yehuda underscores. These should also consider “whether we’re shifting a mindset, which ostensibly could be enduring, or suppressing symptoms that will kind of creep back up when whatever biologic change we’ve made with the drug stops working.” 

By Jolanda van Hal