A Single Dose of Psilocybin Leads to Significant Improvements in People With Major Depressive Disorder
Researchers are hopeful the psychedelic may offer a new and effective way to treat depression.
Just one dose of psilocybin, given with close supervision and psychological support, improved depression symptoms and functioning in people with major depressive disorder for up to six weeks, according to new research published in JAMA on August 31, 2023.
In the largest and most rigorous study ever conducted across a wide spectrum of people with major depressive disorder, psilocybin produced a rapid, large, and sustained antidepressant response, said corresponding author Charles Raison, MD, in a press release from the medical research nonprofit Usona Institute.
Dr. Raison is a researcher and professor of psychiatry at the University of Wisconsin School of Medicine and Mental Health in Madison and medical director of translational research for the Usona Institute. The Institute provided the psilocybin for the trial, and its researchers designed the study, participated in data interpretation, and wrote the scientific manuscript.
“[Psilocybin] could provide hope for those who have not responded to other treatments, and it could also present a viable option for individuals seeking to avoid long-term treatment with standard antidepressants. We see a signal of benefit suggesting that psilocybin may be a new option to aid people in all stages of their struggle with depression,” said Raison.
“I thought that the trial was fascinating, and it was done very well,” said Rachel Yehuda, PhD, a professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York City and author of an accompanying editorial published in JAMA, in a JN Learning podcast interview. “The results showed that patients had sustained their gains that were observed as early as eight days after the psilocybin, well into 43 days later, and so that was really exciting,” she said.
Although It's Illegal in Most Parts of the U.S., Evidence on Psilocybin’s Effectiveness in Treating Depression Continues to Build
Also known as “magic mushrooms,” psilocybin comes from certain types of Psilocybe mushrooms. Per research, this naturally occurring compound belongs to a class of compounds known as tryptamines, similar to lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and mescaline.
Currently, most psychedelic compounds are illegal under federal law. Since the 1970s, these drugs have been categorized as Schedule 1 (the most restrictive class of drugs) by the Drug Enforcement Administration, meaning that they are considered to have high potential for abuse with no accepted medical use.
“However, the ever-growing global mental health crisis, coupled with the shortage of effective therapeutic strategies, has given rise to a reconsideration of the therapeutic potential of these compounds in recent years,” wrote the authors of the editorial.
There have been recent small studies that suggest that psilocybin improves depression symptoms quickly, and the response continues long after the drug continues to be present in the body. A Johns Hopkins study published in February 2022 in the Journal of Psychopharmacology found that two doses of psilocybin may ease depression symptoms for up to 12 months.
Another small study published in November 2020 in JAMA Psychiatry found that half the participants were no longer considered to be “in the throes of major depression” one month after psilocybin treatment.
Study Used Synthetic Psilocybin for Double-Blind Randomized Trial
The new study included 104 participants between 21 and 65 years of age who met the criteria for major depressive disorder but otherwise in general good health. The research was held at 11 sites in the United States between 2019 and 2022.
Half of the participants were women and close to 90 percent were white, and most were experiencing ongoing depression.
People were excluded from the study if they had moderate or severe alcohol use disorder, used a psychedelic within the past five years, had suicidal thoughts or behavior in the past year, or were being treated for depression with deep brain stimulation.
In the weeks before receiving the active drug or placebo, participants were slowly tapered off their regular antidepressants.
A total of 50 people were given psilocybin — not mushroom derived, but rather psilocybin synthesized in the laboratory under U.S. Food and Drug Administration (FDA) standards in a very labor-intensive process.
The remaining participants received niacin, also known as nicotinic acid or vitamin B3. It was chosen to be the active placebo because it commonly causes a physiological reaction including warm or flushing of the skin and mild dizziness, which could hopefully help mask whether a participant was given the active drug or the placebo, according to the authors.
Each Participant Received Intensive 6 to 8 Hour Preparation
Before getting their dose, each participant spent six to eight hours with two research staff to prepare for their experience.
The dosing session lasted 7 to 10 hours and was conducted in a comfortable room under the supervision of staff. Participants were encouraged to wear eyeshades and listen to a curated playlist of relaxing music on headphones while reclining.
The dosing was followed by a four-hour integration session with staff, during which participants discussed their experience.
People Taking Psilocybin Had a ‘Large Scale Reduction’ in Depression Symptoms
Depression symptoms were assessed at the start and then 2, 8, 15, 29, and 43 days after dosing of psilocybin or niacin. Over the telephone, participants were evaluated via a standardized tool known as MADRS (Montgomery and Åsberg Rating System) — as detailed in research — to assess depression severity at baseline and throughout the study.
The measure evaluates patients’ symptoms in 10 areas, including sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lack of energy, inability to feel, pessimistic thoughts, and suicidal thoughts.
Each area is assigned a score from 0 to 6 to produce a total scale score from 0 to 60, with higher scores reflecting greater depression severity.
The improvements in depression symptoms in the psilocybin group were observed within eight days of psilocybin dosing and those improvements were maintained across the six-week follow-up period, according to the authors.
Highlights from the findings also included:
- On average, participants who received the single dose of psilocybin had a 19.1-point drop in the MADRS compared with the group getting the placebo, who experienced a 6.8-point drop, a 12.3-point difference, which was a “large scale reduction,” said Raison in the JN podcast.
- Sustained response and sustained remission were maintained by 41 percent of the people taking psilocybin, compared with 11 percent who received niacin, a “very statistically significant” difference, according to researchers.
Raison considered that metric very robust, pointing out that it meant that participants meeting that threshold had a sustained response at every post-dosing visit, which was at one week, two weeks, four weeks, and six weeks.
“At the six-week endpoint, 60 percent (more or less) of the people who took the psilocybin dose had a response, meaning they'd had a 50 percent reduction in their starting score, and 44 percent of them were in remission, meaning that their score had dropped to a level that is close to how people function when they're not depressed,” said Raison in the podcast. This is very different from the niacin — only 20 percent of the niacin people had a response at week six, and only 11 percent of the niacin people had remission, he added.
Side Effects and Safety of Psilocybin
“The good news about side effects with psilocybin is because the drug is only in the body for six hours or so, the side effects tend to be very time limited. So almost all the side effects occur on the day of dosing, and they're mostly resolved within a day afterwards,” Raison said in the podcast. But those experiences can be “very powerful experiences that people can struggle with,” he said, adding that there will likely be more adverse events as the field expands.
The most common side effects were nausea, headaches, and then visual effects. Some people see hallucinations, and some people see patterns, he said. “There were some people that have anxiety, and that is not uncommon because this experience is so intense, but in general, the side effects resolved within a day,” Raison said in the podcast. The exception was headache, which for some people lasted into the next day, he added.
There were no serious adverse events related to dosing: No one died, and no one went to the hospital, said Raison. None of the participants taking psilocybin had clinically confirmed suicidal thoughts or behavior.
Study Participants Mostly White With Higher Incomes
The authors acknowledged a few limitations in their findings. For starters, the study size was small, and it was likely that some of the participants figured out whether they were given the active drug or the placebo because of the acute psychoactive effects of psilocybin, they wrote. To try to compensate, the study used off-site evaluators of depression symptoms.
Another limitation of the study was the homogeneity of the group: Most participants were white, non-Hispanic, and the annual incomes skewed toward higher income brackets — which isn’t representative of the U.S. population.
Findings May Signal a New Way of Treating Depression
Although there are limitations in the study, the important question is whether we should continue to invest in this approach, said Dr. Yehuda in the JN Learning podcast interview.
“Is it promising enough? Should we invest our time in learning more about this? And 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,” she said.
Psilocybin ‘Might Galvanize a Deeper Healing Process’
It’s important to emphasize that the dose is given in the context of a plan to improve depression, said Yehuda. “There's a lot of preparation that occurs before taking the psilocybin. There can be facilitation during the session and then there's a process of integration, where we help patients make sense out of the experience that they've had,” she said.
What’s radically new about this approach is that it combines the power of a pharmaceutical drug that can change the brain and activate receptors and bring about a lot of different neural chemical events, and clinicians can help people harnessing that experience by being in the right frame of mind, having an intention to deal with your mental health problem, and using the altered state as a way to gain an insight to embark on introspection, said Yehuda.
“When we're talking about mental health syndromes like depression, like PTSD, like anxiety disorders, there's definitely a biochemical component, but there's also an existential component. What I really like about this approach is that it brings the ‘psyche’ back in psychiatry, it reminds us that healing occurs in the context of both addressing the biologic dysregulation and allowing a process where somebody can start to see something in a different way, and have some ideas and thoughts about it, that might galvanize a deeper healing process,” she said.
Advice for People Who Are Interested in Trying Psilocybin
In the JAMA Podcast, Raison was asked what advice he would give to clinicians when patients come to them having heard about this study and similar studies and eager to try this new area of treatment.
“That is a tough one, because these substances are still federally Schedule 1 illegal substances,” Raison answered. The evidence is encouraging, but existing studies are small and there’s a lot that’s still unknown about how to optimally use agents such as psilocybin, he added.
“On the other hand, while we've been doing this and pursuing an FDA route (this trial was a phase 2 clinical trial), both Oregon and Colorado have legalized the use of psilocybin in constrained ways, and that is now an option for people. You can actually go someplace in the United States and pay to have a psilocybin experience,” he said, and added that the efficacy and risks of those experiences are not fully known or understood.
“I think we're a couple of few years away from it being FDA-approved for it to be available that way, so it's hard. We had thousands of people on our waiting list wanting to get into the study. We desperately do need something like these new agents, because there's a huge unmet need,” said Raison.