Psilocybin, the active psychedelic ingredient in magic mushrooms, has been proven to impact patients with depression positively. Vail Health's OPTIMIZE study, which will administer doses of psilocybin to all 140 participants, aims to investigate how to predict and enhance this effect.
"In our (psilocybin) studies, only half the people that get a high dose are really feeling completely fine six weeks later," said Charles Raison, director of Vail Health's Behavioral Health Innovation Center. "We want to try to see, can we get 70 percent of people there, 80 percent of people?"
The OPTIMIZE study examines the impact of noninvasive vagus nerve stimulation on patients with depression who have received a strong dose of psilocybin.
"Eight weeks after you get the psilocybin dose, studies would suggest that people will still, on average, feel considerably less depressed," Raison said.
"What we're curious about is whether (vagus nerve stimulation) extends and increases the antidepressant effect," Raison said. "Nobody has ever done that. No study has ever done that."
The OPTIMIZE study is unique for several reasons. All participants receive the same strong dose of psilocybin in a clinical setting. All participants also participate in two types of real-life monitoring before and after they are dosed to examine their behavioral changes.
"It's really a lot of novel interventions smashed into one mega trial. It's definitely more complex than the average clinical trial, but I think it will be a really interesting study, for both participants and for the scientific community," said Chloe Sorenson, a clinical research supervisor at the Vail Health Behavioral Health Innovation Center.
In a typical clinical trial studying psilocybin, only half the participants receive the drug. In the OPTIMIZE study, all patients will receive a 25-milligram dose of pharmaceutically produced psilocybin from the Usona Institute in Wisconsin. The large dose, selected for its proven effectiveness in treating depression, can only be administered in a clinical setting.
Participating in the study "becomes a way for folks that are struggling with clinical depression to get exposure to this novel treatment," Raison said. "It's one of the cool things about this study."
Not all participants will experience an antidepressant effect from the psilocybin.
"We don't want people coming into this thinking, "this is going to cure me," because that creates a false expectation," Sorenson said. "It's possible that people will see a benefit in their depressive symptoms, but it's also possible that they won't. It's also possible that they could have a worsening in their symptoms. Some people have bad experiences with psilocybin, and that's not something we can control, but one of the other aims of the study is to see if we can predict who is going to have a good experience."
The vagus nerve runs between the body and the brain. When the nerve is stimulated, "we think that what it's doing is helping reinforce the power of emotionally powerful memories," Raison said. "People have very powerful memories about psychedelics. We're curious if we can make those memories more powerful and last longer, because we think if we do, people might continue to feel emotionally better for longer, too."
In the OPTIMIZE study, the vagus nerve will be stimulated through the ear via an earpiece participants wear for 20 minutes in the morning and evening for seven days after they receive their dose of psilocybin.
Following dosing, participants are randomized to one of three groups: Active vagus nerve stimulation, sham vagus nerve stimulation or no vagus nerve stimulation.
Members of the first two groups are blinded to which group they are in; both receive the same device, consisting of an earpiece and the calculator-like device it attaches to. Both wear the device for 20 minutes each morning and night for seven days following their dosing day.
But only the active vagus nerve stimulation group experiences the stimulation for the full 20 minutes, while the other group's earpiece will stimulate at first and then shut off.
"The reason that you can't tell the difference between the two is because you habituate really quickly to the sensation. It's a really mild prickling," Sorenson said.
The participant experience in the OPTIMIZE study lasts three to four months, including eight site visits and at-home work. Just one of the visits is the "dosing day," when the participant receives the psilocybin dose.
On dosing day, the participant is monitored by two trained facilitators who remain in the room for the entire dosing experience, which lasts a minimum of eight hours.
The dosing room has been deliberately designed to be calming, with a bed for participants to sit or lie down in, two chairs for facilitators and relaxing decor. Participants will have access to headsets, eye masks, art supplies and snacks, and can bring food and journaling supplies from home.
"Sometimes, it is helpful to talk to the facilitators, but sometimes, the facilitators are just there to be present," Sorenson said.
For safety reasons, the U.S. Food and Drug Administration requires that participants are not allowed to leave the facility for eight hours after receiving the dose of psilocybin.
Immediately after the dosing session, before the participant is discharged, the study team asks the participant to write a reflection on the most meaningful moment from their experience. The participants receive a copy of the narrative during vagus nerve stimulation sessions and during three integration sessions with their facilitators, during which they talk through their experience.
The study uses two types of technology to monitor patients' behavior before and after they receive the psilocybin.
The Fabla app, an ecological momentary assessment app, pings participants multiple times per day with brief questions about how they are feeling. The study provides a standard set of eight questions, and participants also work with the study team to design two personalized questions.
"Typically, when you have people in a clinical trial, they are coming into the clinic, they're doing structured assessments in the clinic, and you're only really getting a glimpse of what they're like in that moment. The idea of doing an EMA is to do a lot of brief assessments as they go about their daily life so you're getting a broader picture of what their behavior is like outside of the clinic," Sorenson said.
The app also has a voice diary function and participants will be asked to talk about their day at the end of each day for a few minutes.
For four days at a time, participants will also be asked to carry an electronically activated recorder, a phone-like device that contains software that "noninvasively captures audio snippets as they go about their daily life," Sorenson said.
The device records roughly 30 seconds of audio every approximately 12 minutes without notifying the participant. It is programmed to be off when participants are asleep and they can turn it off if they enter a setting that cannot be recorded.
"The idea behind the EAR is to capture real-world interactions," Sorenson said. "You can actually pick up a lot just by listening to these little audio snippets."
A team at Emory University collects and analyzes the data from the EAR and the Fabla.
The OPTIMIZE study is currently enrolling participants from Eagle County, surrounding counties and the Front Range.
The study, which will run for an estimated three to five years, will collect data from 140 participants.
"We are interested in anybody who is willing to participate," Sorenson said. "It is a pretty intensive study."
The study enrolled its first participant last week. The first dosing is slated for July.
Participants must be medically healthy adults ages 18-70 who struggle with clinical depression. Applicants can currently be taking an antidepressant, but will only be enrolled in the trial if it is ineffective, and the participant will not receive psilocybin until they have been weaned off the antidepressant.
Individuals who have used cannabis or psilocybin in the past can qualify for the study but cannot be taking the drugs right before or for the duration of the study.
All potential participants must first fill out an online survey for the study team detailing some of their mental health and medical history.
More information about qualifying for and applying to participate in the study can be found at VailHealthBH.org/Optimize.
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