First modern-era Colorado psilocybin clinical trial for depression set to launch this fall

Back in the 1950s and 60s, scientists did extensive research on psychedelics. Then research ground to a halt. Now, scientists are studying whether psychedelics, like magic mushrooms, could lead to much-needed new therapies for people coping with depression.
May 10, 2023
The first modern-era Colorado psilocybin clinical trial for depression aims to find much-needed new treatments. Photo: Getty Images.
The first modern-era Colorado psilocybin clinical trial for depression aims to find much-needed new treatments. Photo: Getty Images.

The first modern-era Colorado psilocybin clinical trial for depression is set to launch this fall at the University of Colorado Anschutz Medical Campus in Aurora.

The researchers will test whether psilocybin —  the chemical compound that produces psychedelic effects in “magic mushrooms” — can help with treatment-resistant depression.

There’s a great need for new treatments for people with depression since so many people are suffering. And it’s been decades since new medications have emerged to help people with depression.

The research on psilocybin is not related to Proposition 122, a ballot measure that Colorado voters approved last fall that allows people ages 21 and older to grow and share psychedelic mushrooms. That new law doesn’t go into effect until next year.

But the groundbreaking Colorado psilocybin clinical trial comes amid increased focus and research across the U.S. on an array of psychedelics from psilocybin to ayahuasca and MDMA (also known as ecstasy).

These compounds remain illegal under federal law, but with permission from the U.S. Food and Drug Administration (FDA), a growing number of researchers across the U.S. are studying whether psychedelics can help people with a variety of mental and behavioral health challenges from depression to post-traumatic stress to substance use disorders.

To learn about the new Colorado psilocybin clinical trial, we consulted with psychiatrist and principal investigator, Dr. Andrew Novick, and Dr. Scott Thompson, a neuroscientist in the University of Colorado School of Medicine Department of Psychiatry.

The department’s innovative research and therapeutics mission aims to discover changes that occur in the brains of people with psychiatric disorders and to identify better therapies to treat them.

Why is new research on psychedelics — including this Colorado psilocybin clinical trial — so critical?

“Major depressive disorder is one of the most common and costly neuropsychiatric syndromes,” said Thompson, who has a Ph.D. in neuroscience and is one of the world’s leading researchers on how psilocybin works in the brains of animals and humans.

Scott Thompson is one of the leading researchers in the world on how psilocybin affects the brain. He's helping with a new Colorado psilocybin clinic trial for depression that is set to start this fall. Photo courtesy of Dr. Scott Thompson.
Dr. Scott Thompson is one of the leading researchers in the world on how psilocybin affects the brain. He’s helping with a new Colorado psilocybin clinic trial for depression that is set to start this fall. Photo courtesy of Dr. Scott Thompson.

As many as one in four women and one in six men are likely to suffer from depression during their lifetimes. Severe depression causes tragic reverberations from suicides to multi-billion dollar annual economic burdens, said Thompson.

Experts who care for people with mental health challenges have not had any new treatments for decades, Novick said.

And traditional antidepressant medications — selective serotonin reuptake inhibitors (or SSRIs) like Prozac — do not work for as many as one-third of people who try them.

“Even with the 2/3 of people for whom they work, it can take months and months before doctors find the right dose and the specific drug that works,” Thompson said. “So, the promise and hope of using drugs like psilocybin is that a single dose may produce an immediate therapeutic benefit that may permanently alleviate symptoms.

“Instead of having to go through months and months of trying to find the right medication and having the chance of not responding, the hope is that many people will respond to psilocybin,” Thompson said.

Researchers elsewhere have found that a single dose of psilocybin may help people with depression for as long as a year.

“That’s why people are so excited about this work,” Thompson said.

Novick has worked with countless patients who have struggled with depression and were desperate to feel better but failed to respond to traditional antidepressants and felt incurably broken.

Finally, with new research, hope is on the horizon.

“It’s really important that we do this research for the sake of our patients,” Novick said.

If psilocybin helps with depression, exactly how might it work?

Researchers don’t know exactly how psilocybin works for depression (if it does), but the short answer is that it may help reset the brain.

“For people with depression, there are circuits in the brain that are not working properly. And the compounds in psilocybin may help restore and repair those circuits so the circuits behave properly,” Thompson said. “We don’t know exactly how, but psilocybin may essentially fix a broken brain.”

Thompson has done groundbreaking research on how psilocybin can change the brains of mice.

Researchers now are learning much more about how psilocybin affects the human brain.

“We know that the brains of people with depression function differently than the brains of healthy, control subjects,” Thompson said. “And we know that administering psychedelic compounds tends to make those differences smaller.”

Thompson uses the example of eating a piece of chocolate cake.

For people who like chocolate cake, but are depressed, a bit of cake might not yield much pleasure.

“You can still taste it. It’s chocolate. But, somehow the stimuli of chocolate and the creaminess and all the good stuff doesn’t get to the place in your brain where you can say, ‘Wow. That feels and tastes really good,’” Thompson said.

“Something connecting the chocolate cake with the reward center in your brain is not wired properly,” Thompson said. “The hope is that psilocybin may help reset these connections so when you taste something rich, creamy and chocolatey, you say, ‘Wow. That tastes really great.’”

Rewiring the brain might help boost pleasure while also disrupting persistent negative thought patterns, which often overwhelm people who are suffering with depression.

“They might think, ‘everybody thinks I’m stupid or ugly or fat. Nobody loves me I’m unlovable. I’m broken. Nobody cares about me,’” Thompson said.

It’s possible that psilocybin and other psychedelic compounds may help restore a balance between negative and positive thinking.

What is treatment-resistant depression?

“It’s depression in individuals who have failed to respond to conventional treatments like antidepressants,” Novick said.

When is the Colorado psilocybin clinical trial due to start?

The researchers are making final arrangements and hope to officially start the clinical trial sometime in the fall.

Who is eligible to participate in the psilocybin research?

The researchers are still finalizing eligibility for participation in the clinical trial. Patients need to have been diagnosed with treatment-resistant depression. For this reason, study managers may recruit study participants from those who were already in the care of a provider in the Department of Psychiatry at the University of Colorado School of Medicine prior to the spring of 2023.

The process of selecting volunteers will be complex. Along with verifying that study participants have treatment-resistant depression, doctors and study managers will conduct a comprehensive screening process. Therefore, Novick and Thompson do not recommended that individuals seek out treatment in the Department of Psychiatry for the sole purpose of wanting to volunteer for the study.

“We provide exceptional care to our patients,” Novick said. “So if that’s something you need, we offer a lot of services. But I would hate for someone to switch their care to our team with the expectation that they will get to participate in our study only to be disappointed.”

Are there some people who should not use psychedelics and thus, would be ineligible for the clinical trial? I’ve heard, for example, that psychedelics can be dangerous for people with bipolar disorder and schizophrenia. Is that true?

Yes. Some people are not eligible to volunteer for the psilocybin trial. These groups of people include those who are at risk for schizophrenia and those with bipolar disorder. In addition, people who have had any kind of brain tumor, seizures or a history of strokes cannot participate.

“It also would not be appropriate to administer psilocybin to people who have compromised blood flow in the brain, like a history of aneurysm, or to those with dementia or Alzheimer’s,” Novick said.

Dr. Andrew Novick is leading a new Colorado clinical trial that will test how psilocybin affects treatment-resistant depression. The Colorado psilocybin clinical trial for depression is the first of its kind in Colorado in the modern era. Photo courtesy of Dr. Andrew Novick.
Dr. Andrew Novick is leading a new Colorado clinical trial that will test how psilocybin affects treatment-resistant depression. The Colorado psilocybin clinical trial for depression is the first of its kind in Colorado in the modern era. Photo courtesy of Dr. Andrew Novick.

For some people, psychedelics can trigger bad reactions or psychosis.

Whether people are participating in research or are taking mushrooms recreationally, they should be cautious.

“These are powerful compounds,” Thompson said. “If you talk to psychiatrists who deal with schizophrenic patients, it’s very common for these patients to report that the first time they had a psychotic episode was when they took a psychedelic drug.

“That’s why we are very careful in our clinical trial (as are other researchers who are testing psilocybin elsewhere) to exclude people who have a risk of schizophrenia and bipolar disorder,” Thompson said.

Doctors don’t know exactly why and how psychedelics may trigger latent psychosis in some people, and a definite cause and effect relationship is hard to prove. But the phenomenon is serious enough that both Thompson and Novick advise people to speak honestly with their doctors before using psychedelics.

“The age group of people who are using psychedelic drugs, often people in their 20s, overlaps exactly with the age when people at risk are most likely to have their first psychotic episode,” Thompson said.

“If you’re using drugs illegally, and you don’t know your medical history and haven’t talked to a professional about risk factors, you are at risk,” he said.

Novick said some patients with psychosis can connect hallucinogenic drugs with the onset of mental illness.

“Schizophrenia seems to have been triggered in some of these patients,” Novick said. “In retrospect, when you look back, there are risk factors. A relative might have been institutionalized. The patient might have had bizarre experiences in the past that we call prodromes. These are signals that something is coming on regardless of drug use. Nonetheless, until we know more, we think it would be inappropriate to subject a vulnerable person to a drug that could contribute to a serious mental illness.”

For these reasons, researchers approach psychedelics “with an abundance of caution,” Thompson said.

“We strongly discourage anybody with a potential risk for mental illness from using psychedelic drugs illegally,” Thompson said.

While it may sound like a cliché, Novick strongly encourages people to talk with their doctors about drug use.

Among the many outcomes of the Colorado psilocybin clinical trial, researchers are hopeful that they can provide much better information for doctors so they can properly advise patients about psychedelics.

“On the one hand, these drugs may hold great promise for people with depression. On the other hand, they may not be appropriate for others,” Novick said.

Back in the 1950s and 1960s, psychologist Timothy Leary was such an advocate for psychedelics that he wanted to add them to water supplies.

Both Novick and Thompson warn people about being too cavalier about psychedelics.

They may be groundbreaking for some people, but harmful to others.

“Here’s an analogy,” Thompson said. “We give cancer patients chemical toxins that kill cells as therapeutic agents. They’re very powerful. When you need them, they work really well. But they’re not for everybody.”

If I have treatment-resistant depression and I received care from a University of Colorado psychiatrist prior to the spring of 2023, how can I volunteer to participate in the clinical trial?

Once study managers start enrolling volunteers, information on participation will be posted on this website:  Although the study team is aiming to start the clinical trial this fall, it’s possible that it will be delayed.

How do medical providers formally determine who has depression?

Diagnosis of major depressive disorder is done through a clinical interview to determine whether individuals meet specific criteria, as outlined in the American Psychiatric Association’s Diagnostic and Statistical Manual. Symptoms must be present for a prolonged period, must cause significant distress and/or impairment in everyday life, and cannot be better explained by another medical problem.

How will the clinical trial work? What will the patients do?

The clinical trial will include 40 people who are randomly assigned to one of two groups: an “active” group of 20 people and the “control” group of 20 others. People in the active group will receive a larger dose of psilocybin, while those in the control group will receive a very small amount, which is considered a “non-therapeutic dose.”

The day before patients receive their dose, they will spend time with a therapist who will serve as part of a two-therapist guide team when the patients receive psilocybin.

Then, on the day of the study, participants will receive a specific dose of psilocybin. Two therapists (one of whom met with the volunteer the day before) will support the patients for several hours as they experience the effects of the psilocybin.

A day or two later, once patients no longer are experiencing the hallucinogenic effects of the psilocybin, they will return for what’s called a “reintegration session” with their therapists.

“They talk about their experiences to flesh them out,” Thompson said.

In addition to the therapists, Novick monitors the study participants’ experiences in case anyone has an adverse reaction that requires medical intervention.

“I’m always on site as the medical doctor and psychiatrist. If there were to be a rare instance when a participant had a negative reaction or felt things were getting out of hand, I could come in and evaluate the patient,” Novick said.

When people are experiencing bad side effects while under the influence of psilocybin, doctors can use antipsychotic medications to reverse the effects of psychedelics.

“The psychedelic state of mind is not equivalent to psychosis. With that said, we can use antipsychotics to help stop some of the experiences with psychedelics,” Novick said.

Will patients know which dose they have received?

Some study participants may guess which dose they received due to the hallucinogenic effects that most people feel when they take mushrooms. Studies with psychedelics are complex for this reason. Even so, neither the patients nor the researchers will know for certain during the clinical trial which participants have received which dose. That’s because the highest quality clinical trials are what’s known as “double blind,” meaning that both researchers and study participants do not know which medication or control sample they have received.

What is unique about this clinical trial?

Elsewhere around the country, at a handful of other academic medical centers, researchers have begun to test how well psychedelics work for depression.

What’s unique in the Colorado study is how researchers will measure and assess the study participants’ depression.

“We are specifically looking at a symptom of depression called anhedonia, which is the lack of an ability to feel excitement or pleasure from activities. Anhedonia is one of the more difficult symptoms to treat,” said Novick, who is also an assistant professor of psychiatry at the University of Colorado School of Medicine.

Anhedonia is one of the most debilitating and challenging aspects of depression, Thompson said.

“It has a huge impact on quality of life,” Thompson said.

And most researchers measure anhedonia by simply asking patients how they feel.

That’s not always an accurate measure. People who are suffering from depression want to feel better, and many want to please their psychiatrists or therapists. So some people with depression might think they feel better when, in fact, it is just a transient feeling of hope.

So, how will Colorado researchers more accurately measure anhedonia?

The researchers will measure anhedonia in three ways. The first is the traditional “subjective self-report.” That involves asking patients how they are doing, and it can be inaccurate.

The second method involves observing a patient’s behavior when they are asked to complete tasks that yield a reward.

“And there’s a subconscious response,” Thompson said.

The patient is not aware that they are revealing a response, but researchers can measure it.

The third method is linked to brain imaging.

“That’s called a neural or neurobiological measure, which allows us to actually see what is going on in the brain,” Novick said. “Does the treatment change patterns in the brain associated with anhedonia and motivation.”

When will you do brain scans on study volunteers?

Participants in the Colorado psilocybin clinical trial will get MRIs on their brains two times: once about a week before they take psilocybin and once about a week after they’ve received psilocybin.

“Thanks to the neuroimaging, we get to see what the participant’s brain is doing almost in real time,” Novick said.

While some researchers elsewhere have done MRIs while patients are under the influence of psilocybin, that won’t be the case in the Colorado study.

How do studies on mice relate to this research?

Thompson was part of a team that conducted groundbreaking research on mice in which they found that psilocybin has fast-acting antidepressant-like properties.

The scientists found that psilocybin strengthens connections in mouse brain cells. These cells are centers for processing rewards and emotions.

While mice don’t get depressed, per se, like humans, Thompson and his colleagues were able to measure anhedonia in mice.

“You give a mouse something that’s rewarding, and you measure the response. That happens with a normal mouse. You give it cheese. It eats it right away. But a “depressed” mouse will not be so excited about the cheese,” Thompson said.

The team also was able to give mice a drug that blocked hallucinations, but preserved the beneficial effects of psilocybin.

“The mice retained some of the benefits,” Thompson said.

While researchers can’t always duplicate results from animal studies in humans, Thompson is hopeful that the Colorado team may be able to harness some of the lessons from research on mice for gains in fighting depression and other mental health challenges in humans.

Since mushrooms are illegal, how are you able to do the Colorado psilocybin trial?

It’s true that psilocybin and other psychedelics are still considered Schedule I drugs, and thus remain illegal under federal law. But researchers, like the University of Colorado team, work closely with health officials at the FDA. In order to do the Colorado psilocybin clinical trial, Novick and his team must complete a rigorous application to study a new investigational drug. They will then receive psilocybin samples from a supplier that is officially designated by the FDA. Regulators from the FDA carefully scrutinize protocols on how researchers study psychedelics and all other drugs under investigation.

Psychologists in the U.S. began doing extensive research on LSD and other psychedelics in the 1950s. Writers at Life magazine coined the termed “magic mushrooms” back in 1957, then a year later, scientists identified psilocybin as the psychoactive agent in mushrooms. It’s possible that Colorado researchers experimented with psilocybin in the 1960s, but research ground to a halt with the passage of the 1970 Controlled Substances Act, which made psychedelics and many other drugs illegal.

Researchers in the U.S. and around the world slowly began studying hallucinogenic drugs again, starting in the 1990s. And federal officials have gradually, but cautiously, approved new research in recent years.

“Among the things that have held up this kind of research are the regulatory hurdles that one has to jump through to get permission to do this kind of trial,” Thompson said. “Federal officials are very, very concerned about safety, as well they should be.

“And so it has taken a lot of people a lot of years to get to the place where we are now. It’s a very complicated process, and the federal government keeps it that way deliberately,” Thompson said.

Where is other research on psychedelics taking place nationally?

A handful of other academic medical centers around the U.S. are conducting clinical trials related to psilocybin and other psychedelics. These centers include Johns Hopkins, Stanford, Yale and New York University, the University of Wisconsin, Madison, the University of Texas, Austin and the University of California, San Francisco.

“There’s a lot of excitement about the new research, but no one else is testing for anhedonia, to our knowledge,” Thompson said.

Who will guide patients through their experiences with psilocybin?

After the study volunteers receive doses of psilocybin, specially trained, licensed psychotherapists will guide patients through their experiences.

Because each patient’s hallucinogenic journey could last for several hours, two therapists will work with each individual.

Some people who have used psychedelics have scary hallucinations. How do you help patients avoid frightening experiences?

To avoid scary hallucinations, researchers have many protocols. These include carefully controlling doses of psilocybin, doing in-depth preparations with study volunteers before they take the hallucinogen and having well-trained therapists guide the study volunteers throughout their experience.

“Researchers have worked out the safest way to administer psychedelic compounds,” Thompson said.

Added Novick: “Patients come meet with therapists in advance. They establish rapport with the therapist. The therapist helps them understand what they’re going to experience while they’re taking the psilocybin.”

For people who have never used mind-altering drugs, the experience can be scary, Thompson said.

“You can feel like you’ve lost your mind and your ability to control your thoughts. The features that we associate with psychedelic experiences can be terrifying for many,” Thompson said.

The therapists talk over the patient’s fears in advance and help people understand that it’s possible to feel a lack of control over their thoughts. They reassure them that a guide will keep them safe.

“And we let them know that the drugs will come out of your body, and once the drug is gone, you will be fine,” Thompson said.

“You’re not permanently going to feel like you’ve lost your mind,” Thompson said.

What are your thoughts on the potential medical benefits of other psychedelics?

“Other compounds like MDMA or ecstasy are really promising,” Novick said. “Our hope is that through the Department of Psychiatry’s new research and therapeutics programs, we can see how effective these drugs are and who they’re going to be best for.

”Colorado researchers may do studies in the future to better understand the benefits of psychedelics for PTSD, for instance.

At other institutions, researchers have found “strikingly good results,” Thompson said.

“It’s different from psilocybin. MDMA requires multiple treatments over the course of a month or so,” he said. “With psilocybin, the psychedelic effects last about six hours. With LSD, they can last 12 hours or more. Study subjects also report that psilocybin is a bit gentler than LSD, for example.”

People use other hallucinogens like ayahuasca, which comes from a tropical vine, and bufotenine, a compound from frog secretions.

“The biologic properties in terms of what they do to the brain may be similar, but they’re not exactly the same,” Thompson said. “Some are more challenging and dangerous.”

The hope is that significant new, high quality research will help experts learn much more about which compounds might be safe and effective for varying health challenges.

“We don’t know yet whether ecstasy (MDMA) is good for depression. And we don’t know if psilocybin will be good for PTSD,” Thompson said.

Based on studies so far, the psychological qualities and relative convenience of psilocybin make it the most promising for potential therapeutic use.

How many psychedelic compounds are there?

There are actually hundreds of psychedelic compounds, including both naturally occurring hallucinogens like mushrooms and ayahuasca, along with dozens of others that chemists created back in the heyday of research on psychedelics in the 1960s.

“Right now, dozens of companies are out there trying to synthesize novel molecules,” Thompson said.

How hopeful are you that research on psychedelics can lead to new antidepressant medications?

The Colorado researchers are optimistic that through their research, they may be able to develop innovative new medications that can help patients access the benefits of psychedelics without negative side effects.

“One of the dreams is that you could take the psychedelic effects out of psilocybin and retain the benefits. If that were true, you wouldn’t need to spend three days in a psychiatrist’s office. That would lead to huge savings in time and money,” Thompson said. “Eventually, people might be able to take a pill at home and be functional at work. We’re dedicated to bringing the newest medicines to bear on psychiatric disease.”

Added Novick: “We want to do the best possible science and give patients who aren’t getting better what they need and they deserve.”

About the author

Katie Kerwin McCrimmon is a proud Coloradan. She attended Colorado College thanks to a merit scholarship from the Boettcher Foundation and worked as a park ranger in Rocky Mountain National Park during summers in college.

Katie is a dedicated storyteller who loves getting to know UCHealth patients and providers and sharing their inspiring stories.

Katie spent years working as an award-winning journalist at the Rocky Mountain News and at an online health policy news site before joining UCHealth in 2017.

Katie and her husband, Cyrus — a Pulitzer Prize-winning photographer — have three adult children and love spending time in the Colorado mountains and traveling around the world.