By Tyler Smith and Katie Kerwin McCrimmon

“Magic mushrooms” may conjure images of people in the 1960s using hallucinogenic drugs to launch journeys of self-discovery.

There is truth in that portrait; Ken Kesey and many others have detailed their experiences with LSD, MDMA, and psilocybin, the active ingredient in magic mushrooms.

There is also a long history of efforts to use psychedelic drugs to treat a variety of mental health conditions. The experiments of the 1950s and1960s ran afoul of law enforcement, when LSD and psilocybin became Schedule 1 drugs under the Controlled Substances Act in 1970.

The legal crackdown did not end interest in psychedelics as a possible aid for mental health professionals seeking new tools for treating millions of patients with major depressive disorder and other debilitating conditions.

For example, a host of clinical trials have tested psilocybin as a treatment for major depressive disorder. One such investigation is now underway at the University of Colorado School of Medicine. More may be spurred in Colorado by the state’s decriminalization of magic mushrooms in 2022.

The new study aims to determine whether psilocybin can help patients with treatment-resistant major depressive disorder and anhedonia — a condition defined by loss of joy and pleasure in everyday activities — compared to a placebo. Researchers in Colorado enrolled their first participant in the clinical trial in August of 2024, said principal investigator Dr. Andrew Novick, assistant professor of Psychiatry at the University of Colorado School of Medicine on the Anschutz Medical Campus.

As of April, the trial had enrolled seven people, with a target of 40, said Novick. He noted the launch of the trial was slower than anticipated because of the time required to clear a host of federal regulatory hurdles. With enrollment now underway, Novick and his colleague, Scott Thompson, a professor with a doctorate in neuroscience, talked about how the clinical trial works and the potential for psilocybin-based therapy.

Is this trial of psilocybin aimed at all patients with depression?

No. The trial is specifically for patients with anhedonia — or loss of joy and pleasure — and major depressive disorder that has resisted previous treatments. There is also a lengthy list of criteria that excludes patient from participating — including medical problems and psychiatric conditions, such as psychosis and bipolar disorder. (Learn more about who is eligible to participate in the clinical trial.)

Who can participate in the clinical trial? Are you accepting volunteers?

Yes. Volunteers can join the clinical trial of psilocybin. People who are interested in participating may fill out a screening form. (View the form.)

What is treatment-resistant depression?

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

Who should not use psychedelics and thus, would not be eligible to participate in the clinical trial?

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.

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.

Why do psychedelics cause psychosis for some people?

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.

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.”

Why is research on psilocybin and depression important?

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.

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

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.

Psilocybin is called a psychedelic drug. What do you call it a psychedelic?

Psychedelics like psilocybin and LSD are drugs that affect consciousness and sensory perception by activating a protein found in the brain and throughout the central nervous system called the 5-HT2A receptor, Novick said.

How is the 5-HT2A receptor involved in depression?

Medical experts and researchers don’t know exactly how or why the 5-HT2A receptor affects depression, but one hypothesis is that activation of the 5-HT2A receptor can change the brain circuits that regulate the release of dopamine, a hormone and nerve messenger that regulates mood, motivation and reward, Thompson said.

If the circuitry that controls dopamine release is disrupted, an individual may lose interest in activities that previously gave pleasure, he said.

For example, when the brain circuitry is humming as it should, people can experience pleasure. Depression can mute those messages, causing a person’s behavior to change.

“If the connections in the brain are weak, the signal peters out,” Thompson said.

When a person’s brain circuitry is intact, anything that is typically pleasurable provides not only the stimulation, but also the motivation to pursue the object of their desire.

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 of Mental Disorders. 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 can a psychedelic like psilocybin help with this disruption to the brain’s circuitry?

The idea is that because psilocybin targets the 5-HT2A receptor, it can help to reset the connections in the brain that have been disrupted and contributed to depression and anhedonia, Thompson said.

That reset, in turn, may “influence other areas of the brain to start getting more activated,” Novick added. The brain finds new pathways of adapting to influences that had mired an individual in negativity — a process summed up in the term “neuroplasticity.” As Novick and Thompson described that term in a 2024 study they co-authored, “The broadest definition of neuroplasticity is ‘the brain’s ability to change.’”

Is the use of psilocybin to treat depression new?

No. Novick noted that researchers have conducted several “extremely well done” clinical trials that compared the effectiveness of psilocybin to a placebo in treating major depressive disorder. These include studies published in April 2021, November 2022, February 2023 and August 2023 that showed promising results.

“There are about 350 people who have been part of these quality trials,” Novick said. “They show significantly better improvements, compared to the placebo, within days. You still have to call it preliminary evidence, but it’s not like we’re hypothesizing from internet forums and anecdotal experiences.”

Is there a key area of the brain that you are observing for changes that psilocybin may trigger?

Yes. One of them is the ventral striatum, an area of the brain “that is heavily responsible for motivation and making someone feel energized so they can put in effort toward reaching a goal,” Novick said. “We think that it’s the neurochemical, dopamine, within this brain region that produces this motivated, energized brain state.”

How are you conducting this psilocybin clinical trial at the University of Colorado School of Medicine?

The Colorado psilocybin study It’s a randomized, double-blind trial. That means that participants receive either a 25-milligram capsule of synthetic psilocybin or a placebo, which is a 1-milligram psilocybin dose. Neither the participants nor the researchers know who received which dose.

Patients first go through a “preparatory phase,” during which the therapy team and the patient get acquainted, Novick said. The team explains what the patient might expect —such as feelings of stress or anxiety — during the dosing session, which lasts eight hours.

The dosing session occurs in a “living-room-type environment,” with a couch and two recliners, Novick said. Patients wear eye masks and lie on the couch with headphones that transmit a special soundtrack designed to mirror the experience of coming up and down from the medication, he said.

The next day, the patient comes back for a two-hour discussion with a therapist about what happened during the treatment. This “integration session” guides the patient in describing how the treatment affected them and what sort of changes they might want to make in their lives going forward, 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.

What is unique about this clinical trial?

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

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

Typically, researchers have measured symptoms of depression by 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.

How do you measure the effectiveness of the psilocybin treatment in the trial?

Researchers measure the effectiveness of psilocybin treatments in three ways. First, patients self-report on whether they feel better, which is subjective and has its limitations.

Second, researchers will look for changes in the way the brain reacts to stimuli, using functional MRI (fMRI) imaging, administered before and after the treatment. This type of imaging offers not only a picture of the brain but also a window into the activity occurring in different regions of its landscape.

Third, patients will complete a “rewards test” during an fMRI brain scan. The test is a game in which they are told they can potentially earn money by responding quickly to an image that flashes before them on a screen. The test essentially helps to show whether individuals respond to the promise of a reward and how hard they are willing to work for it.

“We want to see changes that occur in the brain regions that regulate motivation and reward,” Novick said.

How do you ensure patient safety with a drug that can produce unpredictable effects?

“The biggest thing comes down to preparation and telling people the things they could potentially expect,” Novick said. The symptoms could be physical — nausea and headache, for example — or psychological, such as feelings of loss of control as uncomfortable memories emerge, he added.

As counters, therapists suggest “grounding techniques,” such as deep breathing and encourage patients to communicate to their therapist – who is present throughout the session — when anxiety or painful emotions well up, Novick said.

If these interventions don’t work, the team has other options, including valium to calm a panic attack and anti-psychotics as a “fail-safe” to treat an individual who completely loses control, he added. The latter, he stressed, is very rare.

Novick underscored the importance of preparing patients for “challenging experiences” that psilocybin treatment can produce. Setting aside the type of treatment, psychological challenges are not unexpected for patients who face stubborn symptoms of depression, Thompson added.

“That can happen in conventional psychotherapy,” he said. “If you are working with someone who is dealing with trauma, hopefully you get to a place where they really go head-to-head with their traumatic experience. It’s challenging. There is no other way to describe it.”

How long do the effects of the psilocybin last?

It varies, but the effects of psilocybin generally peak at one or two hours, then plateau, Novick said. All study participants stay for eight hours, but the effects may wear off well before eight hours pass, he said.

“It’s worth mentioning that we don’t have any idea how many hours it takes” for the drug to take effect,” Thompson said.

Instead of giving the drug and waiting eight hours, would the potential benefit be the same if a therapist blocked it with an anti-psychotic medication after one hour?

“No one knows,” Thompson said.

Do you follow patients after they have received treatment in the psilocybin study to see how durable the effects might be?

Yes. Novick is checking in with trial participants for eight weeks following their participation in the psilocybin clinical trial. The primary outcome measure is improvement in the Dimensional Anhedonia Rating Scale (DARS), which patients self-report. The rewards tests results, as revealed by the fMRI, are a second outcome measure.

“What we are hoping to see is changes in brain activity,” Thompson said.

Even if the results of the psilocybin trial are positive, are there caveats?

Yes. The first caveat is that unlike many drug trials, it’s nearly impossible to prevent people from recognizing whether they receive a psychedelic or a placebo. Thompson said previous studies show that about 85% of participants correctly guess which one they received. That introduces an immediate bias.

“That’s an asterisk in the record book,” Thompson said. “Patients may have gotten better, but they were prey to this unblinding.”

The other problem, recognized in the results of previous trials of psilocybin, lies in simply asking patients — particularly those with treatment-resistant depression — how they feel as a measure of effectiveness.

“Patients come in, and they are desperate. They want to get better,” Thompson said. “There is an internal pressure to want to feel better.”

That pressure may lead to improvement that proves only temporary, he added, but the design of Novick’s trial aims to identify more substantial improvement, he added.

“The unique thing about this trial is that we are actually measuring changes in the way the brain cells respond,” Thompson said.

Do we know why psilocybin may work much more quickly to provide relief from depression than other treatments, such as psychotherapy, SSRIs and other medications?

The short answer is no, Novick said, adding that it’s a question that fascinates Thompson and him.

“Why is it that we have these drugs that seem to require weeks of downstream neurobiological activity, and then you have this other one that seems to do it really quickly? In the end, it’s still a really open question.”

With the decriminalization of psilocybin in Colorado, what are your thoughts about people using magic mushrooms on their own to treat their depression?

“For right now, self-administering psilocybin on one’s own without the proper support and monitoring is highly inadvisable as a means to treat depression,” Novick said. “Obviously, psychedelic mushrooms have been a popular recreational drug for a very long time. And compared to other drugs of abuse, such as methamphetamine and heroin, the recreational use of psilocybin-containing mushrooms probably comes with lower risk of harm to both the user and society. Nonetheless, when we are talking about individuals struggling with mental illness, there’s greater risk involved, and the brain needs to be treated with care.”

“Rather than taking psilocybin on your own, Colorado’s newly launched and regulated Natural Medicine Program provides a way for people to take psilocybin under the guidance of an experienced and licensed facilitator,” Thompson added.

Who guides 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 work with each individual.

When do you anticipate finishing the clinical trial on psilocybin, and how soon do you expect to report results?

The Colorado researchers hope to finish the psilocybin clinical trial and report results by fall of 2026.

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.”

Learn more about the University of Colorado psilocybin trial.

Or fill out a screening form to volunteer for the psilocybin trial.