What professionals are saying about using psilocybin as an alternative treatment for depression

The comparison: Two doses of psilocybin, the active component in 'magic mushrooms,' versus a six-week regimen of escitalopram, a widely used antidepressant often marketed as Lexapro or Cipralex. Escitalopram belongs to a category of antidepressants known as selective serotonin reuptake inhibitors (SSRIs).

The anticipated victor: The treatment that shows the most promising results after six months in the battle against depression, a condition that affects over 300 million people globally.

The stakes are incredibly high for psilocybin clinical trials, as there is an urgent need for more effective treatments, especially for those suffering from treatment-resistant depression. Among the 9 million people in the U.S. with major depression who have tried antidepressants, an estimated 2.8 million have not responded to multiple medications.

“I know of one case where someone tried 17 different medications, but none had any effect,” shared Dr. Bertha Madras, a psychobiologist and director of the Laboratory of Addiction Neurobiology at Harvard Medical School’s McLean Hospital in Belmont, Massachusetts.

“Even electroconvulsive therapy didn’t work,” Madras remarked. “It’s heartbreaking when you can’t help someone rise from their bed and engage with life.”

Pros and cons of antidepressants

For many, antidepressants have proven to be a blessing, at least initially in the treatment process, said Dr. Charles Raison, a psychiatry and human ecology professor at the University of Wisconsin School of Medicine and Public Health in Madison.

“I always begin by expressing gratitude that we have these medications,” said Raison, who also serves as the director of the Vail Health Behavioral Health Innovation Center in Colorado, where psilocybin is being researched. “For many, they can say, ‘Wow, this really helped me climb out of a deep hole.’”

However, up to one-third of people with depression find no relief from antidepressants. Even among those who do experience improvement, “the benefits often diminish over time for a significant portion,” Raison noted. “And then there are the side effects, many of which persist long-term.”

Initial side effects like nausea or headaches typically subside within a few weeks of starting an antidepressant, but sexual side effects, such as reduced libido and difficulty achieving orgasm, can persist for months or even years. In rare instances, sexual dysfunction may continue even after discontinuing the medication.

This is a problem that psilocybin doesn’t seem to share, according to David Nutt, a psychedelics researcher and head of the neuropsychopharmacology unit at Imperial College London’s Brain Sciences Division.

“If you have just one session and improve, there’s no lingering drug effect and no long-term sexual side effects,” Nutt explained.

Psilocybin also holds an advantage when it comes to emotional blunting, a common issue with antidepressants where not only depression but also the ability to enjoy life is diminished.

“This has become a well-established finding in research, forming the basis of the theory behind antidepressants — they suppress the brain’s overactive stress center, allowing it to recover,” Nutt said.

“However, antidepressants can also dull the brain’s pleasure center, which we know because when we scan people’s brains, they don’t react as strongly to happy faces,” he noted.

“Some individuals don’t like this effect. They’ll say, ‘I’m not depressed anymore, but I also don’t feel as happy or engaged with life as I used to.’”

The leading psychedelic contender

In the search for new treatment options, psilocybin has emerged as a top contender — perhaps the most popular among a range of psychedelic substances that reached their peak popularity during the Timothy Leary era of the 1960s.

Early clinical trials of synthetic psilocybin have shown promising results for treating conditions such as cluster headaches, anxiety, anorexia, obsessive-compulsive disorder, and various forms of substance abuse.

Psilocybin has garnered its greatest praise for its apparent effectiveness in treating depression. Three variations of synthetic psilocybin have received the FDA’s ‘breakthrough therapy’ designation — in 2018 for treatment-resistant depression, which is diagnosed when patients have not responded to multiple antidepressants, and in 2019 and 2024 for clinical depression, characterized by persistent severe low mood.

The breakthrough therapy designation is a special status that accelerates FDA approval for drugs that show substantial improvements over existing treatments, according to the agency.

MDMA, also known as Molly or Ecstasy, another promising contender, has shown potential for treating post-traumatic stress disorder (PTSD) but has not yet been directly tested for depression.

In 2024, LSD (lysergic acid diethylamide) earned FDA breakthrough status for treating anxiety, and it is also undergoing clinical trials for depression. Smaller trials for lesser-known psychedelics are currently in progress as well.

However, not all experts believe that psilocybin — or any other psychedelic — will ultimately pass FDA scrutiny. In August, the agency surprised researchers by rejecting MDMA as a PTSD treatment, sending its developers back for another round of clinical trials that could take years to complete.

“We have no way of knowing how these drugs will perform in a larger, more diverse population,” said Dr. Madras from Harvard.

“Claiming that psilocybin will be the miracle cure for depression is, at best, irresponsible and, at worst, dangerous,” she warned.

A more receptive mind

Psilocybin affects a different area of the brain than traditional antidepressants, according to experts. The psychedelic targets the brain’s ruminative region, where negative thoughts often spiral uncontrollably. Brain scans taken before, during, and after psilocybin trips reveal that the brain becomes desynchronized, disrupting the cycle of negative thinking and allowing individuals to view themselves from a new perspective.

“People begin to realize that their brain is capable of change, and they can break free from the grip of depression,” said Nutt. “It’s like looking through a door into a new way of thinking, and then being able to walk through that door afterward.”

Experts emphasize that integrating new insights into daily life is crucial for lasting success in treating depression. That’s why psilocybin studies often involve trained therapists during the psychedelic experience, as well as therapy sessions before and after the trip.

“The psychedelic experience creates a critical window where your brain is more malleable, generating new brain cells, much like a child’s brain,” Raison explained.

“But what if you experience a traumatic event, like a car accident or a relationship breakdown, the day after? What if the experience alters your mindset in a way that leads you to take dangerous risks? While these situations are rare, they do pose a risk,” he cautioned.

Psychedelic therapists occasionally report negative outcomes, including difficulties adjusting to life after the treatment and a worsening of anxiety or obsessive thinking, which psychedelics aim to alleviate. Even though such cases are uncommon, Raison argued, they highlight the broader issue of prescribing psilocybin — or any psychedelic — to the general public.

“Let’s assume only 2% or 3% of people experience significant negative effects after a trip,” Raison said. “If 20 million people were to try it, that would still be a problem. These substances are incredibly powerful.”

Promising but inconclusive findings

The original April 2021 study comparing psilocybin with escitalopram was a double-blind, randomized controlled trial involving 59 patients with moderate to severe depression. Thirty participants received two 25-milligram doses of psilocybin, spaced three weeks apart, while the remaining 29 were given one 1-milligram dose of psilocybin along with a six-week regimen of escitalopram. Both groups underwent around 20 hours of psychotherapy.

“This is the first study to examine the long-term behavioral effects of psilocybin in comparison to another treatment — and likely the only one that will ever compare psilocybin directly to an SSRI in such a long-term way,” said Raison, who was not involved in the research. “That alone makes this study significant.”

After six weeks, the study found no significant difference in depression scores between the psilocybin and antidepressant groups. However, brain scans revealed a distinct contrast.

“The brains of those taking psilocybin exhibited greater flexibility and an enhanced ability to shift between different brain states,” said Nutt, a coauthor of the study.

Nutt and his team published the six-month follow-up results in September. While both psilocybin and escitalopram showed similar improvements in depressive symptoms, those who took psilocybin reported a higher sense of joy in their lives — a key factor in preventing relapse into depression.

“Psilocybin outperformed escitalopram in multiple measures of well-being, including life satisfaction, work, and social functioning,” said Tommaso Barba, lead researcher and doctoral candidate at Imperial College London, in a statement.

However, critics noted that participants in the psilocybin group were allowed to seek additional therapy or even start antidepressants between their psilocybin sessions and the six-month follow-up, which could have also contributed to the observed improvements.

Nevertheless, the study revealed that participants who showed the most promising brain scan results after six weeks of psilocybin use also exhibited the greatest reduction in depression after six months, according to Nutt.

“The more adaptable a patient’s brain was three weeks after a single psilocybin session, the better their depression outcomes were at the six-month mark,” Nutt explained. “This shows a biological, physiological change in the brain caused by psilocybin that can be detected three weeks later and predicts long-term results.”

“But before drawing any definitive conclusions, this needs to be replicated,” Nutt cautioned.

Obstacles ahead

Harvard’s Madras and other critics argue that much more research is needed before psilocybin or any psychedelic can be considered a viable treatment for mental health disorders.

“For one, clinical trials have focused on a narrow sample group. In some studies, 1,000 participants may be interviewed, but only 50 are ultimately selected,” said Madras, who was not part of the escitalopram study.

“Why is that? Because researchers must exclude individuals who might be at risk for a psychotic episode, such as those with a family history of suicide, psychosis, or bipolar disorder,” she explained.

Madras further noted that adverse effects are such a concern that researchers in psychedelic trials often specifically recruit individuals who have previously used psychedelics without negative reactions.

Then there’s the issue of blinding. In a properly conducted randomized clinical trial, patients should not know whether they are receiving the actual drug or a placebo — a pill designed to resemble the active treatment being tested.

If a drug performs significantly better than a placebo, it indicates that the positive results are not just due to patient expectations, signaling the clinical trial’s success.

However, creating a convincing placebo that makes people believe they are experiencing a hallucinogenic trip has been difficult. In a study on psilocybin for alcohol addiction, for example, around 95% of participants were able to accurately guess whether they were receiving psilocybin or the placebo.

Another challenge is the cost. It remains uncertain whether the intensive therapy required to maximize the effectiveness of psychedelics like psilocybin will be affordable for the many people suffering from depression who could benefit from it, according to Raison.

“It’s clear that psychedelics work and offer lasting benefits that we still don’t fully understand,” Raison noted. “But how this will translate into long-term depression treatment and how the healthcare system will scale these therapies remains unknown.”