green gloved hands holding up magic mushroom sampleShare on Pinterest
One dose of psilocybin may help relieve treatment-resistant depression, though experts warn this may not be without side effects. Image credit: MICROGEN IMAGES/SCIENCE PHOTO LIBRARY/Getty Images.
  • Treatment-resistant depression affects about 30% of people who have major depressive disorder.
  • A 22-site clinical trial shows a synthesized version of the psychedelic chemical psilocybin helps reduce depression symptoms in people with treatment-resistant depression.
  • Scientists reported some adverse side effects of this treatment, including thoughts of suicide.

An estimated 30% of people with major depressive disorder (MDD) have treatment-resistant depression. That means their condition does not respond to the medications that doctors usually prescribe.

Over the years, researchers have examined the use of psychedelics — substances that alter a person’s mood, thoughts, or senses — as a therapy option for treatment-resistant depression.

One of those psychedelic drugs is psilocybin. Past research shows that psilocybin provides antidepressant effects in people with MDD and reduced depressive symptoms in patients with treatment-resistant depression.

Now, a multicenter clinical trial conducted within 22 international sites, including the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London and South London and Maudsley NHS Foundation Trust, is reportedly the largest study to date to show a specific type of psilocybin therapy helps reduce depression symptoms in people with treatment-resistant depression.

However, researchers did report some adverse side effects of the use of this psilocybin therapy, including headaches, nausea, dizziness, fatigue, and thoughts about suicide.

This study was recently published in The New England Journal of Medicine.

Suicide prevention

If you know someone at immediate risk of self-harm, suicide, or hurting another person:

  • Ask the tough question: “Are you considering suicide?”
  • Listen to the person without judgment.
  • Call 911 or the local emergency number, or text TALK to 741741 to communicate with a trained crisis counselor.
  • Stay with the person until professional help arrives.
  • Try to remove any weapons, medications, or other potentially harmful objects.

If you or someone you know is having thoughts of suicide, a prevention hotline can help. The 988 Suicide and Crisis Lifeline is available 24 hours a day at 988. During a crisis, people who are hard of hearing can use their preferred relay service or dial 711 then 988.

Find more links and local resources.

Was this helpful?

A person has treatment-resistant depression if their MDD — also known as clinical depression — does not respond to at least two different types of medications typically used to treat depression.

Signs of treatment-resistant depression include:

  • symptoms not lessening after taking prescribed medications for at least 10 weeks
  • increased length and/ or frequency of depression episodes
  • short improvement immediately followed by the return of depression symptoms
  • extreme anxiety.

Treatment-resistant depression can occur if a person:

  • is naturally resistant to certain antidepressant medications, including genetic reasons
  • does not stay on their medication for the full prescribed duration
  • has other health conditions that may impact their depression, such as heart disease or thyroid issues.

Women are twice as likely to have MDD as men, and studies have shown that women with depression are more likely to experience TRD. Other people at higher risk for treatment-resistant depression include:

  • those with a previous depression diagnosis
  • people experiencing substance use disorders
  • people taking opioids for the treatment of chronic pain.

Psilocybin is a psychedelic chemical that naturally occurs in certain types of mushrooms that grow in the United States, South America, and Mexico. This is why it is sometimes referred to as “magic mushrooms.”

“Psilocybin in mushrooms has been used for centuries in indigenous populations for therapeutic and religious reasons and ceremonies,” Dr. David A. Merrill, psychiatrist, and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA, explained to Medical News Today.

“In the [U.S.] in the mid-1900s it was used to treat addiction, depression, [and] even things like post-traumatic stress disorder [PTSD],” he pointed out.

The U.S. Drug Enforcement Administration (DEA) considers psilocybin to be a schedule I substance, which means it is not currently accepted for medical use in the U.S. However, the Food and Drug Administration (FDA) recently approved an investigational new drug application for the use of psilocybin in an eating disorder treatment.

In November 2020, Oregon became the first state to legalize the use of psilocybin under supervision.

“There’s been this renewed interest in the use of psychedelic compounds, [with] psilocybin leading the charge,” Dr. Merrill said. “Psilocybin is being looked at a lot now for treatment-resistant depression. And so it’s really a legal, political question of how much data is enough to get legalization of psilocybin given that its efficacy is well established for decades, if not centuries.”

“Results from trials like this are really going for the FDA indication of use for treatment-resistant depression, which will hopefully spur not only legalization but also eventually coverage by insurance payers like Medicare,” he continued. “Typically the commercial health plans tend to follow the decisions of Medicare. So in an ideal world, this data will be leveraged to gain not only legalization of psilocybin, but also insurance coverage to improve access.”

This clinical trial examined COMP360 psilocybin, a synthesized formulation of psilocybin produced by mental health care company COMPASS Pathways.

During the clinical trial, 233 participants with treatment-resistant depression received either a 1 milligram (mg), 10 mg, or 25 mg dose of COMP360 psilocybin. Participants reportedly received their dosage in specially-designed rooms to provide a calming environment.

According to researchers, the psychedelic effects of COMP360 psilocybin last for between 6 and 8 hours. A specially-trained therapist accompanied participants in the room during this time to provide psychological support as needed.

Researchers found that participants who took 25 mg doses of the psilocybin therapy reported a greater reduction in their depression symptoms three weeks after treatment, compared to those who took the 1 mg dosage.

“These findings are a positive step in the right direction,” says Dr. James Rucker, co-lead of the Psychoactive Trials Group at King’s IoPPN and consultant psychiatrist at South London and Maudsley NHS Foundation Trust. “Our task now is to investigate psilocybin for treatment-resistant depression in larger trials with more participants, comparing it both to placebo and to established treatments.”

The research team also reported a number of adverse effects among clinical trial participants.

Over the 12 weeks of the study, 84% of participants in the 25 mg dose group, 75% in the 10 mg dose group, and 72% in the 1 mg dose group experienced headaches, nausea, dizziness, and fatigue.

Additionally, suicidal ideation and intentional self-injury were reported by participants in all dose groups, which according to trial researchers is common in treatment-resistant depression studies. Most cases reportedly took place more than a week after the COMP360 psilocybin session.

Dr. Merrill stressed that these significant side effects show the importance of the use of psilocybin treatment as a medical treatment:

“It’s not a recreational process — it’s not like do-it-yourself self-help. It really needs to be done with professionally trained, licensed, or certified practitioners who understand the power of these drugs to create a mind-altered state. Dissociation, even at times hallucinations, [are] part of the journey of psychedelics to open the mind to new possibilities, but that journey needs to be supported with professional help.”

MNT also spoke with Dr. Greg Fonzo, assistant professor and co-director of the Center for Psychedelic Research & Therapy in the Department of Psychiatry & Behavioral Sciences at The University of Texas at Austin Dell Medical School, about this study.

He said that while it is currently unclear how psychedelics like psilocybin exert efficacy for treatment-resistant depression, what potentially makes them an attractive option is the demonstrated ability to exert rapid-acting and somewhat durable antidepressant effects for at least a subset of individuals that undergo this treatment.

“Given that people with treatment-resistant depression have already failed multiple medication and/or evidence-based psychotherapy trials, the possibility of a rapid-acting treatment that provides some degree of symptom relief within days of administration lasting up to several weeks or more is an option worth exploring,” Dr. Fonzo explained.

However, he said the reported adverse effects are “sobering pieces of information.”

“As suicidal ideation and behavior are already present to some degree in many individuals with treatment-resistant depression, it is currently unclear whether the rate of these adverse events for psilocybin versus another type of treatment in a similar population would substantially differ,” Dr. Fonzo added.

As for the next steps in this research, Dr. Fonzo said they are already underway and include conducting an even larger multi-site, confirmatory efficacy trial in a more diverse population to examine the effect of multiple versus single doses, as well as of magnitude of a dose — referring to the quantity in milligrams — of psilocybin in the context of the treatment protocol.

It would also “determine whether re-treatment of individuals that relapse into depression after either no response to a treatment course or a favorable response that then diminishes over time is a strategy that might boost the long-term efficacy of this approach,” he added, “and begin to establish baseline participant characteristics that predict either a favorable or unfavorable response to this type of treatment.”