Psilocybin for depression: does it work?

You might know psilocybin as “shrooms” or “magic mushrooms.” You may only associate this psychoactive plant with flashbacks and bad trips. If so, it may surprise you to learn that pure psilocybin is currently used in clinical trials and shows great promise in treating depression. 

When using psilocybin for depression, it’s essential to do so with psychological support to help you integrate your experience and heal from depression.

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Psilocybin is a psychoactive substance found in certain mushrooms. These mushrooms were used in mystical or spiritual rituals for centuries in ancient cultures (Nichols, 2016). 

These mushrooms have been called “magic mushrooms” for their hallucinogenic properties. Psilocybin causes intense changes in thought, emotion, and consciousness. It activates the serotonin receptors in parts of your brain that affect your mood, perception, and cognition (Roseman, 2018).

In the late 1950s, Alfred Hoffman extracted the pure form of psilocybin. Pharmaceutical companies then promoted psilocybin for other conditions, including various mental illnesses. But by 1970, psilocybin became a Schedule 1 controlled substance in the United States. This designation meant psilocybin was not accepted to serve any legitimate medical purpose. As such, it became illegal in the U.S. and most of the world  (Carhart-Harris, 2017-a). 

While people continued to use “magic mushrooms” recreationally, the FDA halted clinical testing for many years. That is, until the past decade or so, when researchers began studying it again for its therapeutic potential, especially for severe depression (Carhart-Harris, 2017-a).

The National Institute of Mental Health says that an estimated 17.3 million adults in the U.S.—about 7.1% of all adults—have had at least one major depressive episode (NIMH, 2019). The gold standard for treating depression, major depressive disorder (MDD), and depressive symptoms are antidepressants and psychotherapy. 

Standard antidepressant medications include (Bains, 2020):

• Selective serotonin reuptake inhibitors (SSRIs) like escitalopram, citalopram, paroxetine, fluoxetine, and sertraline

• Serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine and venlafaxine

• Atypical antidepressants like bupropion

• Tricyclic antidepressants like amitriptyline

• Other medications like monoamine oxidase inhibitors (MAOIs) and antipsychotics may also be used.

Combining antidepressants and psychotherapy is more effective at treating major depression than doing either of these treatments alone (Bains, 2020).

Although these standard treatments work well for many people, others have treatment-resistant depression—severe depressive symptoms that can’t be relieved through traditional therapies. For those people, alternative therapies like psilocybin may be a good option. 

There is growing, substantial evidence of the antidepressant effects of psilocybin therapy. A study done at Johns Hopkins University in 2006 demonstrated the therapeutic potential of psilocybin (Griffiths, 2006).

Several scientific studies have used psilocybin in double-blind, random-controlled trials comparing it with placebo for people with life-threatening cancer and depression. Though the studies were small, the results were impressive. Many study participants felt rapid and enduring relief of their depressive symptoms after taking psilocybin (Carhart-Harris, 2017-a).

A follow-up study in people with cancer-related depression found psilocybin’s antidepressant effects lasted up to four and a half years after taking it (Agin-Liebes, 2020).

Dr. David Nutt of Imperial College London did an open study focused on treatment-resistant major depressive disorder only. In this study, trial participants all got psilocybin, and no one received a placebo. All participants had their blood flow measured using an fMRI (functional MRI). The results showed that trial participants had enduring and rapid relief of their depressive symptoms even six months later (Carhart-Harris, 2017-a).

A study published in JAMA Psychiatry found that psilocybin worked better than SSRIs at relieving depression symptoms. More than 70% of people with major depressive disorder showed improvement, and more than half were in remission four weeks after treatment (Davis, 2020). 

A double-blind, randomized-controlled study, published in April 2021, compared psilocybin and escitalopram (Lexapro). The results showed that psilocybin worked as well as the antidepressant. However, experts said the study’s design was limited, and more studies are needed (Carhart-Harris, 2021).

In 2018, the FDA approved psilocybin as a “breakthrough therapy” to treat depression based on several of these studies. They granted clinical trial approval to several institutes that continue to research psilocybin. The initial data on psilocybin shows its promise and potential in treating major depressive disorder and symptoms of depression. However, more studies are needed to determine effective dosing, lasting relief, and long-term effects.

Psilocybin and other psychedelics like LSD, MDMA, and ketamine, can alter a person’s consciousness. This alteration may help people with treatment-resistant depression (Carhart-Harris, 2017-a).

Psilocybin jumpstarts brain connections 

Psilocybin and LSD lead to similar feelings of euphoria and relaxation. Some people may feel like they’ve had an intense spiritual or introspective experience. Hallucinations or psychedelic experiences are also common when taking psilocybin. Researchers hypothesize that hallucinations occur because of heightened connections and communication happening in different areas of the brain. These activated connections and modifications of old networks may help people reduce or eliminate their depressive patterns (Carhart-Harris, 2017-a).

Psilocybin heightens emotional responsiveness 

Psilocybin acts on the serotonin receptors in the brain but differently than most common antidepressants. 

Scientists and researchers recognized depression could arise from a lack of sufficient serotonin in the brain. Many common antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs), were developed to keep more serotonin in the brain for longer. However, SSRIs take at least six weeks to work and only work for about 40% of people. In addition, they reduce depressive symptoms but dampen and blunt positive, upbeat emotions as well. Psilocybin increases sensitivity to emotions and heightens reactions, and it works quickly (Carhart-Harris, 2017-a).

Psilocybin helps to alter activity in key parts of the brain  

Functional MRI (fMRI) studies on people who received two doses of psilocybin showed reduced blood flow to the areas of the brain handling stress and fear. People in the study said they felt their depressive symptoms decrease right after taking the psilocybin (Carhart-Harris, 2017-b).

If you are currently under treatment for depression, you may be taking an antidepressant and receiving psychotherapy. You may see your therapist at a regular interval and take your medication daily. Psilocybin treatment for depression or psychedelic therapy differs from this regimen.

Currently, because of the Schedule 1 classification for psilocybin, all psilocybin treatments happen in clinical trials. However, the treatment protocol is similar for most psychedelic trials. 

Participants meet with a therapist before the psilocybin session. This is to establish the participant’s physical and mental health history, treatment goals, and to foster trust. Psilocybin is given in a supportive and calm environment. The trial participant lies in a comfortable position, often with dim lighting and music. A therapist is present to help provide emotional support and guide the participant for the next few hours after receiving the dose. The therapist then helps the participant integrate their experience (Roseman, 2018a). 

While psilocybin isn’t currently widely available, it’s showing promising results in clinical trials for people with treatment-resistant depression. It offers some powerful benefits over traditional therapies.

Long-lasting 

It appears that psilocybin relief lasts for a long time. Early studies in 2016 showed substantial relief at the one week, four weeks, three-month, and six-month marks after a psilocybin dose (Carhart-Harris, 2017-a). Current research shows that even five years after the treatment, some trial participants still felt relief. Participants attribute positive changes in their lives to their experience with psilocybin (Agin-Liebes, 2020). 

Faster relief

Psilocybin works much faster than common antidepressant therapy. Studies show that psilocybin works within one week of the first dose. Many antidepressants can take six weeks or even longer to show any effects. In addition, antidepressant medication must be taken daily and usually long-term to achieve depression remission. In contrast, psilocybin therapy for depression uses one or two doses for relief. Both antidepressant and psilocybin therapy work best when combined with psychotherapy (Carhart-Harris, 2017-a).

Less harmful 

Psilocybin has very low toxicity (Jo, 2014). Older studies found that even long-term adverse effects from repeated use were subtle or nonsignificant. It’s important to note, though, that supervised clinical studies use only pure drugs. Recreational versions of psilocybin that you may purchase illegally may be contaminated or have questionable strength. Recreational psilocybin may carry more risks than what’s used in clinical studies (Nichols, 2016).

Fewer side effects 

Psilocybin’s side effects are not as lengthy and long-lasting as antidepressants. Many antidepressants list side effects like constipation, diarrhea, drowsiness, insomnia, and some even have sexual dysfunction issues that continue as long as you take the medication. Psilocybin side effects are usually minimal and temporary (Carhart-Harris, 2017-a).

Non-addictive

Psilocybin is one of the safest central nervous system drugs. It is not believed to cause addiction. There have been no reported overdose deaths from a typical dose of psilocybin (Nichols, 2016). 

There’s one primary risk of using psilocybin for depression. It can cause psychologically and emotionally painful hallucinations, a potential risk of all psychedelic drugs. 

These hallucinations do not last very long but can be traumatic for certain people. Some people may call painful hallucinations a “bad trip.” When people have repeated bad trips, that’s referred to as “flashbacks.” These can happen with recreational “magic mushrooms” and with pharmaceutical-grade psilocybin used in clinical trials. This is why having a psychotherapist or two therapists present when taking psilocybin and for a while afterward helps in case of a “bad trip.” Thoughtful and guided integration helps mitigate bad trips and flashbacks (Nichols, 2016).

“Bad trip” experiences include (DEA, 2020):

• Paranoia

• Frightening hallucinations

• Confusion 

• Derealization—where you are detached from your surroundings and environment

• Depersonalization—where you feel you aren’t real or have an out-of-body experience

• Psychosis (rarely)

In some cases, psilocybin may also cause (Carhart-Harris, 2017-a):

• Psychological distress

• Dizziness

• Drowsiness

• Inability to concentrate

• Nausea and vomiting

• Muscle weakness

• High blood pressure

• Tachycardia (rapid heart rate)

People who feel anxious about trying psychedelic drugs or have mental health conditions like schizophrenia may risk having a poor experience with psilocybin mushrooms. 

If you have depression and want to try psilocybin treatment, you will need to enroll in a clinical trial. Researchers continue to study psilocybin’s effects on depression and other mental health conditions. The results of using psilocybin for mental healthcare are encouraging, especially when compared to the potential side effects and effectiveness of standard antidepressant treatments.

If you are interested in seeing if you qualify for a psilocybin clinical trial, you can check out the Psychedelic Clinical Trials Database to see if you are a candidate. Speak with your healthcare provider to help you manage your depression so you can feel better.

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Current version

July 21, 2021

Written by

Tobi Ash, MBA, RN, BSN

Fact checked by

Steve Silvestro, MD

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About the medical reviewer

Steve Silvestro, MD, Ro

Dr. Steve Silvestro is a board-certified pediatrician and Associate Director, Clinical Content & Education at Ro.