table of contents
- What is psilocybin?
- How is depression typically treated?
- What does science say about psilocybin?
- How does psilocybin help to relieve depression?
- What is the treatment protocol for depression with psilocybin?
- Benefits of psilocybin for depression
- Risks of psilocybin for depression
- What’s next for psilocybin treatment for depression?
If you have any medical questions or concerns, please talk to your healthcare provider. The articles on Health Guide are underpinned by peer-reviewed research and information drawn from medical societies and governmental agencies. However, they are not a substitute for professional medical advice, diagnosis, or treatment.
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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What is psilocybin?
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).
Psilocybin (magic mushrooms): uses, side effects, and warnings
How is depression typically treated?
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 (see Important Safety Information), citalopram, paroxetine, fluoxetine (see Important Safety Information), and sertraline (see Important Safety Information)
- Serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine (see Important Safety Information) and venlafaxine (see Important Safety Information)
- Atypical antidepressants like bupropion (see Important Safety Information)
- 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.
Psilocybin therapy: what science has to say
What does science say about psilocybin?
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.
How does psilocybin help to relieve depression?
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).
Microdosing: types, benefits, methods, and risks
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).
What is the treatment protocol for depression with psilocybin?
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).
Benefits of psilocybin for depression
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.
Treatment-resistant depression: what are my options?
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).
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).
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).
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).
Risks of psilocybin for depression
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):
- Frightening hallucinations
- 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)
Causes of depression: genetics, environment, and others
In some cases, psilocybin may also cause (Carhart-Harris, 2017-a):
- Psychological distress
- 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.
What’s next for psilocybin treatment for depression?
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.
- Agin-Liebes, GI, Malone, T, Yalch, MM, Mennenga, SE, et al. (2020). Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. Journal of Psychopharmacology, 34(2). 155-166. doi: 10.1177/026988119897615. Retrieved from https://journals.sagepub.com/doi/10.1177/0269881119897615
- Bains, N., & Abdijadid, S. (2020). Major depressive disorder. [Updated Apr 20, 2021]. In: StatPearls [Internet]. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK559078/
- Carhart-Harris, R. L., & Goodwin, G. M. (2017-a). The therapeutic potential of psychedelic drugs: past, present, and future. Neuropsychopharmacology, 42(11), 2105-2113. doi: 10.1038/npp.2017.84. Retrieved from https://pubmed.ncbi.nlm.nih.gov/28443617/
- Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., et al. (2017-b). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports, 7(1), 1-11. doi: 10.1038/s41598-017-13282-7. Retrieved from https://www.nature.com/articles/s41598-017-13282-7
- Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., et al. (2021). Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine, 384(15), 1402-1411. doi: 10.1056/NEJMoa2032994. Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMoa2032994
- Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., et al. (2021). Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry, 78(5), 481-489. Retrieved from https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2772630
- Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187(3), 268-283. doi: 10.1007/s00213-006-0457-5. Retrieved from https://pubmed.ncbi.nlm.nih.gov/16826400/
- Jo, W. S., Hossain, M. A., & Park, S. C. (2014). Toxicological profiles of poisonous, edible, and medicinal mushrooms. Mycobiology, 42(3), 215-220. doi: 10.5941/MYCO.2014.42.3.215. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206786/
- National Institute of Mental Health (NIMH). (2019). Major depression. National Institute of Health. Retrieved from https://www.nimh.nih.gov/health/statistics/major-depression
- Nichols D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264–355. doi.org/10.1124/pr.115.011478. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813425/
- Roseman, L., Demetriou, L., Wall, M. B., Nutt, D. J., & Carhart-Harris, R. L. (2018). Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression. Neuropharmacology, 142, 263-269. Retrieved from https://www.sciencedirect.com/science/article/pii/S0028390817306391
- Roseman, L., Nutt, D. J., & Carhart-Harris, R. L. (2018a). Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Frontiers in Pharmacology, 8, 974. doi: 10.3389/fphar.2017.00974. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776504/
- US Drug Enforcement Agency (DEA), (2020). Drug fact sheet: Psilocybin. Retrieved from https://www.dea.gov/sites/default/files/2020-06/Psilocybin-2020.pdf
Dr. Steve Silvestro is a board-certified pediatrician and Manager, Medical Content & Education at Ro.