By Maisha Pathan, March 9, 2024

Depression is a debilitating condition that affects up to 17.8% of American adults as of
2023 (Witters). Although there are countless treatment options in the form of antidepressants,
and therapy, sometimes, these treatments may still not be enough to provide relief for those
suffering from depression. Shrooms, also known as magic mushrooms may be an emerging
answer to those seeking an alternative. This unorthodox form of treatment called
psilocybin-assisted therapy (PAT) is gaining popularity, and the results are significant enough to
be brought to the public’s attention. In PAT, the patient is given a dose of the psychedelic
psilocybin, also known as magic mushrooms, in a controlled setting while their assigned
therapist stands by to monitor the experience. Despite its low toxicity and even being safer than
nicotine and aspirin, the stigma surrounding psychedelics causes people to hesitate even
considering this as an option, on top of which it’s still a controlled substance by the government
(Lowe et al. 20). However, research obtained from clinical trials shows that in a controlled
environment and administered by a trusted professional psilocybin has a powerful impact on
depressive symptoms, and many participants report improvement in their condition after their
sessions. For the people struggling with treatment-resistant depression, severe depression, or
anyone who finds that medication and therapy aren’t helping them: psilocybin-assisted therapy
could be a viable option for treating depression and should be offered alongside therapy and
medication.

Historically, psilocybin mushrooms have been in use for centuries, prominently in the
Aztec empire around the 15th century. The substance was referred to as “god’s flesh” in Nahuatl
and used in religious and healing rituals (Nichols 679). However, it wasn’t until 1957, when
Albert Hoffman a chemist who (also created LSD) isolated psilocybin from a Mesoamerican
psilocybin mushroom, and published its effects, that magic mushrooms entered modern
American society (Nichols 680) . Although the substance was then used in psychedelic therapy,
it became popularized for its recreational use during the 60’s aided by the hippie movement,
until the USA passed the Comprehensive Drug Abuse Prevention and Control Act of 1970,
which marked it as an illicit drug along with LSD and other psychedelics. Despite these
restrictions, psilocybin continued to be used recreationally by citizens and has been gaining
more traction in media.

Major depressive disorder is a serious depressive disorder that can have a lasting impact
on the brain. This damage essentially rewires the brain which can keep the person in their
depressive state for a prolonged amount of time. The compounds that makeup psilocybin can
sometimes reverse, or rewire, the damage depression does to the brain. According to an article
published by Healthline, a medical information website, depression can shrink regions of the
brain governing memory (hippocampus), emotion (amygdala), and cognitive functions
(prefrontal cortices). As a result of shrinking, function in these brain regions such as emotional
regulation and interest, memory, and concentration are also diminished (“5 Ways Depression
Can Physically Affect the Brain”). Psilocybin, specifically psilocin comes into play here due to
its role as a subtype of serotonin receptor. It activates a serotonin receptor called the 5-HT2A
which increases serotonin levels similar to SSRIs (2-Minute Neuroscience: Psilocybin, 0:16). In
a study conducted by researchers at Weill Cornell Medicine, an fMRI was used to show how the
activation of the 5-HT2A serotonin receptor by psilocin affected the brain landscape. The results showed that on psilocin, the brain lowered energy barriers between different regional
connections in the brain which allowed regions of the brain that were typically not stimulated to
be activated. Due to the flattening of the brain’s energy landscape, new connections could be
made between different brain regions, enabling neuroplasticity and promoting neurogenesis,
which is generation of new neurons. This opens up space that allows the brain to rewire itself,
and if the psilocybin is taken in a clinical setting such as in a PAT session, old patterns of
thinking can be replaced with new, expansive thought patterns which can reverse the effects of
depression on the brain by fostering new connections (Kuceyeski).

The structure of PAT is what makes it so successful and extremely safe in treating
depression. It’s is controlled by doctors and therapists in a clinical setting and is spread
throughout three stages: a preparatory stage, an administration stage, and an integration stage
(Schuitmaker 2). Each stage of PAT plays a significant role in how effective the treatment will
be for the patient while maintaining the environment in a controlled setting.

In the preparatory stage, participants attend several psychotherapy sessions to set their
goals and intentions for their experience. This creates the set and setting. Although individuals’
experiences on psilocybin vary from person to person an important factor to the experience is set
and setting. An article analyzing PAT in medicine by Cureus, a peer-reviewed medical journal,
explains that set refers to a patient’s goals and intentions for their psilocybin experience and is
discussed with their therapist so that it could be used to guide the individual and keep them on
track. The setting refers to the patient’s mental, physical, and emotional state prior to and during
the treatment. Attending these preparatory therapy sessions helps the therapist assess when and
where treatment should take place (Ziff et al. 7).

Once the patient is prepared, the next stage is “administration” which the Yale Manual for
Psilocybin-Assisted Therapy of Depression details. Typically, on the day of administration, the
patient is taken to a homey, welcoming room, where they lie down on the couch, put on
headphones, run a musical playlist, and wear a blindfold. The dose of psilocybin provided can
vary but typically is less than 1 gram and based on what the participant can handle. The music,
lying down, and blindfold work together to create a relaxing environment where the patient can
feel safe. They know that if they need any support they have their therapist right there next to
them. These measures create a controlled environment for the patient, minimizing possible
adverse reactions like anxiety or paranoia which can lead to nausea or vomiting. Once the patient
is settled and has consumed their psilocybin dose, the drug slowly takes effect, guiding them on a
journey into the depths of their mind. The therapist only guides the patient when needed based on
the goals and intentions set in the preparatory sessions, and otherwise does not interfere with the
psilocybin trip (Guss et al. 45-50).

The day after administration takes us to the third stage, “integration.” Integration
consists of several sessions through the following weeks during which the therapist asks the
patient about their experience, what they saw, felt, learned, what they’d like to take away from
their experience, and how to integrate that into their lives (Guss et al. 51-60). Although all three
stages of psilocybin-assisted therapy are equally as important, integration ensures that the
positive experiences are incorporated into the patient’s life and have a lasting effect while the
negative experiences if any are worked through. This structuring makes the therapeutic
administration of psilocybin safe and maximizes the benefits the substance can provide a
patient.

The effectiveness of psilocybin-assisted therapy as a treatment is evident in a number of studies.
In an article published by Johns Hopkins Medicine, the efficiency of using psilocybin to treat
major depression is explored through two studies conducted under their Psychiatry and
Behavioral Sciences department. The results found from both studies showed that using
psychedelic therapy by giving each participant a dose of psilocybin followed by psychotherapy
significantly reduced the symptoms of depression in both studies. Half of the participants in the
first study entered remission from depression at the end of the four-week follow-up. In the
second study, participants with a long history of depression on antidepressants were provided two
doses of psilocybin in a few weeks. They took a GRID-Hamilton Depression Rating Scale before
and after. The results showed that 67% of the participants showed a reduction in their symptoms
after a week, and four weeks after treatment, 54% of participants in the study were in remission
(“Psychedelic Treatment with Psilocybin Relieves Major Depression, Study Shows”). In another
study conducted by the Psychiatric University Hospital of Zurich, 52 participants suffering from
major depressive disorder were treated with psilocybin-assisted therapy. Half of them were given
psilocybin while the other half, 26 individuals were given a placebo. The results showed that
psilocybin significantly decreased depressive symptoms in those who had it, more than those
who received a placebo along with their therapy sessions. By the end of the study 14 out of 26,
met the criteria for remission from depression on the Montgomery–Åsberg Depression Rating
scale. In comparison to the placebo group in which the treatment was technically seven required
therapy sessions, 4 out of 26 met the criteria for remission demonstrating that psilocybin was the
driving force for the symptom reductions (Rotz 7-10).

In one clinical PAT trial conducted by NYU School of Medicine, the participants were four
cancer patients struggling with depression and anxiety. At the end of their participation which
spanned 26 weeks, each patient demonstrated a significant reduction in their depressive
symptoms which resulted from the experiences they had during their trips.
Many people suffering from depression who participated in psilocybin-assisted therapy
clinical studies report having positive experiences that aided in reducing their depressive
symptoms. Chrissy, a 50-year-old female with stage 4 breast cancer stated “[The psilocybin
experience] brought my beliefs to life, made them real, something tangible and true – it made my
beliefs more than something to think about, really something to lean on and look forward to,”
(Malone et a. 4). Although Chrissy knew that she was still going to pass, she was able to accept
and even look forward to the time she had left. In a separate trial by the Faculty of Medicine at
Al-Hikma University, ten participants struggling with depression were treated their with
psilocybin-assisted therapy. During an integration session with their therapist, a young adult
known as Participant 1 stated, “My whole thought pattern changed. I was so relieved. My head
had never been clearer. I was so happy the day after cried to my trip buddy about how I could see
again…. I was on three different anti-depressants, valium, and sleeping pills. This stopped within
2 weeks of my first dose,” (Hisham et al. 3). Many other participants from the same study
reported the experience was mind-expanding, and gave them a more positive outlook in life. The
experiences of the participants in this particular study are consistent with the neuroplasticity
effect psilocybin can have on the brain which allows it to create new connections and eradicate
old, negative thought patterns.

Psilocybin-assisted therapy has proven to be a worthwhile treatment venture for many of the
patients who participated in treatment for their depressive disorders. It’s important to note that psilocybin in this case is being used for treatment, not for recreation or self-exploration and
because it is being used for treatment by entrusted clinics it poses a relatively low risk, if at all to
those who receive it. However, that is not to say that this should be an option for everyone.
Studies have shown that people who are genetically predisposed to psychotic disorders such as
Schizophrenia can be triggered if exposed to any psychedelic substances such as psilocybin, in
the case where if they hadn’t been exposed to the substance they would not have developed any
form of psychosis (Ziff et al. 8). This is however, managed under psilocybin-assisted therapy as
before being able to receive it, all patients must undergo medical health screening to ensure it
will be an appropriate option for them. Many of the clinical studies on PAT usually begin with a
large pool of participants, which is slowly trickled down to a very small number via medical
health screening. The doses of psilocybin provided by these clinics are also quite moderate, and
typically less than even 1 gram which is the starting dose for recreational users. Years of research
and studies have gone on to show that psilocybin-assisted therapy can bring profound
improvement to depressive symptoms, especially for those who have exhausted all other options
such as medications and therapy. Age, health, and environment are all factors to consider when it
comes to PAT and it should be offered based on a mutual decision between the patient and their
mental healthcare provider. Although psilocybin-assisted therapy is not currently offered as an
official treatment and can only be accessed by participating in clinical trials, this may change
soon. In 2018, the FDA granted psilocybin-assisted therapy “break-through therapy” status
which means they will prioritize reviewing it soon for approval meaning it could soon be widely
offered for treatment (Coleman). For those struggling with depression who haven’t found relief
from any of the current treatment options, or are interested in trying psilocybin-assisted therapy,
this may be good news. Still, as in all cases, it’s important to do your own research to determine
whether this is the right option for you.

Bibliography

1. Alshaikhli, Hisham, et al. “Effectiveness of Psilocybin on Depression: A Qualitative Study.”
   Electronic Journal of General Medicine, vol. 18, no. 3, Apr. 2021, p. em296,
   https://doi.org/10.29333/ejgm/10862.
2. Coleman, Theara, and The Week US last updated. “The Legal State of Psychedelic Therapy in
   the US.” The week, 25 June 2023,
   theweek.com/drugs/1024449/the-state-of-psychedelic-therapy-in-the-us. Accessed 26
   Oct. 2023.
3. Guss, Jeffrey, et al. “The Yale Manual for Psilocybin-Assisted Therapy of Depression (Using
   Acceptance and Commitment Therapy as a Therapeutic Frame).” Yale Manual for
   Psilocybin-Assisted Therapy of Depression , Aug. 2020,
   https://doi.org/10.31234/osf.io/u6v9y. Accessed 4 Nov. 2021.
4. Kuceyeski, Dr. Amy. “Psychedelic Drugs Flatten the Brain’s Dynamic Landscape.” WCM
   Newsroom, Weill Cornell Medicine, 2022,
   news.weill.cornell.edu/news/2022/10/psychedelic-drugs-flatten-the-brain%E2%80%99s
   dynamic-landscape.
5. Lowe, Henry, et al. “The Therapeutic Potential of Psilocybin.” Molecules, vol. 26, no. 10, Jan. 2021, p. 2948, https://doi.org/10.3390/molecules26102948.
6. Malone, Tara C., et al. “Individual Experiences in Four Cancer Patients Following Psilocybin-Assisted Psychotherapy.” Frontiers in Pharmacology, vol. 9, 2018, p. 335252, https://doi.org/10.3389/fphar.2018.00256. Accessed 26 Oct. 2023.
7. Nichols, David E. “Psilocybin: From Ancient Magic to Modern Medicine.” The Journal of Antibiotics, vol. 73, no. 10, May 2020, pp. 679–86, https://doi.org/10.1038/s41429-020-0311-8.
8. Neuroscientifically Challenged. “2-Minute Neuroscience: Psilocybin.” YouTube, YouTube Video, 5 May 2020, www.youtube.com/watch?v=XBEas8MGzd0.
9. Rotz, Robin, et al. “Single-Dose Psilocybin-Assisted Therapy in Major Depressive Disorder: A Placebo-Controlled, Double-Blind, Randomised Clinical Trial.” EClinicalMedicine, vol. 56, Feb. 2023, p. 101809, https://doi.org/10.1016/j.eclinm.2022.101809.
10. Schuitmaker, Nicole. “Psilocybin-Assisted Therapy: A Scoping Review of Participants’ and Facilitators’ Experiences in Qualitative Studies.” Research, Society and Development, vol. 12, no. 9, Sept. 2023, p. e12312943308–e12312943308, https://doi.org/10.33448/rsd-v12i9.43308. Accessed 26 Oct. 2023.
11. Witters, Dan. “U.S. Depression Rates Reach New Highs.” Gallup.com, 17 May 2023, news.gallup.com/poll/505745/depression-rates-reach-new-highs.aspx#:~:text=In%202023%2C%2029.0%25%20of%20Americans. Accessed 19 Aug. 2023.
12. Ziff, Shawn, et al. “Analysis of Psilocybin-Assisted Therapy in Medicine: A Narrative Review.” Cureus, vol. 14, no. 2, Feb. 2022, https://doi.org/10.7759/cureus.21944.
13. “Psychedelic Treatment with Psilocybin Relieves Major Depression, Study Shows.” Www.hopkinsmedicine.org, 4 Nov. 2020, www.hopkinsmedicine.org/news/newsroom/news-releases/2020/11/psychedelic-treatment-with-psilocybin-relieves-major-depression-study-shows#:~:text=In%20a%20small%20study%20of. Accessed 26 Oct. 2023.
14. “5 Ways Depression Can Physically Affect the Brain.” Healthline, 24 Oct. 2018, www.healthline.com/health/depression-physical-effects-on-the-brain#reversing-the-effects. Accessed 26 Oct. 2023.