Psychedelic reform is a topic in various cities and states. Coloradans voted to decriminalize psychedelics in 2022. That same year, Oregon voters legalized therapeutic psychedelic use, forging a new space for facilitators and treatment centers in the state. Many of these movements started from a belief that psychedelics could have value, and a recent study in psilocybin for depression is giving those beliefs merit.

A study published by Nature uncovered more about psilocybin, the active ingredient in “magic mushrooms,” and depression. The compound could effectively treat depression that won’t be quelled by antidepressants like SSRIs.

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The study focuses on nineteen adults experiencing treatment-resistant depression (TRD) or a major depressive disorder (MDD) without psychotic features. All of these patients were on SSRIs without relief from symptoms and scored “moderately ill” on the Hamilton Depression Rating Scale, the most widely used assessment scale used by clinicians. They were referred by their mental health practitioners or primary care providers.

This trial hoped to assess the safety and efficacy of one 25 mg dose of COMP360, a proprietary pharmaceutical-grade synthetic psilocybin formulation. The synthetic ‘shrooms were sourced from COMPASS Pathfinder Ltd., and the study was approved by ethics boards in Ireland and the United States.

The study was completed by Worldwide Clinical Trials, a contract research organization, and supervised by COMPASS Pathfinder Ltd. Protocol was in line with the International Conference on Harmonisation Good Clinical Practice guideline and the ethical principles of the Declaration of Helsinki.

Choosing participants: who qualifies for psilocybin treatment?

All participants were pre-screened in a closed-label phase IIb study called COMP 001. Of the 428 screened, 233 were declared eligible, but the study required patients to undergo medication withdrawal.

Before this study, clinicians believed SSRIs inhibit or alter how psilocybin would interact with someone’s system. Following this belief, researchers moved those who refused to go off their antidepressants into consideration for this study.

To be included, participants needed to be taking only one SSRI at least 75 percent of the time for at least six weeks. SSRIs citalopram, escitalopram, fluoxetine, paroxetine, sertraline, vilazodone, and vortioxetine were permitted.

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The exploratory study was phase II of the inquiry into psilocybin for treatment-resistant depression and took place from August 2020 to September 2021. Because it used two drugs at once it’s called a fixed-dose study. Since the patients knew they were getting dosed with mushrooms, it is called an open-label study.

The ins and outs of the clinical trial

Thought went into how to guide patients through a mushroom trip intended to alleviate the heaviness of depression. To create a lush environment for this mission, mental health professionals with relevant experience were paired with individual participants. Therapists met with patients over three sessions before psilocybin was administered. The practitioner used these appointments to build trust, explain the study, provide psychoeducation, and prepare for the overall experience.

The final check-in was scheduled for the day before psilocybin administration. Once fully prepared, patients were administered 25mg of the synthetic psilocybin in a clinical room with the study-appointed therapist. Participants wore eye covers and headphones playing a specifically-designed playlist.

Over the six to eight-hour session, the assigned therapists guided patients to unfold subjective psychedelic experiences with out guiding where it went. There was an additional mental health practitioner on site in the event that a new therapist was needed for any reason.

Could psilocybin for depression be a viable option?

To understand how psilocybin affected TRD, researchers called participants back after three weeks. Using the Montgomery-Åsberg Depression Rating Scale (MADRS), an independent rater measured MADRS levels on the first two days of treatment and once a week for three weeks after psilocybin administration. Researchers took note of anxiety, depression, and adverse side effects before, during and in the days following the study.

The Five-Dimensional Altered States of Consciousness questionnaire provided tangible data from the subjective psychedelic experiences of patients. This assessment prompted more information about visual and auditory hallucinations, derealization, depersonalization, and aspects of a traditional “trip.”

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At the baseline, all participants were classified as having severe depression according to the MADRS score. Following the psilocybin therapy, these scores were cut in half, indicating a notable reduction in symptoms.

Twelve participants reported 17 adverse (but not serious) effects that emerged following treatment.  Most had headaches the day after psilocybin administration that felt better the day-of or the day after they started.

Some also experienced heightened blood pressure, with one patient having additional chest pain. These symptoms were treated, and patients felt better the same day as symptoms arose. There were no increases in suicidal ideation or self-harm following psilocybin therapy.

According to the study authors, “Improvements in quality of life, wellbeing, anxiety, affect, and self- and clinician-reported depression were evident at all time points following psilocybin administration.”

After assessing the data, 14 participants could be considered “minimally improved,” and seven were considered “responders,” meaning they really responded to the treatment. No one experienced worsened depression following the trial. Data also showed that all participants reached an altered state of consciousness.

Implications of the clinical trial

These results don’t only show how therapy-supported psilocybin administration could benefit patients battling depression but also that SSRIs may not hinder results of the treatment. Turns out, antidepressant drug withdrawal is not a prerequisite to effective psilocybin therapy.

Researchers encourage additional inquiry into how psilocybin could impact the lives of patients with treatment-resistant depression. These results are making the psychedelic option more accessible by showing that withdrawal isn’t a requirement for effective psilocybin administration.

As states like Oregon trudge through the bureaucracy of creating a state-regulated psychedelic treatment program, studies like this are crucial in setting standards for who can participate and how.