Introduction

Treatment-resistant depression (defined as a failure to respond to two or more treatment modalities) is a severe mental health condition that impacts the lives of nearly three million Americans. Individuals with treatment-resistant depression face a condition that is not only incredibly debilitating, but can also make the search for relief feel hopeless. However, a recent clinical trial conducted by researchers at the prestigious Trinity College in Dublin, Ireland, indicates a single dose of psilocybin may help individuals overcome the symptoms of treatment-resistant depression.^(1, 2)

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Psilocybin for Depression: What You Need to Know

Based on promising outcomes from previous research, this new clinical trial aimes to assess the safety of a single dose of COMPASS Pathways’ psilocybin analog, COMP360.⁽²⁾

COMP360 was developed as a synthetic version of the active chemical found in the psilocybe family of mushrooms, psilocybin (aka magic mushrooms). Designed as a new medication intended to help people overcome treatment-resistant depression, addiction, anxiety, and eating disorders, COMP360 has shown very promising results to date. Researchers compared the effects of two dosage levels, starting at 10mg, then moving up to 25mg. They also examined the efficacy of each dosage and noted the varying degree to which participants responded to the medication. As a Phase II study, researchers also examined the safety and how well participants tolerated the drug.

Results were presented at the American Psychiatric Association’s annual meeting in New Orleans in the spring of 2022. The study was later featured in the New England Journal of Medicine, one of the world’s leading peer-reviewed medical journals. Moreover, psilocybin-assisted therapy is gaining widespread media attention for its potential as a fast-acting and highly effective way of helping people suffering from depression.⁽²⁾

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What Is COMP 360 Psilocybin?

As mentioned, psilocybin is the active compound in certain varieties of ‘magic mushrooms’ known for their powerful effects, and COMP360 Psilocybin is a lab-made version of it. COMP360 has been tested for its potential use in treating mental health disorders such as bipolar depression, post-traumatic stress disorder (PTSD), treatment-resistant depression (TRD), and anorexia nervosa.

Scientists believe COMP360’s antidepressant effects come from the psychedelic experience, which has the potential to support people in becoming more receptive to change. Researchers hypothesize that altered states of consciousness can positively affect the psyche. COMPASS Pathways and their research team verified this hypothesis, and while further clinical trials were needed, the results were quite promising.⁽³⁾

Psilocybin breaks down into psilocin in the body, which impacts the serotonin system, causing a temporary increase in the available serotonin in the brain. Psilocybin’s impact on the brain doesn’t stop there. In addition to affecting the serotonin system (which is partially responsible for regulating mood, behavior, and other important functions), psilocybin also alters activity in a few other key regions of the brain. This includes the default mode network (DMN), which includes the medial prefrontal cortex (mPFC) and the posterior cingulate cortex (PCC).⁽⁴⁾

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What is the Default Mode Network (DMN)?

The DMN is an important brain region responsible for certain internal mental processes. It governs functions such as self-referential thinking, introspective thoughts, ruminating, daydreaming, memory, and thinking of the future. It is most active when the mind is at rest or not performing task-focused thinking.⁽⁴⁾

Scientists also believe dysfunction within the DMN may be partially to blame for certain symptoms of treatment-resistant depression and major depressive disorder (MDD). Specifically, the DMN may contribute to negative thinking and self-deprecating rumination in patients with depression. However, how and why this may be the case is still not fully understood and requires further study.⁽⁴⁾

When discussing psilocybin (or COMP360) and its impact on the DMN, it is important to understand how this compound may be impacting the overall function of the DMN. Psilocybin seems to cause certain parts of the DMN to exhibit reduced activity. Two key regions of the DMN that appear to be impacted are the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC). Neuroimaging (scans of the brain) of individuals on psilocybin show a distinct disconnect and reduction in activity between these sections of the DMN. This could indicate that psilocybin may help actively reduce negative thinking and rumination while increasing feelings of psychological well-being.⁽⁵⁾

This, in turn, may be why psilocybin seems to alleviate some of the symptoms of depression associated with this particular area of the brain. At the same time, psilocybin appears to increase functional connectivity with other parts of the brain that may not normally work together.⁽⁵⁾

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About the Psilocybin Trial

The COMP360 study was a double-blind clinical trial, which means neither the researchers nor participants knew which dose participants received until the trial was complete. A study like this is less likely to be biased, as the intent is to limit preconceptions about the outcomes. There were 233 participants, all with confirmed diagnoses of treatment-resistant depression. They were divided into three groups and given COMP360 psilocybin and psychological support from trained therapists.⁽⁶⁾

Seventy-nine participants received 1 milligram of COMP360 psilocybin (this group acted as a control group), 75 received 10 milligrams, and the remaining participants received 25 milligrams.⁽⁶⁾

 When interpreting the results, researchers focused on the following:^(3, 6)

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About the Montgomery-Åsberg Depression Rating Scale (MADRS)

As mentioned, researchers in this study used the MADRS scale, a well-established tool for assessing the severity of depressive disorders. It measures how well someone responds to antidepressant medication based on ten criteria:

Individuals with treatment-resistant depression are likely all too familiar with the symptoms mentioned above. Each item is assigned a severity score between 0 and 6, with a total available score of 60. A total of 35 to 60 is associated with severe depression, while a score between 20 and 34 indicates moderate depression. A score between 7 and 19 represents mild depression.⁽⁶⁾

In this study, the mean MADRS total score before treatment was 32 or 33 in each group of participants. 

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Psilocybin Study Results

Dr. John R. Kelly, psychiatrist and clinical senior lecturer at Trinity College, said, “This is the largest and most rigorous clinical trial of psilocybin to date. It shows a promising antidepressant signal for 25 milligrams (the highest dose given during the trial) COMP360 psilocybin with psychological support and has paved the way for Phase III clinical trials, which will determine whether it translates into a much-needed complementary treatment strategy in the psychiatry clinic.”

In other words, if it succeeds in the next round of trials, psilocybin-assisted therapy could be widely available to individuals with a treatment-resistant depression diagnosis. People who have been testing out various forms of medication and therapy to no avail could have access to this treatment which, for some, is both fast and effective.

The study results are highlighted below:⁽²⁾ 

• The group that received 25 milligrams of COMP360 psilocybin with psychiatric support experienced a rapid, significant decrease in symptoms of treatment-resistant depression compared with those who received 1 milligram COMP360. 
• Almost 30% (29.1%) of the participants in the 25 mg group met the criteria for remission at week 3.
• Roughly 37% of the participants who took COMP360 met the criteria for response at week 3, according to the MADRS score.
• About 20% of the participants who received 25 milligrams of COMP360 met the criteria for sustained response at week 12. Only 10% of those who received 1 milligram of COMP360 achieved sustained response at week 12.
• COMP360 was generally well tolerated. The most common side effects reported were headache, nausea, and dizziness. These side effects were noted on day one of the treatment and were dose-dependent. In other words, those who received higher doses were more likely to experience these side effects.
• Researchers recorded cases of suicidal ideation and intentional self-injury in all treatment groups and noted these issues are common in studies involving individuals with treatment-resistant depression. Additionally, the majority of these events occurred more than a week after the medication was given. No aggravation of suicidal ideation was reported in any treatment group based on the MADRS score. 

Researchers pointed out that the 25-milligram remission response rate was even better than the results seen in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Funded by the National Institutes of Health, the STAR*D initiative was the world’s largest and longest study to assess depression therapies. It aimed to determine how effective treatments were for individuals with major depression who didn’t respond to antidepressant medication.⁽⁷⁾

In some cases, psilocybin is used along with psychiatric counseling to further improve the antidepressant effects. However, in the studies assessing the benefits of COMP360, psychological support is focused on safety. It’s not psychotherapy aiming to relieve depression.⁽³⁾

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Potential Impact of the Study

According to Scott Aaronson, MD, the principal investigator on this trial, over 100 million people worldwide struggle with treatment-resistant depression. The research carried out on COMP360 psilocybin therapy for treatment-resistant depression is the largest study of its kind, and shows great promise for people afflicted with this disorder. A significant number of the participants who received 25 milligrams of COMP 360 experienced improvement in symptoms, and these positive effects lasted up to at least three months.⁽³⁾

It’s a Phase IIb clinical trial, only one step away from a Phase III trial in which the emerging medication is compared to existing treatments for effectiveness. In fact, COMPASS Pathways, the study’s sponsor, has already designed the Phase III clinical program, with plans to commence at the end of 2022.

Once a Phase III study is successfully completed, a pharmaceutical company can request FDA approval to market the drug. If given, this would trigger a mandatory rescheduling of the drug under the Controlled Substances Act. This is thought to be likely, as the current administration has indicated that they believe both psilocybin and MDMA will be available as treatments within the next few years. Results like these let the world know that psilocybin is a viable option for managing and treating depression and gives hope to millions worldwide.