The Largest Phase 3 Trial on Psilocybin for Depression Has Kicked Off

As our social fabric is fraying and depression rates continue to rise, affecting approximately 310 million people globally, psilocybin research has given us a glimmer of hope that things may be about to change for the better.

The largest Phase 3 clinical trial investigating the safety, efficacy and tolerability of psilocybin as treatment for treatment-resistant depression (TRD) has finally begun.

In late 2022, Compass Pathways announced that their Phase 3 program, composed of two separate pivotal trials totaling 946 participants and one long-term follow-up study, was set to launch.

In November 2022, the company's first pivotal trial, involving 378 participants, began recruiting subjects. However, the actual study did not begin until January 19, 2023. The trial aims to compare a single 25mg dose of COMP360 synthetic psilocybin paired with psychological support to a placebo, with the hopes of replicating its Phase 2 positive results. This first study is expected to end in October 2024.

Overall, 378 participants will be randomised in a 2:1 ratio to receive COMP360 25 mg or placebo. Source: ClinicalTrials.gov

In February 2023, the company began recruiting for its second pivotal trial and is expected complete the study by May, 2025. In this trial, 568 randomized participants will receive COMP360 25 mg, 10 mg or 1 mg with the objective to examine whether a second dose can increase the number of people with positive response to psilocybin therapy or improve the response observed in the Phase 2b study. The trial also aims to investigate the potential for a “meaningful treatment response from repeat administration of COMP360 10mg.”

Overall, 568 participants are to be randomized in a 2:1:1 ratio to receive COMP360 25 mg, 10 mg or 1 mg. Source: ClinicalTrials.gov

According to ClinicalTrials.gov both studies are still recruiting participants, meaning that individuals diagnosed with treatment-resistant depression wishing to find a legal and free psilocybin treatment may be in luck!

What we know so far from Compass' Phase2b trial involving 233 participants treated with either a 1mg, 10mg, or 25mg dose of COMP360, is that most patients' depression scores improved greatly following a single dose of psilocybin with 30% of patients being in remission at week 3. Unsurprisingly, those treated with the highest dose of COMP360 were observed to have the most significant improvement in symptoms.

However, what we also know is that 12 weeks later, only 20% of the subjects treated with 25mg of psilocybin still had a sustained response, indicating that psilocybin's efficacy fades after 3-12 weeks for those suffering from TRD. Of course, those who were hoping for a single magic bullet were left disappointed.

Needless to say, these findings explain why Compass Pathways is conducting their second Phase 3 pivotal trial. It seems like repeated treatments may be necessary for severe cases. Fingers crossed, we'll be able to see positive results above 30% with the Phase 3 trial.

To end on a positive note, though the possibility that a single large dose of psilocybin combined with psychological support may not deliver the stellar results we all were hoping to see for treatment-resistant depression, it may be a solution for depression in cancer patients. Last week, Sunstone Therapies' investigator-initiated Phase 2 study assessing COMPASS Pathways’ synthetic psilocybin announced some impressive long-term follow-up data. A single 25mg dose of psilocybin alongside therapy has resulted in sustained remission of depression in 57% of patients, with 64% experiencing a significant improvement 18 months later.

Read also: Single Dose of Psilocybin Yields Long-Term Depression Remission in Over 50% of Cancer Patients

The psychedelic industry will experience some significant shifts in the next couple of years. Starting July 1st, Australia will begin treating PTSD with MDMA and TRD with psilocybin. We are also expecting positive results from MAPS' MDMA for PTSD Phase 3 study which could lead to FDA approval for MDMA therapy by the end of this year. Meanwhile, more and more psychedelic treatment centers will begin opening up in Oregon and Colorado as psychedelic reform efforts across the United States continue to progress. If Compass' Phase 3 clinical trial delivers positive data, we may also see FDA approval for psilocybin therapy in 2025. As Violet Vane once said, “Good things come to those who wait”.