The psychedelic drug psilocybin, the compound found in magic mushrooms, is highly efficacious as therapy for treatment resistant depression, found the largest yet randomised, controlled, double-blind trial, reports STAT News. The US Food and Drug Administration has granted COMPASS Pathwaysʼ treatment breakthrough therapy designation.
MedicalBrief writes that although hailed as “adding considerable weight” to earlier psilocybin results the study, which have not been published in a medical journal or peer-reviewed, drew some critical comments:
- Patients in the high-dose group reportedly exhibited a higher frequency of treatment-emergent adverse events in the trial, compared to those receiving lower doses.
- The drug's clinical benefit among responders waned at the 12-week mark, although a fair number of patients did show a sustained response to treatment at this key benchmark.
StatNews writes that mental healthcare company COMPASS Pathways said the Phase 2b randomised, controlled, double-blind trial showed patients who were given the highest dose of COMP360, 25mg, had a significant decrease in depressive symptoms compared with those given 1mg, which is such a low dose it functions as a placebo.
Overall, 29.1% of patients in the highest-dose group were in remission three weeks after treatment, compared with 7.6% of those in the control group, and more than a quarter of the patients in the 25mg arm were still in remission three months after treatment.
Those who received the highest dose also experienced an average reduction on a measure of clinical depression (the Montgomery-Asberg Depression Rating Scale) that was 6.6 points greater than those who took 1mg. Other patients were given a 10mg dose, but there was not a statistically significant impact for those patients, compared with the 1mg group
“Everyone agrees such a result hasnʼt been seen before in depression research, so weʼre incredibly happy with that result,” said Lars Christian Wilde, co-founder and president of COMPASS.
Boris Heifets, a neuroscience researcher at Stanford who studies psychedelics and was not part of the study, agreed the results are “super promising”. The effectiveness of psilocybin at three weeks, according to COMPASS study, is roughly comparable to the effects of ketamine at one day, according to a smaller 2013 study, he added, which suggests the benefits of psilocybin hold up well over time.
“Weʼre still missing a lot of the detailed data,” he added, but the summary results are “pretty good news.”
The study, which enrolled 233 patients at multiple sites across Europe and North America, is the most rigorous trial on psilocybin for treatment-resistant depression and adds considerable weight to earlier, smaller studies of the drug that were also promising.
The US Food and Drug Administration has granted COMPASS Pathwaysʼ treatment breakthrough therapy designation, meaning the drug approval process will be accelerated if studies continue to show positive results. COMPASS plans to start a Phase 3 trial next year; current results suggest it is likely to use a 25mg dose, but Wilde said that decision would be made after conversations with regulators.
The results released by the company included side effects data showing a small number of serious adverse events.
Overall, 12 patients reported treatment-emergent serious adverse events, five of whom were in the 25mg group and six in the 10mg group; these included suicidal behaviour and self-injury. Just one patient in the 1mg group experienced a serious adverse event.
“The suicidal behaviours were reported at least one month after the administration of treatment and they occurred in patients who were essentially non-responding,” said Guy Goodwin, Compassʼ chief medical officer. In at least one case, though, suicidal ideation was reported early on in treatment, he added.
The numbers are small enough for the difference between treatment arms not to be statistically significant, said Wilde, noting that suicidal behaviours and ideation are common among depressed patients. “Weʼre dealing with a severe patient population, both in terms of patient severity and duration of their depressive episode,” he said. “Unfortunately, those events have to be expected.” There were three suicides in studies of esketamine, the only psychedelic currently approved for treatment-resistant depression, he pointed out.
Researchers in previous studies have reported a “disappointment reaction,” whereby patientsʼ symptoms worsen because the novel treatment doesnʼt immediately cure their depression. The difference between the treatment arms is unexpected, said Heifets, as patients tend to get more depressed if theyʼre assigned to placebo and donʼt get effective treatment:
“If anything, Iʼd expect it to go the other way.” But, he added, suicidal behaviours are common in research on depressed patients. “That means itʼs not attributable to psilocybin having a suicidal side effect,” he said.
Goodwin said the researchers plan to study the data in more detail, including analysing responses to a questionnaire all patients took for suicidal assessment, to better understand the connection.
Market reaction to results
Nasdaq.com, giving a market assessment of the trial, noted that COMP360 might be one of the first viable pharmaceutical options for this patient group. “Nonetheless, the company will still have to contend with an onerous regulatory pathway for COMP360 due to psilocybin's Schedule I status in the United States. This experimental drug may also have to compete in a jam-packed space by the time it gets through a phase 3 program and lands an OK from the Food and Drug Administration.”
COMPASS study
In the randomised, controlled, double-blind trial, a single dose of investigational COMP360 psilocybin was given to 233 patients in conjunction with psychological support from specially trained therapists. All patients discontinued antidepressants prior to participation. The trial was powered to compare two active doses of COMP360, 25mg and 10mg, against a comparator 1mg dose. The 25mg group vs the 1mg group showed a -6.6 difference on the MADRS* depression scale at week 3 (p<0.001). The 25mg group demonstrated statistical significance on the MADRS efficacy endpoint on the day after the COMP360 psilocybin administration (p=0.002). The 10mg vs 1mg dose did not show a statistically significant difference at week 3. The MADRS was assessed by independent raters who were remote from the trial site, and blind to intervention and study design, effectively creating a triple blind. At least twice the number of patients in the 25mg group showed response and remission* at week 3 and week 12, compared with the 1mg group.
The protocol-defined sustained response* up to week 12 was double, with 20.3% of patients in the 25mg group vs 10.1% in the 1mg group. Using a definition of sustained response* that is consistent with other TRD studies, the difference was more than double, with 24.1% of patients in the 25mg group vs 10.1% in the 1mg group. COMP360 was generally well tolerated, with more than 90% of treatment-emergent adverse events (TEAEs) being mild or moderate in severity. 179 patients reported at least one TEAE; the most common TEAEs across treatment groups (>10% overall incidence) were headache, nausea, fatigue and insomnia. There were 12 patients who reported treatment-emergent serious adverse events (TESAEs). These TESAEs included suicidal behaviour, intentional self-injury, and suicidal ideation, which are regularly observed in a treatment-resistant depression patient population, and which occurred more frequently in the 25mg group than in the 10mg or 1 mg groups. Overall, 209 patients completed the study; there were five withdrawals from the 25mg group, nine from the 10mg, and 10 from the 1mg.
This randomised, controlled, multicentre, double-blind phase IIb trial is the largest psilocybin therapy clinical trial ever conducted, with 233 patients from 10 countries in North America and Europe. 94% of the patients had no prior experience with psilocybin. The objective of the trial was to find the appropriate dose for a larger, pivotal phase III programme, which COMPASS expects to begin in 2022.
Depression that isn’t helped after two or more adequate antidepressive treatments is referred to as treatment-resistant depression (TRD)1,2. More than 100 million people worldwide are affected by TRD1,2, and as many as 30% of these attempt suicide at least once during their lifetime3,4. The TRD population is by definition more difficult to treat and more likely to relapse than patients with major depressive disorder. In 2018, COMPASS received FDA Breakthrough Therapy designation for its COMP360 psilocybin therapy for TRD.
Key findings:
• COMP360 25mg vs 1mg: a difference of -6.6 points in change from baseline in MADRS total scores at week 3 (p<0.001), with a statistically significant difference seen from day 2 up to week 6
• COMP360 10mg vs 1mg: a non-statistically significant numerical treatment difference of -2.5 points at week 3 (p=0.184)
• At least double the number of MADRS responders, remitters, and sustained responders with 25mg vs 1mg; rapid response and remission from day 2 to week 3
o 36.7% (29 patients) in 25mg group showed response at week 3, compared with 17.7% (14 patients) in 1mg group
o 29.1% (23 patients) in 25mg group were in remission at week 3, compared with 7.6% (6 patients) in 1mg group
o 24.1% (19 patients) in 25mg group were sustained responders at week 12, compared with 10.1% (8 patients) in 1mg group
• COMP360 was generally well tolerated, with more than 90% of treatment-emergent adverse events (TEAEs) mild or moderate in severity
• Treatment-emergent adverse event (TEAE) incidence
o 83.5% (66 patients) in 25mg group
o 74.7% (56 patients) in 10 mg group
o 72.2% (57 patients) in 1 mg group
• Treatment-emergency serious adverse event (TESAE) incidence
o 6.3% (5 patients) in 25mg group
o 8.0% (6 patients) in 10 mg group
o 1.3% (1 patient) in 1mg group
COMPASS is conducting comprehensive secondary analyses which are expected to further inform the clinical development programme for COMP360 psilocybin therapy.
COMPASS article on Psilocybin therapy (Open access)
See more from MedicalBrief archives:
Research probes ‘magic’ mushrooms to treat depression, addiction and PTSD
New research propels psychedelics into the mainstream
World's largest pyschedelics research centre launched
'Magic mushroom' compound reduces depression symptoms